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·HYPERTENSION
VOLUME VI
MINERAL METABOLISM
Proceedings of the Council for
High Blood Pressure Research, American
Heart Association, November, 1957
EDITED BY
Eric Ogden, M D
Professor of Plus stolomy
Ohio State University
Columbus, Ohio

·COUNCIL TOR
HIGH BLOOD PRESSURE RESEARCH
1937
1958
President
Vice President
Secretary
Treasurer
Officerg of the Council
VIR MAI NARD MURCH
VIR FRANK E JOSEPIL
MB GEORCE E MERRIFIELD
MR 1 F FREIBERGER
Officers of the Medical Advisory Board
Chairman
MEYER FRIEDWAN MD
Vice Chairman
ERIC OGREY M D
Chairman Publications Committee
SIDLEY HOORLER M D
PUBLISHED APRIL, 1958 BY THE
AMERICAN HEART ISSOCIATION
41 EAST 23rd STREET
NEW YORK 10 NEW YORK
Copyright 1938 by the American Heart As ociation
Requests for permission to reprint any part
should be addressed to the Association
PRINTED IN US

·CONTENTS 4 7 23 SYMPOSIUM ON MINERAL METABOLISVI INTRODUCTIOY — George A Perera MD SODIUM AND LIYPERTENSIOV - Simon hodbard MD DISCUSSION SODIUM AND WATER RATIOS IN THE PATHIOGENESIS OF HYPERTENSION – I eo A Sapi tein MD DISCUSSION EXPLORATION OF RFVAL EXCRETORY MECHANISMIS WITH RADIO ACTIVE SODIUM AND POTASSIUV -- Francis P Chinard MD DISCUSSION CHRONIC SODIUM CHLORIDE TOXICITY AND THE PROTECTIVF EFFECT OF POTASSIUM CHI ORIDE - George R Menetly M D and Con OT Ball DISCUSSION 2 36 99 63 65 85 REPORTS OF COMMITTEES COMMITTEE ON INSTRUMENTAL TECHNIQUES — WF Hamilton Chairman 83 COMMITTEE ON CHEMOTHERAPY IN HYPERTENSIOY- Milton Mendlowitz Chairman 90 COVVITTEE OY SURGICAL TREATMENT OF HYPERTE\SIOVEdward D Freis Chairman 91 COMMITTEE ON EPIDEMIOLOGY OF HYPERTENSIO-- Kenneth C hohlstaedt Chairman 96 100 LAY PRESENTATIONS SURGERY FOR IIYPERTENSIOY AND RELATED CARDIOVASCULAR DISEASES -heith S Grim on MD THE WAY TO A MAS HEART — George A Perera V D Tue LSEFULNESS OF DRUGS IN THE TREATMEYT OF HIPERTE15101 Harriet F Du tant MD) 10 107 1 3 # ·INTRODUCTION GEORGE A PERERA, MD Department of Medicine, Columbia Unuersity College of Physicians and Surgeons, New York City The subject of this year s conference makes me think of Rachel L Car son s best seller The Sea Around Us perhaps our theme might be called Hypertension or the Sea Within Us I hope now to bring us all up to the same starting point at the water » edge so we can swim together As you know you and I are about sixty percent water Into this medium the good Lord dumped a little more than one pound of salt That pound according to some authorities is a mighty busy one It races around so that well over fifty pounds cross the walls of our blood ves sels in one direction or another in the course of a day About three pounds are filtered through the glomeruli of our kidneys daily -- all but a tea poonful is reabsorbed Plus or minus one or two teaspoons in via the diet and one out via the urine and we remain in balance with mechani ms available to han dle a variety of conditions from low salt drets to Smorga bord from the Sahara to an overdose of cascara The hypertension story is as follows Based on the theory that there may be chloride retention in hypertension Ambard and Beaujard in 1904 reported that the blood pressure fell after salt poor die Pfeiffer in 1911 shifted the emphasis to odium rather than chloride Allen and Kempner have been among the enthusiastic supporters of low odrum diets in hypertension To day after considerable controversy and a voluminous literature it is ac cepted generally that rigid sodium restriction will often lower the blood pres sure and that this is achieved directly on the peripheral re istance through the modification of a non neurogenic component Most of us would agree that some patients have fewer ymptoms congestive failure is helped and retinopathy is improved We debate about the heart size after salt restriction feeling that only the failing heart gets smaller We are troubled about the limitations and restrictions impo ed on the patient not only becau e of the unpleasant features and the unpalability of such drets but also becau e they do not eem to help the kidneys very much in fact if we re trict the salt too much in the pre ence of renal damage the kidneys may lo e too much alt with resultant symptom and further impairment of renal function The 4 ·bent fits of the e los salt diets on blood pressure are less evident in patients with the accelerated form of hypertension Let us briefly ummarize a few of the re ult which have been reported on the experimental ide In many forms of experimental hypertension the ad dition of sodium chloride eems to make the hypertension worse and the pathological changes more advanced We are under the impression that the hypertensive patient tolerates a low odium diet somewhat better than a normoten e subject if there is no renal damage present and that other dif ferences in re pon e are present such as a omewhat greater sodium diuresis when hypertensive individuals are treated with thiocyanates There are re ports of an increa e in odium in the va cular mu culature of hyperten ive animal of increa es in total erchangeable odium and of an abnormal dis tribution of tissue electrolytes in hypertensive subject Desoxycorticosterone requires at least some dietary salt for its pres or action Finally several groups have reported that there is an augmentation and perhaps an increa ed rate of excretion of a odium load when given to hyperten Ne subjects in comparison to control tudies in normotenaive individuals There are al o some puzzles For example low sodium diets reduce the blood pre sure but also timulate the elaboration of aldo terone why no nie in blood pres ure? Desorycorticosterone in the pre ence of odium elevates the blood pressure and lowers the total amount of pota sium in the body but there are everal reports that a low pota sium diet may lower the blood pres ure The rauwolfia alkaloids lower the blood pres ure yet on occasion cau e sodium retention Why no elevation of blood pressure in these ca es? Before closing I hould like to mention a few of the reasons for caution in the way we conduct our tudie- Many reports in the literature dealing with sodium restriction or load fail to consider the antecedent diet of the patient For example it takes on the average at leat four days after a change in diet to achieve electrolyte balance therefore an adequate ba eline is en en tral Furthermore there are big differences in patients who have a little renal damage as compared to tho e with no renal damage One must be certain that renal respon (do not reflect damaged kidneys rather than di turbed metabolism The weight of evidence today favors an a ociation between sodium and the blood pre sure There are many reports now that lend support to the idea that there is a di turbance in sodium metabolism in hypertension What is cau e and what is effect remains to be een whether sodium 19 related to a fundamental mechanı mis till in doubt I feel sure that some of the peak ers in this sy mpo tum will bring us much closer to the truth about the sea within us and perhaps in this way we will be a little le s at sea 5

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·SODIUM AND HYPERTENSION SMO RODBARD,MD, PhD From the Unirersity of Buffalo Chronic Disease Research Institute, Buffalo, Nero York A RELATION between the blood pre sure level and the amount of salt inge ted has long been ugge ted by the hypoten we effects of low salt drets in some cases of hypertension (1) and in pre eclampsia (2) as well as by the clinical value of a high salt intake in the control of the hypotension of adrenal insufficiency (3) A high alt intake can produce ri es in blood pressure in a variety of experimental animals similar mechani ms may be operative in the production of es ential hypertension in man A timulus to the following epidemiologic study was the apparently high in cidence of hypertension among Megroes The impression that this race was particularly subject to hypertension had already been sugge ted by several stali tical studies from the South (46) from prison populations (7) and from the tropics (8 9) Etiologic factors uch as diseases of the kidney the adrenal gland or the nervous system have not clarified the mechanisms of hyperten son in these ca es Environmental factors such as previous his tory and occupation usually provide no significant clues Recently a urvey of the hypertension produced in animals by a high salt diet impelled u to re examine the possible relation between salt intake and blood pressure level A further stimulus to this study came from the report of Dahl and Love (10) who asked employees of the Brookhaven National Laboratory whether they alted therr food before tasting after tasting or rarely Their results showed that patients with blood pressures above 140/90 had a greater ten dency to salt their food before tasting while hypertension was infrequent in individuals who rarely salted their food Salt Ingestion in Man In this cooperatne tudy with Dr Milton Terris of the Department of Public Health and with Dr Franklin Zeplowitz a questionnaire was de signed to obtain information on the salt ingestion habits of patients in the associated teaching hospitals of the University of Buffalo School of Medi cine The study was broadened to include Whites as well as negroes and a total of 210 patients was studied The medical records of hospitalized hypertensive patients were examined by a medical student for comparison a normotensive on the same ward 1 delly a grant f om the Un led States Pablc Health S ruce Vats nal Hea 1 Institute 1 271 The Chronic D ase Research In tutut is supporled in part by a grant f m the New York State Department of Health 7 ·who was matched as far as possible for age ex height weight race and occupation was also selected These data along with the dia, nosie the duration of the stay in the hospital and blood pressures on admission while in the hospital and at the time of the questionnaire were placed on a spe cial form The names of the matched pairs without other identifying data were then given to a second student who used a second questionnaire to ob tain information on previous habits of diet salt and water intake Analysis of the data obtained showed that the following factors did not correlate with the blood pre sure previous residence in the South amount of salt used in cooking whether the patient salted his beer or watermelon the volume of fluid taken and the degree of nocturia Blood pressures of the patients correlated poorly with the cause of death of parents although more than twice as many hypertensives as normotensives reported a stroke in their parents Out of the 240 record obtained many were eliminated becau e of acute alcoholism (which usually gave ri e to transiently elevated blood pressure levels on admission) a tay in the hospital of more than one month pri mary renal disease and previous treatment of hypertension as well as for unmatched case The remainder of the data could be matched satisfactorily for 126 patient The e records were then divided into four categories ac cording to the diastolic pre sure at the time of the interview below 80 mm Hg in the 80s in the 90s and above 100 mm Hg Three ets of correla tions then appeared Only marginal support for the pecific findings of Dahl and Love (201 appeared in the answers to que tions (oncerning the saltıng of food prior to tasting Thus twenty five percent of the patients with diastolic pressure below 80 mm Hg salted their food before tasting thirty percent in the group with pressures in the 80s forty five percent with pressures in the 90s and forty percent in patients with diastolic pressures of 100 mm Hg or more (Fig 1) Our data therefore suggest that the simple salting of food at the table prior to ta ting is not a sufficiently satisfactory sign of the presence of a rai ed blood pre sure A better correlation was found between the blood pressure level and the respon e to a question concerning the amount of salt used at the table (Fig 2) Thu eventy percent of the group with pres ures below ninety stated that they used either little or no salt at the table while esent percent of the patients with pressures of ninety mm Hg or more stated they used some or much salt at the table It is immediately apparent that the e qualitative terms are eriously limited ince what may seem to be much for one patient might be lutle for another leverthele s it was of interest that o many hypertensives eemed to think that they u ed considerable salt at the table while normoten ives generally had a contrary impresion 8 ·DIASTOLIC ABOVE 100 mmHg 90-99 80 89 % Pts salting food before tasting BELOW 79 1 0 10 30 60 80 % Pts in each BP group FIGURE I Percentage of appro imately thirty pat ents in each of four diastolc blood pressure levels who reported that they u ually salted their food b fore ta tin DIASTOLIC % Pis using some or much mmHg salt at table ABOYE 100 90-99 80 09. BELOW 79 20 30 40 50 60 70 80 % Pts in each BP group FIGURE” Percent ge of pproximately thi ty patients in each of four diastolic blood pres ure levels who repo ted th t they used some or much" salt 1 the table 9 ·Support for the thesis of a higher salt intake in hypertension was found in an analysis of questions concerning the intake of highly salted foods A sig nificant correlation was shown between the blood pressure level and the number of highly salted foods which each patient reported he ate regularly (Fig 3) A list of fifty highly salted foods was read to each patient and he DIASTOLIC mmHg ABOVE 100 % Pts eating more than 25 highly salted foods weekly 90 99 80 89 BELOW 79 1 1 0 110 50 60 30 40 % PAS in each BP group FIGURE 3 Percentage of approximately thirty patients in each of four diastolic blood pressure levels who reported that they ate more than twenty five highly salted foods at weekly interyals was asked if he took each of these daily weekly monthly or rarely The e foods included salt or smoked fish herring cod clams crab meat flounder oyster fresh or canned salmon tuna and sardines among the meats listed were corned chipped or dried beef canned chicken smoked meats ham salt pork bologna salamı liver sausages and frankfurters vegetables in clude raut canned corn a paragus mushrooms or tomato juice olives beans chili canned soups calad dressings and mayonnat e alted snacks included french fried or chipped potatoes pretzels salted soda crackers chee es nuts and dairy products including buttermilk salted butter or margarine Only twenty percent of the patients with blood pre spres Je s than eighty mm Hg ate twenty five or more of the e alted foods at approximately weekly intervals forty percent of the patients with dia tolic pressures in the l'Os and fifty five percent of tho e with pre ures in the 90s reported more than 10 ·twenty five such foods being taken while eventy five percent of the patients with pressures of 100 mm Hg or more reported this higher intake of salted foods The data pre ented above suggests that hypertensile patients may have a greater than normal appetite for salty foods A possible relation between salt intake and hyperten ion has recently been emphasized by Mo er (11) who reports that hypertension is so common in the Bahamas that almot everyone on these i lands has a relative with the high blood or has had a troke or has died of hypertension In some of these i land the drinking water is said to contain a high concentration of odium chloride A clinical impression is that half of the West Indians over age of forty actually have sy tolic hypertension by commonly accepted criteria More than twenty percent of the males and thirty percent of the females in the third decade of life had diastolic pressures over 100 If ninety mm Hg were accepted as a criterion for diastolic hypertension two thirds of the landers over forty would be in this classification A remarkable finding in the Bahamas is the high alt intake on some of the islands (11) As a ba eline we may consider that the water supply in Na sau and ome of the outer i lands is said to contain three grams of sodium chloride per liter in Eleuthera one of the maller 1 lands it is five grams per liter If some of these natives consumed two liters of water a day they would be getting ten grams of odium in their daily water ration alone The Ba hamans are reported to drink a great deal of water becau e of a con tant thirst po ibly induced by the hot climate as well as by a high salt intake Further a common item of the diet is salt pork which contains about eight grams of salt per pound While the relation of salt antake to hypertension is only now under in tensive clinical investigation a considerable literature on such a relation in animals has appeared in the lat decade Salt induced Ilyperlension Hypertonic salt solutions as drinking water have been demon trated to raise blood pressure in various experimental animal Some years ago we showed that the addition of table alt to the drinking water of the chick produced a rise in blood pressure within a few days (12) Thus 09 percent sodium chloride in the drinking water produced a pre- ure nu e (optical re cording) from an average of 135/125 mm Hg to an average of loy 135 mm Hg, in two weeks When the concentration of salt was increased to 12 percent the blood pre sure increa ed further to 180/150 mm II: Within a week after normal tap water was provided the pre ure fell harply to the control level When the animals were again placed on drinking water containing 1.2 percent salt the blood pre ure ro e again falling toward normal at a somewhat slower rate when the animals were once again per mitted to drink tap water The ratio of net heart weight to body weight 11 ·the animal might properly be considered to be hypertensive compared with its own basal level It is probable that simlar problems of differentiation of normotensives with pressures in the upper range of their distribution from hypertensives in the lower range of their distribution are alen SYSTOLIC mmHg 2404 230- RATION CONTAINS 10% SALT 2204 210- 2004 190 180 170 160H WATER .= AD LIBITUM O = LIMITED 150 140- 130 120 140 150 160 170 130 190 200 mmHg DIASTOLIC FIGURE 5 A plot of systolic F4 diastolte arterial pres ures in chicks at (ſteen weeks of age All animal had salt added to their mash The sol d dots represent values for chicks taking tap water ad libitum The open circles represent values for animals receiving I mited drinking water pre ent in man This would suggest that the measurement of the blood pres cure alone may not be sufficient to determine the pre ence of a hyperten ive proces in a given individual The reduced pul e pressure of the animals on the alt diet may be related to changes in aortic tone or to a reduction in stroke output The e mechani ms 14 ·2 have not yet been analyzed in our laboratory The change in pres ure 19 probably not a sociated with change in body fluid compartment While a tran ient edema appeared hortly after the on et of a high salt intake the weight fell in hort term experiments at the end of the first week on alt and it was assumed that dehydration had probably taken place This sugge ted that one of the contributing mechanı ms may be the relative amounts of salt in gested compared to the water available for its excretion I'ater Intahe Experiments To test the role of water intake in salt fed animals experiments were carried out in sixty chicks given ma h to which table salt was added In the econd week of life one percent odium chloride was mixed with the mash this was increased to three percent during the period three to week to five percent during the sixth week to si percent during the eventh week and to ten percent during the last eight weeks of the experiment Unlimited drinking rater Half the animals were allowed fre h tap water ad libitum The feed intake per kilogram of body weight was approximately equal to that of animals on a normal ma h diet without salt These animals gained weight at a normal rate and howed no igns of toxicity Twenty four of the thirty ammals survived to the end of the study The blood pre sures in these animals averaged 183/143 with a mean of 160 mm Ig «Fig 5) and a heart rate of 330 beats per minute Analysis of the data howed that some of the animal, had dia tolic pres sures below 130 mm Hg or distinctly within the normal range Mine of the twenty two chicks tudied had diastolic values of 150 mm Hg or higher Limited drinking water Another group of thirty chicks was given the same alted diet except that thee animal were provided with only ten percent of the water taken by the first group These animals howed toxicity and a large number of them died during the course of the experiment The animals grew poorly weighing only half their control The heart rate of ome of them was as slow as 250 beats per minute but the slowed rate was unrelated to changes in pres ure or in pul e pres ure At the end of the ex periment the blood pre sures in this limited water group were esentially similar to the comparable group which had acce to unlimited drinkıng water (Fig 5) Compari on of the re ults obtained with the preceding two groups hows that the development of toxicity as indicated by poor growth can re ult from a high alt intake flowever the availability of an adequate upply of drinking water reduces this manifestation of toxicity By contra t the hyper tensive effects of a high salt intake eem to per it whether or not uch toxicity 19 present Furthermore the hyperten son induced by a high salt intake appears unaffected by the availability or re traction of fresh drink ing water Animals taking salt in the drinking water took more salt and had gen erally higher pre ures than did tho e taking alt mired with the mash 15 ·This may uggest that the hypertensive process is a function of the total quantity of sodium ingested the animals taking the most salt also had larges adrenal glands per kilogram of body weight (Table 1) In man with es ential or renal hyperten on the adrenals are al o reported to increa e about twenty five percent in weight(13) TABLE 1 EFFECT OF SALT ON BODY AND ADRENAL WEIGHTS IN CHICKS Number of Average animals Weight kg Adrenal It Salt added Body W g/kg/ x 10 day 9 0 14 9 Water Saline 39 13 17 09 > Water ad Irb 21 17 9 10% Salt in ration Limited Water 18 09 10 5 (See tert for details of experiment) Self Selection Experiment Excess alt intake disturbs water balance and poly dipera and polyuria develop Di turbances of the electrolyte pattern brought about by salt or desoxy cortico terone admini tration show that these changes depended on renal function We hase examined the role of the kidney in the mechanism of polydipsia and salt hunger (14) Rats were placed in Richter elf selec tion cages (15) each with four graduated tubes containing either tap water or olutions of five percent glucose 09 percent odium chloride or 09 per cent potassium chloride The control animals preferentially took a daily alera e of eighty ml glucose solution and ix mi of salıne The administra fion of de orycorticosterone caused the animals to incres e their saline in take to eighty ml of salıne in addition to the usual glucose intake On the first day after total nephrectomy the animals sharply reduced the saline in take to eleven ml although an average of thirty two ml of gluco e olution was taken Amall amount (ten ml of gluco e solution was taken on the second day but salıne was avoided No fluid were taken on the third and fourth day after nephrectomy These results indicate that the increa ed odium appetite induced by de ou corticosterone is dependent on a continuing diuresis It may be con sidered that the adminı tration of DCA rai es the ability of the cells of the 16 ·body to hold sodium and in this way causes a relative alt deficiency or hunger The taking of odium by mouth then cau es considerable pillage which must be replaced when the loss is stopped as after bilateral nephrec tomy sodium appetite ceases The role of these odium exchange mechan isms in the development of hyperten non remains to be determined DISCUSSION A number of workers hold that arterial hypertension is secondary to a disturbance in the salt water balance in the body Eichelberger (16) has sliown that the sodium chloride content of skeletal muscle increa es in renal hypertensive dogs while the potassium decreases and the extracellular water tend to increa e Green and Sapir tein (17) have noted that in hyperten ive rats in which only a portion of one kidney remains intact the total body body odium increases as much as twenty five percent Since the plasma sodium remains at normal level and the extracellular space is not markedly expanded some of the retained sodium probably enters the intracellular compartment Braun Menendez (18) holds that an increa e and maldı tribu tion of odium and water occurs in the three types of hypertension induced by disturbing the renal blood ſou by removing both kidneys or by ad ministering desoxy corticosterone Hollander and Judson (19) have shown that hypertensive patients have an increased ability to excrete sodium perhaps associated with an increa e in intracellular sodium They also sugget that the di tribution of sodium rather than its total in the body might be related etiologically to the raised blood pres ure Muirhead et al (20) hase reported that the administration of pressor drugs produces a rapid mea urable fall in the pla ma odium with a concomitant rise in potassium they believe the e changes reflect the en trance of sodium into the cellular compartment as potassium leaves tlır cell These effects are rever ed at the end of the pressor infu ion Similar sonic changes in the pla ma have been observed by the Friedmans (21) Tobian and Binson (22) have reported that water and sodium accumu late in muscle brain and in the blood vesel wall of hypertensive animale and they have sugge ted that the increa ed peripheral res tance may Irault from edema of the vessel *all Such edema could act to reduce the lumen of the arterioles From physical con derations even small returten in the radius of a blood ve el would markedly reduce the blood flow this myle it (Poiseuille) unless a higher pressure were provided The blood pressure will fall if ufficient odium is lot from tlır Bwrdy * occurs in rigid dietary odium re triction in man For many years atar effect could not be produced in the dog ince the sodium con (1911 y love tion of this animal is o efficient that sodium lo s is minimal events in ditions of rigid restriction (23) The odium blood pres ure relatio! Ich ·even in this pecies however since intensive peritoneal lavage can reduce the plasma sodium from about 145 to 115 meq per liter with a reduction of the blood pressure to normal in hypertensive dogs Mormotensive dogs subjected to the ame procedure have no fall in pressure (21) Sodium restriction also reduces the blood pre aure of hypertensive rat and increases their survival time (25) Somehow the e animals seem to ap preciate this physiological situation since they will decrease their sodium in take when a choice of drinking olutions is permitted This low salt prefer ence of hypertensie rats 18 maintained even after adrenalectomy during administration of desorycorticosterone or during a forced increased fluid Intake (26) On the basis of more complex experiments using the parabolic rat Ledingham has shown that the hypertension which develops in a nephrec tomized Parabiont is followed by a return of the blood pressure to normal upon removal of the adrenals of the hyperten ne animal Ledingham (27) thus feels that the raised blood pressure is due to an adrenal pressor material normal ly eliminated or neutralized by the kidney In previous studies we have hown that the pre or principle of Goldblatt hypertension is eliminated by a sim alar mechanism that ja by the metabolic activity of normal hidney 1 sue (28) A factor which probably contributes to the difficulty in determining a quantitative relation between sodium intake and the blood pressure level is the complexity of sodium potassium balance Thus a high sodium intale can lead to a period of arterial hypertension but this may be followed by the development of severe hypokalemia generalized weakness and a fall in blood pressure to normal or even subnormal levels (2931) The reactivity of the arterioles appears to be involved ince the pres or re ponses to ep nephrine norepinephrine renin and angiotonin are dimını hed (32) The mechanism appears to depend on the hypokalemia since admını tration of pota sium alts touch animals cau es a return of vascular reactivity to pres or drugs within an hour or o (32) In the absence of the adrenal gland pota sium repletion or retention does not result in a rie in blood pres ure The admını tration of corti one or ACTH will restore the reactivi ty and tend to raise the pressure (33) Similar effects occur in man (31) For cample orthostatic hypotension occurred in a patient who was sub ject to chronic pota jum Jo , pota sum replacement Improved the ability to regulate the blood pressure (31) These hypotensne and a thenic responses are related to the exce s renal pota sum »a tage induced by a high salt intake The sodium con erving function of the kidney is so efficient that this son tends to be reabsorbed from the glomerular filtrate in the renal tubule however a potas ium ion mu t be excreted by the tubular cells in order to accomplish some of this sodium reab orption (35 36) 18 ·The physiological actions of sodium and potassium balance have long been studied in the 1 olated heart More recently attention has been called to the ubiquitous redor pump which normally pumps sodium out of the cells while maintaining a high potassium concentration within the protoplasm (37) This action depends on the pre ence in adequate amounts of pota sium in the extracellular fluid For example when the concentration of potassium in fluid urrounding frog skin is diminished the normally high intracellular pota sum is diminished while the intracellular odium which is normally low increases (38) Conway (39) has recently hown that the sodium pump mech anism in yea t cells is more effective when pota sium is pre ent in the extra cellular solution DCA appears to weaken the ability of the cell to eliminate sodium from the protopla m (39) It is evident that desorycorticosterone and certain other steroids modify odium exchange DCA given in large do es to dogs produces hypertension associated with di turbances in salt water balance and this may per ist for weeks after ces ation of the compound (40) This hyperten ion is potent ated by a simultaneous admını tration of sodium salts (11 44) DCA pro duces an early retention of sodium and water followed by an increa ed renal lo s of the e materials Sub equently a odium appetite and hyperten sion develop The di turbed odium balance induced by DCA 19 evident in tissues other than the kidney since the neat glands (45) and the terminal oleum (46) al o show a reduced odium ercrebon Long term DCA ad ministration will ultimately result in a depletion of body potassium with the development of a thenia and a tendency to a fall in blood pressure im ular to that produced by evce s alt intake The physiological ignificance of DCA has long been in que tion However aldo terone has es entially sim ular physiological effect It is of pecial interet therefore that arterial hy perten ion is reported to be as ociated with a tate of mild chronic hyper aldosteronism as indicated by urinary excretion tudies (47) Other sub tances may al o produce blood pres ure changes Thus Selye has ugge ted that omatotrophic hormone increases the en itivity of the rat to alt or to DCA with the induction of hypertension (43) and that other steroids uch as methylandro tenediol can raise the blood pressure although this latter hy en ion can be presented by adrenalectomy (49) When the mechanism of e ential hypertension is finally clarified salt and water regulation will probably play a ignificant role in its pathogenesis The hidney as the ultimate organ involved in electrolyte balance would appear to be a key tructure in determining the blood pres ure change The adrenal cortical effects on jonic balance and neurohypophy al effects on water er change probably contribute less directly 19 ·SUMINIARY A questionnaire surtey of salt intake habit of 126 matched ho pitalized patients revealed that hypertensies were more likely to u e ome or much -alt at the table while normotensises generally reported little or none salt Usage The hypertensies al o reported they ate regularly (weekly) a larger number of highly alted foods (eg potato chips french fries alt pork ham fish etc ) than the number of these foods reported taken by the normo tensies In experiments on chicks addition of 1 2 percent table salt to the drink ing water or 10 percent salt in the mash resulted in a di tinct nie in blood pre sure in most of the animals Animals on a high salt limited water intake tended to be stunted in growth and to have a high mortality rate The groups taking the greatest quantity of salt had the highest blood pressures the e animals also shoned larger adrenals per unit of body weight Some mechanisms involved in salt water balance and in blood pressure regulation are discus ed BIBLIOGRAPHY 1 Chapmap C B and Gibbong TB The diet and hypertension Medicine 29 29 1930 2 Gray VJ and Plent! A A The variations of the bod om space and the total exchangeable sodium during pregnancy J Clin Invest 33 347 1936 3 Thorn CW The diagnosis and treatment of adrenalinsaſ ciency Charles C Thomas Publ Springfield Ill 1919 4 Schnab E. H and Schulze I E Heart disease in the american negro of the south Am Heart J 7 710 1932 5 Schulze E. and Schwab E, HI Arteriolar hypertension in the american negro Am Heart J 11 66 1936 6 Weis V BI and Prusmack, J J Essential hypertension in the negro Am J Med Sc 195 510 1933 heellman, V The tncidence of essential hypertension in white and negro males Med Rec 154 16 1911 8 Saunders C Man Bancroft II Blood pressure studies in negro and while men and women living in the Virgin Islands of the United States Am Heart J 23 410 1919 9 Taylor CE Racial di tribution of Nephrylis and hypertension in Panama Am J Path 21 1031 1912 10 Dahl, L. and Love RA Etiological role of sodium chloride intake in essential hypertension in humans JLI YA 161 397 19 7 20 ·11 Poser M In "Conference on Bas e Mechanıms in Ilypertension Circulation 17 April 1998 (In press) 1? Lenel R., hatz L M anl Rodbards Arterial hypertension in the chicken Am J Phys ol 35' 557 1918 13 Daw on MP Changes in the ad enal cortex in essential and renal hypertension J Path Bact 12 393 1956 14 Mills CR an] Rodbard S Voluntary fluid and lt intake in the normal and the nephrectomized rat recen in de oxycortico terone J Urol 63 192 19 0 15 Richter CP Total self regulatory functions on animals and bun an be ngs I rvey Lect 38 63 1914 1913 16 Ecl elberger L The distribution of water and electrolyte Petxeen blood and sheletal muscle in experimental hypertension J Exper Med 77 205 1913 17 Green RW and Sapirslein L1 Total I ody sodium potassium and nitrogen in rats ma le hypertensive by subtotal nephrectomy Am J I lys ol 169 343 1952 18 Braun Wenendez E. Water and electrolytes in experimental hyperten 1on Coba Foundation Symposium on llypertension P 238 49 Little Bron & Co Boston 1991 19 Hollan ler Wand Judson E Electrolyte n l water excretion in arter al hypertension 20 Mu heal EE Goth 4 und Jones F Sodium an 1 potassium exchang s associated with a rep nephrine infusiong Am J Physiol 191 19,4 91 Fr e Iman S M Fredman C Lan Maha huma l Cationic shifts an l blood pres ure regulation Crc Research 5 261 19,7 Tobian L Jr an IB n on JT Tissue cat ons and water in arterial hypertension Circulation 5 751 195 23 Samler J., Katz L N. Pick R and Rodbar1 S D etary and hormonal factors in exper ment 1 atherogenesis and blood pres ure regulation R Prog Hormone Res II 401 1955 21 Frieden J Samler J Wang II, Kuramoto k and hatz L N Effet of ch onc sodium d plel on on blood pres ure of renal hypertensive dogs Am J Physiol 168 200 1957 2 Danford HG Dieter DG Christofferson and Herrin RC Effect of diet ry re tr tion of salt an protein on blood pressure of hyperlens e rats Am J Phy ol 163 190 19 O 6 Toste on DC DeFrez AIC Abrams M., Gott chalk CW. nd Land, EM Efects of adrenalectomy desoxycorticosterone acetate and increased fund intake on intake of sodium chloride and bicarbonate by 1 ypertensne and normal rats Am J Physiol 161 369 19 1 21 ·27 Ledingham J M The nature of the hypertension occurring in the nephrectomized parabiotic rat Clin Sc 10 423 1951 98 Rodbard and Katz LN The role of renal metabolism in hyperten ion and uremia J Exper Med 3 357 1911 29 Friedman M Rosenman RH and Freed SC Depressor effect of pota sium deprivation on the blood pre sure of hypertensive rats Am J Physiol 167 457 1951 30 Freed SC Rosenman RH and Friedman MI The relationship of potasium in the regulation of blood pressure with special attention to corticoid hypertension Ann NY Acad Sci 56 637 1933 31 Perera GA Depressor effects of potassium deficient diets in / ypertensive man J Clin Invest 32 633 1933 39 Rosenman RH Freed SC and Friedman M The peripheral va cular reactivity of potassium-deficient rats Circulation 5 412 1952 33 Ro enman R H., Freed S C and St Geor e S Cortisone hyperten ion in potassium deficient rats with a renal ligature Circulation Res 4 57 1956 31 Huth E J and Squire RD The relation of cardiovascular phenomena to metabolic changes in a patient with chronic hypohalemia Circulation 14 60 1956 33 Berliner R V., Kennedy T J Jr and Orloff J Relation hip between acidification of the urine and potassium metabolism Am J Med 11 74 1951 36 Seldin, D W Welt LG and Corb J H The role of sodium salts and adrenal steroid in the production of hypokalemic acidos19 lale J Biol & Med 29 229 1936 37 Scott C T and Haywood HR Sodium and potasium regulation in ulva lactuca and valonia macroplysa pp 35-61 in "Electrolytes in Biolo Ical System A M Shane ed Am Physiol Soc 195 Washington DC 38 Huf E. G Ion tran port and son exchan e in frog skin pp ?05 238 in Electrolytes in Biologi cal systems" AM Shanes ed Am Physiol Soc 19 5 Washington DC 39 Conway EJ Fundamental problems in the hormonal control water and salt electrolyte metabolism pp 321 in "The Comparative Endocrinology of Vertebrates II The Hormonal Control of Water and Salt-electrolyte Metaboli min Vertebrates IC Jones and P Eckstein ed Cambridge U Fress 1956 40 Rodlard, S and Freed SC The effect of desoxycortico terone acetate on the blood pre sure of the dog Endocrinology 30 36191 41 Friedman S M., Fredman, C L and Polley JR Potentiation of hyperten Ive effects of desorycorticosterone acetate by various sodium salts Am J Physiol 153 226 1918 22 ·4* Selye H I Stone II., Timeras P S and Shaffenburg C Jofluence of sod um chloride upon the actions of desoxycortico terone acetate Am Heart) 31 1009 1919 43 Freman S MI. Friedman C. L. and Makashima MI Action of ortisone on card ova cular effects of desorycortico terone Am J Physol 163 319 1990 41 Creene D M., Saunders FG Jan Arman C C. Cale n. L.D and Curte apt FM Hech n gms of desoxycorticosterone action. Il Temporal relat onships of polyuria poly Jup a sodium exchange and hypertension Am J Physiol 1 0 486 19 1) Davies D F and Clark, H E. A hypertensive syndrome with relat e adrenal cortical chaty Circulat on 2 191 1990 46 Field, H Jr., Daily R E. Bogd R S and Swell, L. Effect of restrict on of dietary sodoem on electrolyte compo ation of the contents of the terminal colon Am J Physiol 1.9 477 19, 47 Genest J. Lemieur G. Davignon, A., Koi E., Nowaczynsk and Steyert rk P Human rterial hyperten 1on a state of m ld chronic hyperaldo teron in Science 123 503 1906 18 Selge H Role of somatotrophic hormones in the production of malign nt nephrosclerosi periartentis nodosa and hypert niste di ease Br! Med J 1963 1931 49 Salgado E. an? Selve H The production of hyperten von nephrosclero 19 and card ac lesions by methy land ro tenediol in the rat Endocrinology 53 530 19 $ DISCUSSION DR GEORGE A PERERA I hase everal questions I am troubled about the West Indies becau e on ome of the islands the incidence of glomerulonephritis is high I am troubled that in New York the greater tendency of Negroes to develop hypertensive dı ease is limited to malig nant hypertension does an excess of salt affect only one form of hyper tension? When He hase corrected for age we have been unable to find any difference in dietary sodium intake or sodium excretion in the urine in hy pertensive versus normoten use ubjects Dr Podbard did you take age into consideration? I su pect as we get older our dietary habits change DR IRVIVE I PACE The a essment of the amount of alt people tale in ome ways ea rer and in ome more difficult than the amount of fat they eat I have tried the interrogation method with many patients and am al together unconvinced that many of their an wers are reliable True there are people who eat extreme amounts or hase no taste for it at all and they know it I am concerned with the run of the mine hypertensive patient who has no trong feelings one way or the other When I was working with Dr Van Slyke at the Rockefeller In fitute he in 1 ted that a daily or tri neellz urinary chloride was the only way to get 23 ·an idea of salt intake even when the diet was believed to be rigidly con trolled This I learned to believe after we found a patient getting a large amount of salt from her tooth paste Thus I hesitate to accept surveys pur porting to determine alt intake Untıl salt is actually mea ured I doubt if an epidemiological survey would be meaningful As you know Dc Corcoran will lead an expedition to St Kitts i land to study the incidence of sascular disea e and its relation to the diet es pecially as it concerns salt intake Ve know of the high incidence of strokes in Japanese fishing villages when salt is u ed as a food pre ervative in fan ta tically large amounts It is too easy to convince your elf of the validity of your own precon ceived notions with an epidemiological survey for in tance a physician in Cleveland is convinced he has shown a direct relationship between hyperten ion and eating pepper and highly ea oned foods This ummer he pub lished a note showing hypertension could be so produced in rats Now he Is more convinced than ever You will al o recall the supposed relation hip to tale coffee I would therefore plead for much more careful and penetrat ing epidemiological studies before a stand is taken which then the invets sator feels impelled to defend DR St EY FRIEDY AN I too like Dr Perera am puzzled and troubled by a number of things With Dr Page I think the a ociation of alt intake with the pre ence or absence of hypertension is at the moment 1 matter of a ociation only We find that if high salt diets are gren to rats for sufficient periods of time (three to five months) the hyperten ion tends to disappear It is a long jump and a hazardous one from the amount of salt taken in to exactly how the salt is being handled I think the sodium handling mechan um 14 of fundamental importance and directly determines the tate of tonus of the smooth muscle cell Therefore salt intake may be e sentially leter mined by the alt output and that ased for the body It seems rather tricky to try to deduce from measuring one of the parameters exactly what the re lationship of the alt intale to the blood pressure level 15 Regarding adrenal size I have an anatomical bias I feel it is difficult to decide on the basis of size whether or not an organ is hyperfunctioning It may be impossible to decide whether a measurement of increase in size should be ba ed on absolute size of that organ related to the animals age or computed back to the animals weight The method chosen may lead to entirely different results the interpretation of which is determined by per sonal bias DR GEORGE R MEVEELY We tudied 3 000 human beings in one group and another smaller group Among the first there was absolutely no correla tion between the amount of salt they said they ate and their blood pressures We did sodium excretion for 24 hour periods on a few of these youn, draftees and found no correlation with what they said they ate ·The other group came from an indu trial plant Indu try is becoming highly intere ted in this que tion ince it is well known that the mo t valu able employee is the one with years of ervice and hypertension cau es a relatnely high lo s rate for uch employees Some industries which have men working in a hot environment requiring the u e of alt tablets are quite concerned about the salt question in this indu trial population we did find a correlation between the stated salt intake and the ob erved blood pre sure This group was middle aged similar to that oh erved by Dahl and all were healthy enough to work Some other group mentioned here were also elected in that they were patients I believe this election of special groups is bia ing the data on po sible relations between human alt intake and blood pre ure Dr Henry A SCHROEDER The question of course is whether you get hypertension by eating salt or you eat more salt because you have hyper tension One of the best places to study this matter is where the salt diet is higher than it is here The measured intake of the average Japanese is about ten grams of sodium chloride a day Sodium intake is said to be much gher (up to thirty grams per day) in certain Japanee fishing villages and rural areas At a meeting of the Japanese medical ociety last Spring 1 a ked about tnenty five people if they had mea ured urinary output of sodrum or chloride in hyperten ive and normal people to find out how much sodium they did eat and nobody had The Japane e had a habit of feeding soldiers extra salt in Manchuria in cold weather because studies howed that this practice rai ed the metabolic rate The Japanese have more hypertension in some age groups particularly in women over forty than we do statistically and about as much as we have in other age groups About two years ago Dr Homer Smith said there was one thing we knew about the hypertensive kidney - and much of this comes from Dr Hoobler s laboratory – that it a alt losing kidney Now if it is a alt losing kidney and if as we believe the sea within us is constant and must remain a con stant or we will get sick Itke Dr Rodbard s dogs with low serum odium levels then if we lose salt we have to eat more salt This is a question that mu be studied more extensively DE ARTHUR M VISIIBERG The percentage of patients with ential hy perten ion in the ho pital in which I work and in my private practice who develop malignant hyperten ion has decrea ed teadily over the lat twenty years This experience is contrary to that in ome municipal ho pitals particularly those that care for a large number of Negro patients I now find it difficult to find patients with papilledema in the malignant phase of essential hypertension to demon trate for didactic purpo es The only er planation I can offer is this the private patrent and al o the type of ward patient we have do not eat much salt Doctore and new papers have taught them alt is bad for them Thile not on a low odium diet certainly not 25 ·on any approach to a 200 mg figure they consume far less salt than be fore The decrease in the proportion of patient with e sential hypertension who enter the malignant pha e long antedated the widespread u e of anti hypertensive drugs but has been accelerated since As regards heredity my experience differs with that of Dr Rodbard per haps because histories are more easily obtainable In my material the enormous importance of the genetic factor in the causation of essential hy pertension is clearly discernible DR JOHN H MOYER I would like to refer back to basic mechanı m About two years ago we tudied the effects of alıne infusions over a pro longed period of time in lightly anesthetized dogs Our mortality rate was extremely high climbing to eighty percent after an infusion of twelve hours or more When we used five percent gluco e it was probably less than ten percent which raises a question which I po e here in postulating that the effect of salt in hypertension is a direct one on the blood ves els why is the central nervous system always overlooked? Sodium retention may actually increase sympathomimetic activity and hypothalamic imbalance in the ex periments I jut mentioned I feel these dogs died a central nervous system death We observed some ne in blood pres ure followed by vascular col lapse not as ociated with pulmonary edema Secondly I want to outline a simple experiment for Dr Page if he plans to attend the forthcoming Bahamas medical conference He and his col leagues should have their blood pressures taken every day for two weeks before departure At the conference they should drink tap water and record blood pressures for two weeks while drinking this water which has such a high odium content When I was there la t year I developed moderately evere edema of the ankles Out of interet I recorded the blood pressure I do not believe I have ever had a systolic blood pressure of over 120 before in my life but it was 133 mm Hg and remained so for about ten days after I left Nassau and returned to the States DR CMC MASSOY I would like to expand the remarks concerning the relation hip of hypertension and the handling of talt regarding the au-cep tibility of various animal pecies to salt hypertension or to de oxycorticos terone hypertension which is a kind of salt hypertension The mo t suscepti ble are the chick and rat which respond to salt by a severe and rapidly pro gealle type of hypertension The dog is relatively refractory to satt hyper tension with large doses of desory corticosterone or of ome of the highly active synthetic teroide the most that can be obtained is a nie of 20 to 50 mm Hg even if the animals have been adrenalectomized They never show malignant hypertension in the rabbit alt and de oxycortico terone cau e hypotension in tead of hypertension The e examples how that handling of alt is more important than salt intake 26 ·Dr. Simov RODBÅRD Many more problems have been rai ed than can be answered in the time available Dr Perera mentioned a high incidence of glomerulonephritis in the Wet Indies I have no personal data on this but Drs Mo er Hoobler and a sociates are investigating this The validity of questionnaires their value in the tudy of an epidenuologi cal problem and the a ociation of pecific ets of data and a guen di ea e are always subject to careful evaluation Correlations in a gien survey may have only an accidental relation with the di ea e we mut face this risk in any research study of any nature The que tions we a ked were prepared only after extensive consultation with experienced epidemiologi ts Pairing of patients erved to reduce chance a cociations The correlations proved nothing concerning the relationship between salt intake and the occurrence of hy pertension but they do point clearly to the need for more definituse tudies on the salt hyperten ion question Our data showed no hereditary predisposition to hypertension While the que tionnaire has limitations it is more adequate than the drawing of conclusions on the basis of individual ca es In any event the relation of heredity and hypertension is far from clear and this includes analy is of clinical data in the literature Po sıble errors due to faulty memory of the patient a to what he eats are difficult to evaluate It is hard enough to get valid information when the patient is on the metabolic ward of a re earch ho pital Our data can have meaning even if they repre ent only an ingestion fantasy or wi h or guilt on the part of the patient It appears that many people lising on the maller i lands do take large amounts of salt Dr Schroeder s comments are quite in tructive In this regard it is of some value to reconsider our judgments concerning normal blood pre sure levels of a given cultural group Perhaps our criteria of nor mal pressures belong only to our own part of the world Dr Mas on rai es the que tion of pecies variabihty which becomes quite evident when we remember that even a low dia tolic pressure in the chick is a sesere hypertension for mot mammals including man Malignant hypertension is quite easy to induce in the dog but we have never een it in the chick In answer to Dr Sidney Friedman the weight of the adrenal gland was definitely increa ed in our salt fed animals especially when compared with body weight This appears to be a more ati factory ba is of compari on than calculating the ize of the actual gland again t the size of a pre umed normal animal Whether the hypertrophy is a ociated with hyperactivity is not known The remainder of our di cus ions in this conference will I hope provide definitive answers for ome of the questions which hare been raised 27 ·SODIUM AND WATER RATIOS IN THE PATHOGENESIS OF HYPERTENSION LEO A SAPIRS CEIN Department of Physiology, The Ohio State Unnerstly, Columbus, Ohio THAT there is a di turbance in the metabolism of sodium and water Tin Numarand experimebant hypertension has been suggestion repeatedly Unfortunately the nature of the disturbance is not so clear as one mi, ht wish The hypertensive subject is said to show an increased salt appetite (1) but the renal hypertensive rat shows salt aversion (2) (3) Intracellular sodium has been reported increa ed in hypertensive animals (4) and men (5) other tudies indicate it is decrea ed an experimental hypertension (6) Some work suggests that sodium excretion is depres ed in experimental renal hy pertension (7) other investigations imply that the hypertensive animal or patient is actually a salt loser (8) (91 (10) In an attempt to reconcile ome of the e ob ervations I will show that a preponderance of the evidence indicates that in hypertensile rats there is an imbalance between sodium intake and sodium output which predi pose to ward sodium retention I will also show that this imbalance cannot be de cribed properly unless the sodium balance is related to the balance of water Obriously in a chronic condition there cannot be a continuing imbalance between the intake and output of sodium A previous period of imbalance may leave its imprint on the body s sodium content and concentration but this may be concealed in a short term metabolic study For the most part a history of positive sodium balance cannot be ob tained practically Instead we must rely on evidence which suggests that in crea «d sodium intahe has exceeded the excretory capacity or that damage to the excretory mechanism has reduced the excretory capacity below normal Only direct determination of body sodium can demon trate a pre exi ting po itne balance of sodium iſ indeed uch eri ts Much data is available indicating that excessive ingestion of odium pre umably above the level which can be effectively excreted induces hyperten McQuarrie (11) first reported the des elopment of hypertension after gly ing ma sive do es of sodium chloride to diabetic children Later Lenel Rod bard and Katz (12) described the rapid development of hypertension in the chicken receiving 1 otonic or hypertonic alıne in its drinking water Sapır tein Brandt and Drury (13) made rats hypertenle by sub titutin, hyper tonic (2 percent) aline for drinking water The e results were confirmed by 10n 28 ·Mas on and Corcoran (14) and by Mucio et al (15) Meneely (16) demon trated the occurrence of hypertension in the rat expo ed to a high alt diet The clear relationship demonstrated by Dahl and Love between the ub jective evaluation of alt con umption in man and the incidence of hyper ten ion suggests that the adult human subject may be similarly affected by excessite salt intake The epidemiologic tudies of Mo er (17) among the natives of the Bahamas whose well water contains large quantities of sodium chloride and who di play an extraordinarily high incidence of hypertensive di ease are al o impre sne However there is al o a very high proportion of hypertensive disease among the Virgin Islanders (18) who are said to u e rain water rather than well water for drinking and cooking There is ample evidence to suggest that the sodium content of the body is increased in the animal made hypertensne by renal manipulation or salt load ing This phenomenon was first noted by Erchelberger (19) in the mu cles of renal hypertensive doga Laramore and Grollman (20) later described an increase in the sodium concentration of most organs in renal hypertensive rats Similar findings were reported by Greene and Sapırstein in the renal hypertensive rat (4) Mucio et al (15) reported very substantial increases in the salt content of the skeletal muscles heart and liver of rats made hy pertensive by salt feeding Tobian (21) and Tobian and Binion (22) (23) found increased concentrations of sodium in the aortas of hypertensive human subjects and renal hypertensive rats When sufficiently large groups of hypertensive animals or patients are studied a tendency for the pla ma sodium concentration to be elevated is al mot universally found (Rilin and Elmquit 24 Holley et al 25 and Fregly et al 261 Disappointingly the changes are small The biological significance of such findings mu t remain in doubt particularly when one notes the failure of rats expo ed to kidney encapsulation at an older age to how elevation in erum odium (26) Are reported increases in organ sodium content of brological significance Grollman and his associates (27) (28) have hown a clear increa e in the mannitol and radio ulfate spaces of hypertensive dogs and men the same has been noted by Ros (5) Since only slight elevation of extracellular fluid volume is required to increa e greatly the sodium content of tissues and or gans the po sibility that there increases are due to a minimal edema cannot be ruled out with certainty It seems improbable that expansion of the er tracellular pace could have any but a casual relationship to the hypertensive process particularly when we remember that pontaneous edema and 1 otonic sodium chloride loading (29) are without important eflects on the arterial pre sure Ross studies ("ungest that the excess erchangeable odium of hyper tensive men may be intracellular but the po ibility that the exces> is all eque tered in bone though con idered was not ruled out The work of 29 ·Ledingham (6) indicating that intracellular sodium may actually be de pre- ed in the hypertensie heart and keletal mu cle is also di turbing In a small series Moore et al (30) failed to demon trate that exchangeable odium of the body was elevated in hypertensives The chance that the hyperten 11e subject may have a decreased ability to excrete odium recentes very little experimental support Except for one tudy on renal hypertensive dogs 17) the opposite appears true On the other hand as will be shown below an excretory deficiency toward sodium can be uncovered in the hyperten ise rat or human ubject but only when water reten ion is simultaneou ly considered Braun Menendez description of the water and chloride excretion of the fa ting hyperten le rat is especially illuminating (31) Chloride ex cretion of the hypertensive rat did not differ appreciably from that of the normotensive the hyperten ses however howed considerable polyuria In effect though the hyperten ise urine contained about the same amount of chloride a the normoten le it was being excreted at a much lower con centration Some elementary con iderations may be helpful at this point If one con Riders that the cells of the body are bathed in an environment of iso o motic alt It is clearly of much less concern to the e cells whether the volume of the environment changes than whether the composition of the environ ment is altered It would appear unlikely a priori that 150 osmolar volume changes in the extracellular Auid would produce significant physiological effect When changes in o molarity occur however one might reasonably anticipate that the cells would react Thus a lo s of codium in hyperosmolar solution re ulting in hypo o molar contraction of body fluids might lom cally have the same physiological effect as gain of water without odium re sulting in hypo o molar expansion Similarly odium gains in exces of water producing hypero molar expan ion of the body fluids might be ex pected to have the ame cellular effects as water lo es in excess of sodium producing hypero molar contraction of body fluid Although in a qualitative sen e these propo itions are ell evident it is sometimes difficult from a cur ory examination of the sodium and water balances of the organism to determine the tatus of the fluids remaining in the body For etample it is not immediat obuous whether an individual Jo-ing 100 meg of odium chloride in a liter of urine has uflered a great a di tortion in body fluids as one who has lot 100 odium meq in two liters of ufine A simple formula fundamentally imilar to that of Weat & Rapoport (32) to describe the water economy of the kidney in osmotic loading relates the behavior of sodium to nater in its effect on body ſuid The odium aved for the body through renal formation of urine is the product of the urine volume and the difference betneen the pla ma odium and urinary sodium 30 ·concentrations The odiuni o de cribed is odium in excess of water - in eflect free odium The sign of free odium may be positive ignifying that the kidney has conserved sodium in ercess of water or negative mean ing the body has lost more odium than water through the kidney In the example cited above as uming a pla ma concentration of 150 meg Ma per liter the free odium change represented by the lo s of a liter of urine containing 100 meq/1 19 +50 meq of sodium The individual lo ing 150 meq Ma in two liters of urine has a po iture free odium balance of 150 meg Although odium lo es of the second individual exceed tho e of the fir i free odium saved to the body is much greater in the econd In eflect he is in negative sodium balance compared to the fir t on the basis of ma s of sodium lost but when the simultaneous water losses are con adered he is in a po itve sodium balance with re pect to water when compared with the first individual When the tudies on urinary excretion of salt and water are analyzed in this light a rather trıking consi tency emerges For example Green (8) has shown that hypertensive patients are alt losers But the salt lo es under ba al conditions or loading with isotonic salıne are a ociated with di proportionately large losses of water in the hyperten ive group when the free sodium calculation is made the hyperten ive group is een to be in positive free sodium balance though they are at the same time in negative balance of sodium The data of Weller Cottier and Hoobler (33) are quite similar to those of Green and may be amenable to the same interpretation TACLE I WATER AND SODIUM LOSSES BY HIPERTENSIVE AND NORMAL RATS (12 Hour Metabolic Period) No Load 10 Hypertensies 10 Normals UV V F V F meg ml mpa meg ml meq 2 87 27 1 20 172 7 -063 Difference HT - M = 18 meg F Applying the ame principles to chloride the findings of Birchall et al (9) Teleal an identical pattern Although chloride prcretion is three times greater in the hyperten ise than in the normoten ise ubject the free chloride tatus shows the normals in negative balance for this jon (hith respect to water) while the hypertensives are in po the balance 31 ·Ledingham (6) indicating that intracellular sodium may actually be de pres ed in the hyperten Be heart and keletal mu cle is al o disturbing In a small series Moore et al (30) failed to demonstrate that exchangeable odium of the body was elevated in hypertensives The chance that the hypertensive ubject may have a decreased ability to excrete odium recentes very little experimental support Except for one tudy in renal hyperten se dogs (7) the opposite appears true On the other hand as will be shown below an excretory deficiency toward sodium can be uncovered in the hyperten le rat or human subject but only when water reten ion IS imultaneou ly considered Braun Menendez de cription of the water and chloride excretion of the fa ting hypertensive rat is especially illuminating (31) Chloride ex cretion of the hypertensne rat did not differ appreciably from that of the normotensive the hyperten ises however showed considerable polyuria In effect though the hyperten ile urine contained about the same amount of chloride as the normotensive it was being excreted at a much lower con centration Some elementary considerations may be helpful at this point If one con aiders that the cells of the body are bathed in an environment of 150 osmotic alt it is clearly of much les concern to these cells whether the volume of the environment changes than whether the composition of the environ ment is altered It would appear unlikely a priori that iso osmolar volume changes in the extracellular fluid would produce significant physiological effects When changes in osmolarity occur however one might rea onably anticipate that the cells would react Thus a lo s of eodium in hypero molar olution re ulting in lypo osmolar contraction of body ſuids might logo cally have the ame physiological effect as gain of water without sodium re sulting in hypo o molar expansion Similarly odium gains in excess of water producing hyperosmolar expansion of the body fluds might be ex pected to have the ame cellular effects as water los es in exces of sodrum producing hypero molar contraction of body fluide Although in a qualitative sen e the e propositions are ell evident it 19 sometimes dificult from a cursory examination of the odium and water balances of the organı m to determine the tatus of the fluids remaining in the body For example it is not immediately obvious whether an individual lo ing 100 meg of odium chloride in a liter of urine has suffered as great a distortion in body fluids as one who has lo + 150 sodium med in two liters of urine A imple formula fundamentally imilar to that of let & Rapoport (32) to describe the water economy of the kidney in o motic loading relates the behavior of sodium to water in its effect on body fluids The odium saved for the body through renal formation of urine i the product of the urine Volume and the difference between the pla ma odium and urinary odium 30 ·TABLE 11 VATER AND SODIUI LOSSF) BY HYPERTENSIVE AND NORMAL RATS LOADED WITH 1.5%. Naci (6 houss) 17 Hypertensies 17 Normotensies F F meg meg meq men 414 134-183 103-21 2 Difference IT -- 29 meg F moeten .آی plausible picture of the hyperten ile de turbance evolies One may peculate that the basic disorder in hypertension is that the body flul are alnas on the verge of hypero molanıtı This teetering on the brink may result from hypero'molar loading due to an erce site intake or production of os motically actre ubstances alternatively uch loadıng may re ult during normal intake and production of solutes bendu e of dimını hed water intake Even when thr water intake and production and inge tion of solutes are pormal the kidney s damaged ability to ale water for the body mas induce hyperosmolarity of the body fuide Ancillary esidence in support of this hypothesis comes from the findin, of Ellis and Grollman (3.1 that hypertensire dogs and men how increa ed urinary levels of antidiuretic hormone The lonered water content and elevated cation content of the organs of alt hypertensne rats to) and the higher cation and estrogen content of rats with renal hyperten ron (4) are consi tent with this view Against this theory 19 the fact that hypertension can per it in human subjerts in the pre ence of hyponatremia Peripheral resistance may not be sacreased in uch «uhjects however are the cardiar output is not known The higher than normal water content of hyperten e organs (20 23) appears lo argue again t the hypothesis of hyperosmolarity But when it is recalled that slight expan jon of the ettracellular flund which has a much higher water concentration than intracellular fluid will produce such changes without change in osmolar tatu at becomes que tronable of water conteni of tissura gres upful information regarding the hydration of cells One wonders whether is hypertension treatment hould not be directed to the po ability that the presumed defect in the regulation of osmolarxiv may be remedied by incres ing water intake rather than by decreasing the intake of alt which is after all only one of the o motic loads placed on the kidney To this writers knowledge ne tudies have been made on this point 33 ·SUMMARY AND CONCLUSIONS There is much evidence to indicate that hypertension is associated with abnormal accumulations of odium in the hody At the same time it appears that both human hypertensives and renal hypertensive animals actually excrete more odium in any gnen experimental circumstance than normo tensives The apparent paradox can be re oked by relating the sodium economy of the body to its water economy When this is done it is almost con sistently een that hypertensives though they lo e odium in excess of normotensives al o lo e water in exces of normotensties These abnormali ties in excretion are uch that relatively more water is lo t than sodrum o that the hypertensive subject or animal does tend to accumulate odium at leat with re pect to water It is sugge ted that hypertension may follow hyperosmolarity of the body fluids whether this is induced by loading with hypertonic saltre triction of water or a renal inability to con erve water in relation to omotically actuse olutes BIBLIOGRAPIIY 1 Dall L K and Love RA Enological role of sod am chloride intake in essential Iypertengron in humana JAM A 164 39 1937 2 Abrams M DeFriez AIC Tosteron D C an! Landis E.M Sell selection of salt solutions and water Ly normal and hypertensive rats Am J Physiol 156 33 1949 3 Fregly MJ Effect of renal I vpertension on the preference threshold of rats for sodium chlorile Am J Physiol 187 988 1926 4 Grecne RW and Sapirstein LA Tolal body sodrum potassium and nt ogen in rats made hypertensive by aubtotal pephrectomy Im J Physiol 169 313 19 5 Ro. EJ Total exchangeable sodium in hyperten : e patients Chin Sex I) 81 1956 6 Ledingham ) ) Di Turbances in water and electrolyte metabolim in erperimental hyperten von Brit Med Bull 13 33 19 7 Samler J, Hinang Wand kuramoto h Renal clearances of sodium and chlonde in Goldt Titlyperten ive dar Am. J Phypol 163 328 19 1 8 Green DV. Johan on A D, Bridges and Lehmann, 1 H Stage of salt exchange in cs ential Hypertension Circulation 9 416 1921 9 Birchall R., Tnthill S., Jacobs S, Trautman V J Jr and Findler T Renal excrerron ol water sodrom and chloride Circulation 7 2 8 1993 31 ·10 Sapiretein L. 1 Errow Land Croene R Unpoblished of servation 1 McQuarrie 1 Thompson 11. an 1 Anderson 1 Esterib of extessive ingestion of sod us and pota sium salts on casbohydrate m tal oli mand blood pressure ind aberc ch Joren Nutrition 22 7 1936 #2 Lenel R Rodbart Sankatz LN Anenal hypertenson in the ch cken Am J Physiol 159 557 1948 13 Saperstein L. Brandt Land Dru y DR Production of hypertension in ta by subsiyaning hypertonie sodium chlor! xolut one for drinking water I'ror Soe Exp Biol & Med 73 8. 1990 14 Masson GMC and Corcoran AC Salıne hypertesion in Methode in Medical Rese ich vol 5 Seark Book Pub Chucago 111 79, 15 Vucro G And 0331 and Gess 1 Experimental arterial berienst n in ite albmo rat The relation hetween the Eodem cont at aldlet: ue and the art < al pres te weight the water uptake and Suresis of animals rendered hypertensive Bost Soe 111 Brel Sper 30 939 39 $ 2 The potas rum content of the tasa di animais male hypertensive ud 933 3 The water consent of the cells of 1 seges of animals made hypertensive 3 d 936 16 Mencely GR., Tucker R G Da by J and Auerbach S II Chron csodium chloride forickly 36 l e albino rat. 3 Expul Ved 98 71 39 3 17 Moser M In panel duscus on, "Cer te & Envi onmental Factory in Human Hyperten in V Mchegar llyperrenst Conf Jane 197 Circulation, hum ol 17 19 8 (In press) 18 Coldblan 11 2 panel & ussion ol Wolls and walk HG. A *ummary of experim nealers denee relating life stress to she pathog ness of essentsal hypertes son in m from BET. Speren ton & Symposium Vnty nnesota Pres Minneapolis 191 19 E hellerger I Th d tribution of water ad 1 electrolutes bern en blood and gk i tal muscle in experimental hypestestsson J Exp Med 790 1943 20 Laramore O Can I Grallaan Wat sanlelectrolyte ontent of 6 yes the sormal and has sfen mest Am J Phy rol 363 $ 390 Th el trolytni orterral well in experimental renal hyperten ron Crc Research 4 671 1930 72 Tolon Lan Bin on y Trs ne atrons and water in arter al hype tension Car ulat n57 19 2 3 Tolian Lan B mop 3 Inecy wallet ctrolyses sin renal and DC 1 hyp fins on J Clin Inve £ 33 1407 19 35 ·71 Kylın, E and Elmquist H Uber den Blutnatrium spiegel bei essentieller Hypertonie und Simmondsscher Krankheit Acta Med Scand 88 507 1936 20 Holley H L Elliott, M C Jr and Holland C M JE Serum sodium values in essential hypertension Proc Soc Exp Biol & Med 7* 561 1951 26 Fregly M J., Yates F E and Landis E M Serum sodium concentration of hypertensive rats relation to Naci intake blood pressure and age Proc Soc Exp Biol & Med 90 695 1995 27 Teng I C Shapiro A P and Grollman A Volume of Auid compartments in human and experimental hypertension Metabolism 3 405 1954 28 Grolltoan A Shapiro A P and Gafford G Volume of extracellular fluid in experimental and human hyperten von J Clin Invest 3' 312 1953 99 Grollman A Effect of increasing the extracellular fluid volume on the arterial blood pre sure of the normal hypertensive and nephrectomized do Am J Physiol 173 361 1933 30 Moore FD Edelman IS Olne JM James A M Brooks, L., and Wilson C M Body sodium and potassium interrelated trends in alimentary renal and cardio vascular disease lack of correlation between body stores and plasma concentration Metabolism 3 394 1951 31 Braun Wenendez E Blood volume and extracellular fluid volume in experimental hyperten ion in Bell E T., "Hypertens on A Symposium" U Minnesota Press Minneapolis 1951 P 98 3West CD and Rapoport S Urine flow and solute excretion of hydropenic dog under "resting condition, and during osmotic diuresis Am J Physiol 163 159 1950 33 Cottier P T Weller J M and Iloobler S W Effect of an intravenous sodium chloride load on renal hemodynamics and elec trolyte excretion in essential hypertension Univ Michigan Conf on Hypertension Circulation, April Vol 17 1958 (In presa) 31 Brod ky W A and Graubarth HN Excretion of water and electrolytes in patients wth essential hypertension J Lab & Clin Med 41 43 1993 3. Ellı, ME and Crollman A Antidiuretic hormone in urine in experimental and clinical hypertension Endocrinology 44 715 1949 DISCUSSION DR SIO RODBARD In the work I described this morning it was shown that chickens feeding on ten percent salt and retricted as to water intale did not develop as much hypertension as did the control animals on an unlimited water intake I wonder how these observations can be recon ciled with Dr Sapir tein DR HENRY A SCHROEDER This all inclusive term hypertension views 36 ·does not represent a umform group All kinds of renal disease may be present and of any one kind all stages of degeneration of one or both kidneys The ability of the kidneys to handle electrolytes may therefore differ widely from patient to patient This may account for some of your discrepancies Metabolic balance studies of patients on constant Intakes of water and salt do not result in dehydration even when water is relatively restricted for long period The group of hy pertensive animals may be more umform than hyperten ne patients but the kidney s abslity to handle water and salt and make anmona probably varies according to the degree of disease or disorder present Alo there are probably seseral etiologies of hypertension furthering lack of uniformity Thay theory is fa cinating in regard to experimental animals but at may not make sense in human beings If the hypertensne is really & relaine sodium saver although he is actually & sodsum waster he must eat more salt becau e he has to have extra salt even though he is saving 11 relate to his body fluid concentration Da S18LEY HOOBLER In our water and sodium excretion studies in which the same indo dual has been studied at different blood pressure levels or in which hypertension of various etsology has been examined the blood pressure level has correlated reasonably well with sodsum and water ex cretion* Also Dr Dusta» s work shows in general that when there is an ob structne renal arterial lesion wstă unilateral reduction in renal arterial pressure sodium and wafer output on this side are usually reduced Our own belets that sodium and water excretion ten be correlated with the local pressure within the renal artery We know of no clinical or laboratory investigation that contradicts this generalization originally suggested by Selkurt and Shipley in their work on zsolated krdneys and we believe in cressed sodium and water excretion in hypertension is a funrtion of pressure within the renal artery rather than ome general metabolic disturbance although what arterial pre sure does to kidney cells it may also do to other cells of the body Since Dr Mo er is not here and he has been quoted several times I hall try to speak for him What you have heard about drinking rain water in the Virgin 1 lands does not apply to the Bahaman natives Do Moser vent down there and ob essed that in the inhabitants of the Bahamas urine olume and water and salt zntake were very high He also found odium output in the urine very high They were not drinking rain water DR LEO A SAPIRSTEN As I recall the group on restrxied water werghed less than half as much as the group aloned water ad lib It seems probable to me these animals had so great a reduction in plasma solume and cardiac output that an increased peripheral resi tance may have existed and was Cart PT., Weller } Man Boobler St Effect of an intravenous sodium chloride Ioad an renal hemodynamics and the frolyte excretion is essential hypertennon Unw Us higan Cont en llypertension, Crreal tron rol 17 April, 198 fin pres) 37 ·not displayed as hypertension simply because the animals were unable to maintain a normal cardiac output Dr Schroeder states that hyperten ne patients in long term metabolic studies stay in water balance I do not think there is any real doubt that this has to be the case Obviously any patient with a chronic disease mu ! remain in balance for any inorganic substance during the course of hi disea e But patients can differ with re pect to internal level of a substance required to achieve balance I believe in any long term balance study on a hypertensre with respect to water and sodium his internal level of water and sodium is quickly adjusted to the level required to maintain balance sub equently It is true as Dr Schroeder states that hypertensile patients include a varied group That is preci ely why it is o remarkable that water wasting in exce 5 of sodium 19 o regularly reported in the literature I know of only this one exception which occurs under the unphysiological condition of osmotic loading In such loading the free sodium calculation sometimes hows the hypertensne to be gaining less free sodium than the normal However in terms of water economy which is ordinarily the reser e side of free codrum at least when sodium is the principal osmotic load on the kidney the hypertensive till demonstr ztes his tendency to lose water in exces of osmotically actue olute It is a monotonou ly regular finding not only in hypertensive animals but al o in hypertensive men Although as Dr Schroeder has reported the changes in the alkalı inetal in the erum are by no means impressive it is not so clear that osmolarity control is preserved as well as the sodium and potassium levels For this freezing point determinations would have to be made 1 do not know if anyone has done this Dr Hoobler notes that water and sodium excretion are increa ed as a function of the pressure in the renal artery I think the issue here 19 this Are the two incrersed in proportion to each other? If water excretion is increa ed more than sodium excretion one can anticipate secondary chances in the organı m which could conceivably re ult in the perpetuation of the hypertension Thus a kidney in a temporarily hypertensive animal might by excreting water in excess of salt duplicate the conditions in an animal inge ting alt in excess of water (which leads to hypertension) Th14 14 a perfect etup for a vicious cycle in which a temporary hyperten ion 19 con verted into a permanent one I meant to emphasize that Mo er had done his work in the Bahama (uriou ly in the Virgin Islands where rain water is drunk the incidence of hyperten ion is al o sery high In a way the two toriea supplement each other In the Bahamas Mo er notes the naties drink much alt water and suffer from con tant thir! in the Virgin the native drink a little bit of fresh water and are perpetually short of it The common denominater of the two seems to be not erce s of salt but hortage of water free of salt 38 ·EXPLORATION OF RENAL EXCRETORY MECHANISMS WITH RADIOACTIVE SODIUM AND POTASSIUM FRANCIS P CHINARD, MD Departments of Vedicine and Physiological Chemistry, The Johns llophins School of Medicine and the Medical Dirision, Baltimore City Hospitals Baltimore Wa During the past twenty years a spate of publications has appeared on renal functions in health in dı ea e and in frequently drastic experimental situa tions that may be called the gro ser a pects are firmly delineated We know what to expect clinically from deficiencies or exces es of certain endocrine products from deficiencies or exces es of various components of the diet from certain types of tructural damage and even from changes of posture Changes in the handling of water and of odium hypertensive individual and animals are under intensive crutiny There is for example the recent striking application of experimental studies a a diagnostic tool in de termining the management of patients with hyperten on and one type of unilateral renal dt ea e (12) In ub tance there is available a large body of empirical and practical knowledge Interpretations of these data and of studies of species other than man have led to rather definite classical concepts of the complex mech ani ms involved in the renal handling of odjum water and other ub tances As new experimental facts emerge the validity of the e concepts is que tioned I roerustean techniques may be required if the concepts are not to be modified What follows is a progre s report on continuing experimental tudies in dogs of certain features of the renal handling of odium pota tum and certain other substances Becau e the techniques and procedures u ed have not recensed wide application these are de cribed below and some of the results obtained in tudies with sub tances other than odium and pota sium are outlined briefly E PERIVENT IL PROCEDURF Ane thetized mongrel dors are u ed as ubjects Infusions are given via catheter in a jugular vein When required a midline abdominal incision *The e stad es have b en ca ried out in ollaborat on with Dr Th odo e Enn Dr T Ronlan 1 Taylor and M Mary F Moln an bas I en generou ly supp red by the L fe In an e Nei Re ea ch Fund th Marhle Fo dai nih leter ng 11 m n trat the Un ted Stats Publ c H 111 Service th Unit d tate Aromic Energy C mm In EJ Lally an Comp mynd Irk Sharp an 1 Dohme The #1 tane of VCL Le Vrs B Great HU Nr 4 VcCoy an! We ) Armant in the core of these studes 28 tefully ackn I lge} For all rep rt an I certain pro elur 1 letall Ace referen (3) to (8! Tier Its lown in Figur 2 + a 180 ef on unrull, I d stud 39 ·made and a catheter is inserted into the left renal via the inferior vena cava and tied in place Blood is drawn through the catheter by means of a pump The bladder is exposed opened and a catheter is tied in place in each ureter A left flank incision is made and by retroperitoneal approach the aorta and left renal artery are exposed Injection of test solutions is made through a bent needle in erted into the aorta and turned up into the renal artery The injection solution contains the blue dye T 1824 which is assumed not to leave the circulation to a significant extent on passage through the kidney a glomerular substance such as inulin or creatinine which is neither ecreted nor reab orbed by the tubules and the appropriate test substances The injection is made in less than two seconds Following the injection some thirty samples of blood are obtained from the renal vein catheter over a period of about one minute Thirty or more samples of urine are obtained from each ureteral catheter separately over a total period of five to twenty minutes RESULTS Glomernlar substances Before applying the procedures to other sub tances it was necessary to how that on passage down the tubules diffusion effects were minimal and that little or no separation of glomerular substances occurred Pairs of glomerular substances were tested and results of the type shown in F1, la for inulin and creatinine were obtained The ordinates indicate the fractional excretion in each sample of urine for each substance ample number after injection is given along the abscissae The effects of recirculation are evident in that there is significant excretion of inulin and creatinine from the right kidney Accordingly correction for this is made by subtraction of the amounts excreted in each sample by the right kidney from the amounts excreted in corresponding ample by the left kidney The re ultant values are then plotted to give the excretion curves or patterns shown in Fig lb There is little difference between the two curves similar results were obtained in other experiments (3) There is no evidence of sub tantial separation of the glomerular substances on passage down the tubules Turtual rolumes It was oon noted that the poitions of these excretion patterns varied with the rate of urine Aow More specifically the appearance times the modal (peak) transit times and the mean transit times (9) all were dependent on the rate of urine flow The variation of appearance time with urine flow had already been well documented (10) further our pro cedure was not sufficiently refined (the duration of each urine collection period was too long) to permit obtaining data of the requisite accuracy Ac cordingly attention was focused on the mean transit time. The product of the mean transit time and the urine flow ha the dimensions of a volume The relation hip of these volumes o calculated to the rate of urine flow 19 40 ·shown in Fig 2 ( ee (4) for earlier data) The solumes are roughly twice the urine flow Similar calculations are made in studies of the circulation by the dye di lution method A vascular volume between the point of injection and the point of sampling is calculated from the mean circulation time and the car 50 . INULIN O CREATININE 40 30 FRACTIONAL EXCRETION 107 10 5 10 15 20 25 5 10 15 20 25 SAMPLE For la Excretion patterns of creat o ne Fig lb Excretion patterns of creal a ne (carcles) and of nulin (dot) follow ng (circles) and of juin (dots) after co Injection of a colation contain ng both rection for recirculation Data from ex Aubstances into the left renal artery The upper curve is for the fractional xcre periment shown in F16 Ja Data from tron from the left kidney the lour this expe iment se from ref (3) nd curves re for the fractional ercretions are reproduced by permitsion of the edi from the nn hat kidney Each sample tors of The American Journal at represents a 12 second collection per od Physiology diac output or how These calculated volumes obtained from data with glomerular sub tances might then be similarly considered to represent the volume of urine between the glomerul (the tran at time from renal artery to the glomeruli is quite mall) and the end of the ureters (correction has been made for the catheter volumes) No correction has been attempted for the volumes in the ureters (probably quite small compared to the urine flow lecau e of the rapid peri talss) and for the volumes in the renal pelves Nonetheless this implied relationship bet neen urine Now and volume of urine in the kidney may have its counterpart in hi tological observations The columnar epithelium is reportedly flat and the lumen large in tubules from kidneys excreting urine at a high rate of flow the epithelium is rared and the lumen is incon picuous in tubules from kidneys excreting urine at 41 ·a low rate of flow Posibly the functional variations observed at very high rates of urine flow as in o motie diuresis may be related to these presumed morphological variations Apart from the e considerations the fact that excretion of the glomerular substances is accompli hed not in a very sharp peak but is distributed over 11 101 9 VOLUME Mila CALCULATED GLOMERULAR SUBSTANCES (ONE KIDNEY) of URINE FLOW ml /min Fig" Relat onship of calculated volumes for glome ular substances to rate of urine flow The straight line as regres ion ) ne on the rat of urme flow (least squares methol) Values given are for one kidney several minutes and that the injection takes place in less than two econd points to a dispersion of nephron functions and/or structures As shown later quantitation of this di persion is pos ible Alo in conventional clear ance studies under steady tate conditions it might be more appropriate lo take as correction for delay time either the modal or the mean transit time rather than the appearance lime Urea The clearance of urea is substantially lower at all urine flows than the clearance of glomerular ubstances in the dog and in man there is no evi dence pointing to active transport of urea in either direction acros the tubule cells That the clearance of urea is lower i apparently the result of simple bach diffusion of urea from tubular lumen to peritubular fluid in the type of experiment de cribed above the recovery of urea on the urine hould be * An alla tration of these changes is even in " 4 Textbook of Histology" by A A Vavimow an] V Bloom 2nd Edition WB Saun lers Co Philadelphia 1937 p 479 12 ·le than that of a imultaneou ly injected glomerular sub lance in addi tion there should be some kesing of the urea curve relative to that for a glomerular sub tance some of the vrea that had diffu ed from tubular lumesi to tubule cell would he expected to diffu e back to the lumen as the front of C 14 labelled urea proceeded di talls down the tabule In Fig 3 are foun the results of an experiment with C 14 labelled ures and creatine The urea curve is lower than that for creatimne and it is kewed o that the er cretion of urea is delayed relative to the escretion of creatinine lhe calcu • CREATININE OCH UREA 60 NET FRACTION ~ 103 40 20 5 10 15 SAMPLE Fig 3 Ex reli n pattern of reatinine (dotsi und of CI lab lled area Data f om this experiment are from ref 51 and are reproduced by permis on of the I lors of the American I rol of Physiol gy lated volume available to urea is greater than the calculated volume available for creatinine in pite of the permeability of cells to urea there » no evidence to permit the uggestion that urea has jumped the gap bets een peritubular fluid and tubular lumen via the back door the ercretion of urea is delayed relative to the ercretion of creatinine Such re uits are compatible with the consentional concept of the renal handling of urea Reabsorbed substances Substance which are real orled actively by the tubule cells may be con dered to be ecreted from tubular lumen to pertubular fluid direction appoite to their concentration gradient NE reab orption 1 ·complete none of the substance appears in the urine this is what hap pens with glucose However if an appropriate load of glucose is delivered to the tubules reabsorption is incomplete and glucosuria occurs Under such conditions the excretion curve of C 14 labelled glucose hould be lower than but symmetrical to that of simultaneously injected glomerular sub tance Fig 4 shows the results of an experiment with C 14 labelled glucose and ordinary creatinine under conditions of glucose loading The results are O CREATININE 103 60 o c14 GLUCOSE H22 secs VIL 17 56 NET FRACTION 20+ 10 12 SAMPLE Fug 4 Excretion patterns of creatinine (dots) and of C 14 labelled glucose en presence of glocosuria e entially as predicted There is however an initial delay in glucose er cretion this delay remains to be explained Phlorızın blocks the tubular reabsorption of glucose Following its ad mini tration the excretion cunes of C 14 labelled glucose and of creatinine should be identical The results of such experiments are as predicted though the initial delay in the glucose excretion is again noted Similar re ults have been obtained with vylo e which is reabsorbed to a much les er extent than glucose Renal handling of glucose In conventional clearance studies it has been tacitly assumed that there is relatisely little utilization of gluco e by the kidney Various ·mechanisms have been propo ed for the tubular reabsorptie proces Breakdown and re ynthe is of the six carbon chain has been uggested In order to te t the several po ibilities a eries of experiments was carried out with glucose the emphasis now being placed on the patterns ob tained in renal venous blood Here the u efulness of T 1824 becomes evi dent Fig 5 hons the results of a typical experiment in which gluco e (label led in the 1 position with C 14) creatinine and T 1824 were injected The ordinates are calculated in the ame manner as in the experiments in which urine was collected The ab cis al cale is different in that the collection of the thirty or more renal venous blood samples is completed in one minute or 50 in tead of the five to twenty minutes required for the collection of the 40 - NORMAL DOG • T 1824 ဦး 03 O CREATININE 201 O GLUCOSE-1-C14 REABSORBED GLUCOSE iniuma 10 20 30 SAMPLE F&S Renal vein patterns Injection of 1-C14 glu ose with cre I nine and T 18 + See tett for details. Data are ſ om sef (7) and are repro loced by permis Bron of the editor of Science same number of urine samples The curve for the C 14 labelled glucose 1 substantially higher than that for creatinine in the later periods That the C 14 activity was associated almo t entirely with gluco e nas demonstrated by enzymatic methods and by radioautography That the C 14 activity in all samples had remained in the 1 po ition was demon trated by a combination of tepsi e chemical and enzy matie degradations of the gluco e There was no evidence of randomization of the C 14 and hence no evidence of break down and re ynthe is of the 6 carbon chain The recovery of creatinine rela 45 ·tre to T 1824 averaged approximately 70 percent while the recovery of glucose averaged approximately 100 percent It was tempting to suggest that the difference between the gluco e and creatinine curves represented gluco e tran ported by the tubules Evidence sub tantiating this sugge tion was pro vided by imilar experiments carried out after phlorızın had been admin 40F PHLORHIZIN TREATED DOG a los 20 • T 1824 O CREATININE O GLUCOSE-I C14 10 20 30 SAMPLE Fug 6 Rnal vein patterns of 1-C 14 gluco. er atinine and T 18" after al ministration of phloshızın Data are from ref (7) and are suproduced by rer mion of the ed tors of Science istered Under such conditions the gluco e and creatinine curves in renal Venous blood should be nearly adentical Fig 6 shows that this is the ca e On the ba 19 of the e and similar experiments it was concluded that the flucose was transported with the 6 carbon chain intact and that the dif ferences between the gluco e and creatinine curves could be u ed to con fruct a recovery curve for the tran ported gluco e The mean tran il time for this moiety of the gluco e was about ten econd greater than the mean tran it time for creatinine The transit time acro s the tubule cells must then be less than 10 seconds ince a few seronds mut he required for the gluco e in glomerular fluid to travel down to the tubule cells concerned in its te ab orption Sources of renal rein carbon dioxtde A indicated the recoveries of gluco e in renal venous blood without prior admını tration of phlorızın averaged about one hundred percent relative to T 1821 Berau e of the limitations of the recovery calculation 3 more 46 ·direct approach was required to determine whether significant degradation of gluco e to carbon dioxide occurred during a ingle circulation through the kidney To this end the renal venous blood amples were collected anaero bically and the carbon dioxide in the e amples was analyzed for radio activity Less than 01 percent of the radioactivity injected as C 14 gluco e was recovered as carbon dioxide Gluco e does not contribute significantly to renal vein carbon dioxide under the conditions of the e experiments LACTATE-1 C14 30- • T 1824 CREATININE O NONVOLATILE C14 205 o Rx103 C'402 10 30 20 SAMPLE F1g 7 Ren 1 in p tterns of C110 afi inje tion of 1 ctate 1 C 14 The elimination of gluco e as a major direct ource of renal carbon diox ide sugge ted that other potential sources hould be investigated Both lactate and pyruvate have been tried Re ults obtained with C 14 labelled lactate are hown in Fig 7 Aub tantial fraction of the injected radioactivity is re coverable as carbon dioxide The chemical nature of the non volatile C 14 activity has not yet been determined The transit time relation hips permit the calculation of a mean reaction time of about four seconds for the trans formation of lactate to carbon dioride Similar re ults have been obtained with pyruvate Control experiments involving the injection of labelled bu carbonate into the renal artery have provided omewhat surprising but no unpredictable results there is apparently sub tantial fixation of carbon de ovide by the kidney These re ults are preliminary Honeer this technique offers the po ibil ity of tudying not only the metabolic activities of organs in uno but alo ·tre to T 1824 averaged approximately 70 percent while the recovery of glucose averaged approximately 100 percent It was tempting to sugget that the difference between the glucose and creatinine curve represented glucose tran ported by the tubules Evidence substantiating this suggestion was pro vided by imilar experiments carried out after phlorızın had been admin 40 PHLORHIZIN TREATED DOG $15 20 • T 1824 O CREATININE O GLUCOSE-1 c14 10 20 30 SAMPLE Fug 6 Renal vein patterns of 1 C 14 glucose creatinine and T 18 i aft r au ma tration of phlorh in Data are from ref 171 and are reproduced by per mi ton of the editors of Science i tered Under such conditions the glucose and creatinine curves in renal venous blood hould be nearly identical Fig 6 shows that this is the case On the basis of these and imular experiments it was concluded that the glucose was tran ported with the 6 carbon chain intact and that the dif ferences between the glucose and creatinine curves could be used to con truct a recovery curve for the tran ported gluco e The mean transit time for this morety of the gluco e was about ten econds greater than the mean transit time for creatinine The transit time across the tubule cells must then be less than 10 seconds since a few econds mu t be required for the gluco e in glomerular fluid to travel down to the tubule cell concerned in its re ab orption Sources of renal zein carbon dioxide As indicated the recoveries of gluco e in renal venous blood without prior admını tration of phlorızın averaged about one hundred percent relative to T 1024 Because of the limitations of the recovery calculatione a more 16 ·tration the recovery of hippurate in urine is less than that of creatinine possibly becau e of binding of the hippurate to the plasma proteins The vagaries of the creatinine curse illustrate one of the difficulties encountered with this technique and result from irregular and unequal urine flons from the two kidneys Experiments with PAI and I 131 labelled diodrast have given results which parallel closely those obtained with hippurate 120+ • T 1824 O CREATININE o C14 HIPPURATE 100: H 152 seconds X 19 56 * 80F AFTER BENEMID NET FRACTION X 103 201 12 16 20 24 SAMPLE F1g 8b Renal vein patterns of C 14 labelled hippurate creatinine and T-1894 Effects of prior admin strat on of Benem d Relative to the velocity of urine down the tubules hippurate is brought quite rapidly to the tubule cells by way of the peritubular fluid The delay in excretion of hippurate may therefore be considered in large part a measure of the time required for the ecretory process to take place This delay averages about seventy econds a con iderably longer time than is required for the secretion of gluco e in the opposite direction It is evidence for the transient storage during the ecretory process of huppurate and its congeners in the tubule cells Our re ults are consi tent with tho e that have led to the devel opment of the I 131 labelled diodrast renal uptake test (11) The renal handling of potassium Early ideas about the renal handling of potassium consisted in the imple hypothesis that urinary pota ium was filtered pota lum that had e caped 49 ·tubular reabsorption Occasional clinical reports indicated that the clearance of potassium could be greater than the clearance of inulin or creatınıne Be cause the data were obtained in studies of patients with renal disease the valid 0 O 70F CREATININE C14 HIPPURATE 23 2 seconda H 241 seconds 60 10 19 56 9950 AFTER BENEMID CONTROL FRACTION x 10 40 NET 10F 4 20 SAMPLE Fug 9 Excretion patterns of creatinine and C 14 labelled hippurate The left panel shows the control experiment The right panel shows the effects of prior administration of Benemid ity of the inulin clearance as a measure of the glomerular filtration rate was questioned Subsequently Mudge Foulks and Gilman (12) and Berliner and Kennedy (13) demon trated that under occasionally dra tic experimental con ditions in dogs the clearance of potassium could be made to exceed sub stantially the concomitant clearance of creatinine This establi hed that potas sium ecretion could occur Sub equent work led to the current hypothesis that under ordinary circumstances all the pota sium excreted in the urine atems from distal tubular secretion and that all of the potassium crossing the glomerular barrier 19 reabsorbed by the tubules and returned to peritubular fluid Further studies particularly tho e of Black (14) and of Morel (15) howed that there was an extraordinary uptake of radioactive potassium 1-42 on a single pa age through the kidney and that urinary excretion of this k-12 was related to gradual relea e from a pool in the kidney rather than to N-42 freshly arriving to the kidney from the renal artery Our own tudies confirm these later findings and are consistent with the hypothesis that most of the urinary potassium stems from tubular secretion Figures 10 50 ·11 and 13 16 illu trate results of experiments in which both renal venous blood and urine amples were obtained Fig 10 shows that under the usual conditions of the e experiments there is almost complete uptake of 142 by the kidney and that there is gradual protracted relea e to renal venous blood 80- T 1824 CREATININE K 42 KIDNEY II 5-57 1 60F FRACTION X 103 2012 10 15 SAMPLE Fug 10 Renal vein patterns of T 1894 creatinine and 1-2"" indicates dura tion of sampling interval of the 6-12 as demon trated by the tailing of the curve Under similar con ditions the urine excretion curves how an unusual pattern (Fig 11) There is a peak of K42 excretion which sub tantially precedes the peak of creat inine excretion Again in the urine there is protracted tailing of the 6-12 excretion The pota jum 1 not all accounted for in the duration of these experiment A large fraction remains in the kidney mainly in the corter as hown in Fig 12 in which the relative radioactivities of different portions of the kidney are plotted Under conditions of higher potassium clearances the recovery of K-12 in the renal vein 33 18creased (Fig 13) 85 is the peak of potassium excretion in the urine (Fig 14) Finally under conditions im ular to tho e u ed by Mudge and his collaborators to achieve clearances of 51

·URINE
o C14 CREATININE
80+
X 42
Ts 30 secs
SALYRGAN
II 15 55-1
60
Wc
x203
40F
20
10
NAMPLE
F18 11 Excretion patterns of creatinine and A-2 after the administration of
Salyrgan
ordinary potassium greater than clearances of creatinine (12) the overall
uptake by the kidney is further decreased as shown by the greater recovery
in renal venous blood (Fig 15) In the urine the 6-42 peak is almost as high
as the creatinine peak
As indicated these results are consi tent with the hypothesis of tubular
ecretion of potassium The early urine peak may be considered to represent
the potassium brought to the distal portions of the nephrons by way of the
peritubular fluid thus accounting for the shorter appearance time and modal
transit time of pota sium relative to the corresponding times for creatinine
The ecretory process for potas ium would then be fast compared to that for
PAll and po sibly of equal rate to that for gluco e The tailing of K 12 in
52

·the renal venous blood and in the urine reflects gradual release from a large pota sram pool probably in the more proximal portions of the nephrons* It appears from the rough reciprocal relationship between optake and excretion of potasssuts that there may be no distinct potassium pools in the kidney the capacities of which are variable and inversely related Ordinarily the proximal pool has a high capaczły and the distal pool a low capacity so that the clearance of potassium is low When the clearance of pota sium exceeds the creatinine clearance the capacity of the proximal pool is decreased and that of the distal ecretory pool is ncreased Under the latter conditions the possibility of some contribution to urinary potassium of potassium e caping tubular uptake cannot be excluded by these experiments The Renal Handling of Sodium While the results and interpretatsons just pre ested may have some novel features by and large they dovetail in satisfactorily with other known facts and concepts about renal functions and metabolism yo INTRA RENAL K42 DISTRIBUTION 2 MINUTES AFTER INJECTION 20F % 101 2 8 CORTEX MEDULLA PAPILLA Fix ] Djstrubatsoa of in sections of kidsey removed and frozen in toud nitrogen two windtes eſtes be sujection of 6-12 sata the renal artery By a combination ol sad gaufographic *od 1 stoebeskal seekniques Essen and Harry {Natuit 380 438 39 3 host demonstrated that the sea and 41 two minuten aft r inject on indeed largely ra the proximal tabole cello 53 ·URINE ocł4CREATININE BLOOD • T-1824 OCH CREATININE 60 70 *2 o K42 7 = 19 secs 35% NaCl JI-9-56 T = 1 0 secs 35% Necz III -9 56 40 50 rx103 We * 103 20 10 5 10 15 20 25 30 SAMPLE F&13 al ove Renal vein pallern of T 1821 creatinine and h-12 after admin tra tion of 3.5" Maci FIK 1 milt Ex relion patterns of creatinine an 1 -12 after administration of 3. Val Data lt m same experiment as shown in Fog 13 5 10 20 30 15 SAMPLE ·URINE 16 80 BLOOD . 1.1824 O Q' CARATININE 142 1315sts 2 %N CL-50%URSA X-9 56 OCH CREATININE F-78 miymin T20 3ec3 2 ANAC2-50% VACA 12 X 9 56 60 www k10 *803 8 10 1 20 10 15 20 25 30 SAMPLE Fix 15 lei R nał ten patterns of T IR'I creatinine and a 12 after almal tra zion af NeCt und 50 UTCO I lg 16 gbose Feetetion pattern of stratinind an 52 allet alanini iration of Naci an 150 urea Data from ame mi erment au loun in 118 15 5 10 25 SAMPLE

·If urinary sodium is solely sodium that has escaped tubular reabsorption
then one would expect to find in the urine a curve for sodium lower than but
20
CREATININE
CONTROL
Oo Na 22
250 seconds
15
Wix103
10
5 10 15 20 25 SO
SAMPLE
Fug 17 Excretion patterns of radioactive sodium and creatinine Control
experiment
symmetrical to that for a imultaneou ly injected glomerular substance Such
a relationship has not been found
Following the simultaneous injection of labelled sodium and of creatinine
there is invariably found precession of sodium over creatinine (Fig 17)
The appearance time the modal transit time and the mean transit time of
odium are always significantly less than the corresponding times for
56

·glomerular substances when a diuretic such as chlorothiazide (Diuril)
was administered following the control experiment just mentioned the peak
ercretion of sodium was substantially increased and more sodium was ex
20-
CREATININE
Omo Na22
245 seconds
AFTER
CHLOROTHIAZIDE
60 mg bor
15
**1055
10
5
20
25
JO
5 10 15
SAMPLE
For IB Same after eblorothiazide (Diar;})
creted under the creatinine curve (Fig 28) With mercurial diuretics the
peak is increa ed but there is even more etcretion under the creatinine cure
The sodium curve has however never been found to be higher than the
creatinine curve except in the first few samples
Table 1 summarizes some of the data obtained with radioactive sodium
To calculate the values shown in the lat column the total of each ub tance
excreted as determined and is a signed the value of 100 The cumulate per
57

·TABLE I Summary of sodium studies Type of Number of experiments experiment Average percent of injected sodium excreted* Average percent of creatinine excreted at 50 percent sodium excretion* Without mercurial diuretic 13 16+09 83 +83 After mercurial diuretic 8 39+21 331 117 *Means and standard deviations centiles of these totals are then calculated and plotted as ordinates with sam ple number as abscissal values From the curves connecting the appropriate percentile values the percent of the total eventually excreted creatinine as deter mined at that time or sample when 50 percent of the total esentually excreted radioactive odium has been collected in the urine This value permits quanta tative assessment of the precession of sodium over creatinine In all experiments this is significant since the mean transit times and the modal transit times for sodium are invariably le s than the corresponding transit times for glomer cular «ubstances There is scatter However the preceasion appears to be quantitatively less when a mercurial diuretic is used in paired experiments in which a control run was followed by a run after administration of a mercurial diuretic the precession decreased quantitatively Figure 19 presents the data from the chlorothiazide experiment in another manner Here the cumulative percentile excretions are plotted as probit units along the ordinates while a logarithmic scale is used for the sample num bers along the absci sae The marked change in urine flow after chlorothia zide was accompanied by a shift of the creatinine curse without a change of slope suggesting that little or no change occurred in the dispersion of this particular nephron function The slope of the sodium curve was changed sig nificantly ugge ting that more than one distribution might now be involied in the excretion of the labelled codium This change of lope is even more marked in erperiments in which mercurial diuretics were admini lered 58 ·1 CONTROL RUN URINE FLOW 046 ml/m 95 DAPTER DIORIL URINE FLOW 243 ml/m O CREATININE O SODIUM 22 75 PROBIT PERCENT RATIOS EXTRACTION Nai/Naist - 0 14 Na na 0 15 25 OT TO wf $ 6 18 9 30 20 WAMPLE Fug 19 Probit log sample number plot of experiment shown in Figs 1 and 18 See text for details A matter of some importance is the extraction fraction of ordinary sodium and of labelled odium In this and other similar experiments the extraction fractions have been approximately the same There is no unexpected dilution of the labelled sodium The data can be summarized in yet another manner by calculation of the Virtual volumes for sodium as was done earlier for glomerular substances The values calculated for sodium V. are smaller than tho e calculated for glomerular ubstances Vc The difference VG-V, may repre ent the vol ume of urine in the nephrons between the glomeruli and the ite of delivery of the radioactive sodium into the urine The values found in a eries of experiments are hown in Fig 20 The lowest values for the differences were obtained in experiments in which mercurial diuretics were u ed Current views on the excretion of sodium can be summarized as follows Analy es of glomerular fluid in amphibia and mammals how that the con centration of odium in this fud 13 the ame as that in pla ma within the 59 ·10 o VG-VN 9 8 CALCULATED VOLUME ml AV O 8 아 URINE FLOW ml/min F18 20 Relationship 10 urine Bow of calcnlated volumes for sodsum () for creatinine (1) and for differences of these values (AV) for cach experiment The dashed line is the regression line (least squares) of on the urine flow for the experiments shown here and differs slugbuly from that shown in Fig 3 for these and other experiments The upper line vo the regression line of urine flow the lower line is the regression line of Avon urine flow on con traints of the Gobbo Donnan equilibrium Ordinarily the amount of sodium excreted per minute is a small fraction of the amount calculated to cross the glomerular barrier Clearances of sodium greater than concomitant clearances of glomerular cubstances have not been reported The logical deduction can be made from these facts that excreted codium is worlum that has escaped tubular reabsorption The data pre ented above are not compatible with this hypothesis The appearance time the modal transit time and the mean transit time all andı cate that the excreted sodium arries in the urine in large part via a hort cut or by pass Much of the excreted sodium must cross directly from peri tubular fluid to the tubular lumen It might be suggested that the preceasion of sodium (which we have also found with radioactive chloride and with or dinary thiocyanate) 19 simply the result of a dillusion ion-exchange mechan ism and has no bearing on the renal handling of sodium In the case of thio cyanate for example a thiocyanate on in peritubular fuld would le ex changed for a chloride ion in the tubular lumen thus permitting the thro cyanate ion to e cape into the urine ahead of simultaneously injected creati 60 ·nine which must percolate down the tubules With this mechanı m it would still be necessary 1) to consider that there was complete reabsorption of thiocyanate crossing with creatınıne into glomerular urine and 2) to accept the reality of a short cut or by pass for thiocyanate In addition there is some difficulty in visualızıng a simple ion exchange mechanism operating acro s the tructural complexities of the tubule cells Such a mechanı m would require permeability of the barrier to sodium chloride and thiocyanate and impermeability to urea urea with a diffusion coefficient nearly as large as the diffusion coefficients of the e long does not how precession over creatı fline (uide supra) In brief we wih to offer the following as a tentative working hypothesis on the renal handling of sodium Under ordinary conditions of sodium ex cretion in the dog proximal reabsorption is almost complete the sodium ex creted in the urine is added to the tubule urine in the di tal portions of the nephrong by mechanisms quite unknown After administration of a mercurial diuretic there is apparently some escape from reabsorption in the proximal portions of the tubules This hypothesis 13 strictly applicable only to anes thetized dogs under our erperimental conditions We hope to carry out shortly similar but far le s drastic tudies in man If this hypothesis 13 correct a revision of the classical views on the renal handling of sodium will be in order and the possibility of tubular ecretion of sodium will have to be considered SUMMARY A new technique has been developed for the exploration of various renal functions Injection of test sub tances is made rapidly into a renal artery of anesthetized dogs Some thirty renal venous blood amples are obtained over a period of one minute while a like number of urine samples are obtained from each ureter separately over a period of five to twenty minutes Plots of the fractional recoveries against time after injection provides char acteristic recovery or excretion patterns for the individual testub tances With pairs of glomerular substances such as inulin and creatinine identical excretion patterns are obtained there is no significant eparation on pa sage down the tubules The positions of the curves vary with the urine flow From the mean transit times and the urine flows virtual volumes of di tribution between the glo meruli and the end of the ureter are calculated The solumes are approumately twice the urine flows The excretion curve of urea is delayed with respect to that for creatinine and the recovery of urea is less as expected from the hypothesis of back diffusion of urea The renal handling of gluco e is examined in ome detail Gluco e 19 transported across the renal tubule cells with the 6 carbon chain intact It does not contribute significantly directly to renal sein carbon dioxide while 61 ·lactate and pyruvate do In the presence of glucosuria the excretion pattern of C 14 labelled glucose is roughly symmetrical to that for glomerular sub tances The excretion patterns of PAH hippurate and diodrast are delayed rela tive to the patterns of glomerular substances Approximately seventy seconds are required for the movement of these substances across the tubule cells Excretion patterns of K42 reveal that the peak excretion of 142 precedes the peak excretion of simultaneously injected glomerular substances There is in addition protracted excretion of the K-42 at a low rate The recoveries of k 42 in renal venous blood are small indicating substantial uptake by the kidney tissue with potassium clearances equal to or exceeding clear ances of creatinine renal uptake is decreased but the peak excretion of X 42 is markedly increased It is suggested that there are two distinct pools for potassium in the kidney of variable and roughly reciprocal capacities A proximal pool is involved in the uptake while a di tal pool is involved in the ecretion of potassium Excretion patterns of radioactive sodium show a similar precession over simultaneou ly injected glomerular substances Ordinarily the precession 15 such that about eight percent of the eventually excreted creatinine is in the urine when fifty percent of the eventually excreted sodium has been col lected The precession of sodium is decreased after mercurial diuretics It is ugge ted that ordinarily most if not all the filtered sodium 19 te ab orbed and that excreted sodium has been added directly to distal urine from peritubular fluid After mercurial diuretic some of the excreted sodium may be derned from glomerular fluid by escape from tubular reabsorption BIBLIOGRAPIII 1 Mueller C B., Surtshin A., Carlin, M R., and White HL Glomerular and tubular Influences on sodigm and water ercretion Am J Physiol 165 411 1931 2 Connor TB., Berthrong M., Thomas W C Jr., and Howard J E Hyperten ion due to unilateral renal disease with a report on a functional test helpful on diagn0919 Bull Jobos Hopkins Hoep 100 941 1957 3 Chipard FI Comparative renal excretons of glomerular substances following "in tantaneous" injection into a renal artery Am J Physiol 180 617 1933 4 Chinard FP Renal dead space as a function of urine flow in the anaesthetzed dog Im J Phy:101. 100 620 1955 S Chioard FP, and Enns, T Relative renal excretion palterns of sodium ion chloride ion urea water and tlomerplar substances Am J Physiol 189 217 1933 62 ·6 Chinard FP Relative renal excretion patterns of paminohippurate (PAM) and glomerular sab tances Am J Phybol 183 413 1936 7 Chinard FP, Taylor VR Noln MF and Enns T The tran port of gluco e by the renal tabule cells of anaesthetized dogg Science 12 736, 1957 8 Chinard FP Vosburgh G J and Enns T Transcapillary exchange of water and of other sub tances in certa n organs of the dog Am J Phys 01 783 991 19 9 Meter P., and Zierler K L On the theory of the indicator-dilution method for me surement of blood flow and volame J Appl Physiol 6 731 1954 10 Morales P A Cowder C. H Fishman A P, Maxwell, M H and Gome PM Measurement and significance of appearance time in the dog Am J Physiol 163 454 19,0 11 Winter CC A clinical study of a new renal fanction test the radioact ve d odrast renogram J Urol 6 182, 1956 12 Mudge G I Foulks ) and Gilman A The renal secret on of potassium Proc Soc Exptl Biol Md 67 545 1918 13 Berliner RW., and hennedy T J., Jr Renal tubular sec etion of potasoom in the normal dog Proc Soc Exptl Biol Med 67 519 1918 11 Black D A Davies H EF and Emery EW The diapo al of radioach e potas um injected intravenously Lancet 1 1097 1997 15 Morel F Origine tubula re du potass um excrete pur le rein d . mamm feres Compt ren) 41 511 195 DISCUSSION DR HENRY A SCHROEDER What happened to pota sium after a mercurial diuretir? DR FRANCIS P CHINARD Diamox alone produces an increa e in the peak pota sium excretion If this is followed by a mercurial uch as Salyrgan the potassium peak becomes decreased as does the fractional excretion of potassium jut as the clearance of potasium increased by Diamor is de creased by ub equent administration of a mercurial diuretic DR LEO A SAPIRSTEIN Do you have evidence of a decrea e in proximal tubular reab orption of odium during o motic loading? DR FRANCIS P CHINARD After an o motic load there appears to be an increase in the early part of the odium escretion ALo there is evidence that more comes donn from the glomeruli no matter what o motic load 15 used Mannitol for example cau es an increase in both the peak and the later position With sodium sulphate loading the peak is again elevated but 63 ·there is still more excretion under the creatinine curse presumably becau e of the pre ence of obligatorily excreted anions DR THOMAS FINDLEY May I ask if you think water could be secreted al o? DR FRANCIS P CHINAPD We have done a number of experiments with labeled water but the curses them elves are not very informative becau e of their spread The appearance time for water is maller than that for creat inine and about the same as that for sodium and potassium The peak of the water curve is delayed with respect to that of creatinine Presumably some of the water may behase as does urea entering tubule cells from the lumen and returning eventually to the lumen For the water the curve could be broken down into three or more con tituent curves Our data do not per mit any conclusion as to the possibility of water secretion DR MEYER FRIEDSIAN Any other que tions? If not I presume this is the ea within us One undoubtedly could u e the inulin clearance just a easily as the creatinine? Dr FRANCIS P CHIYARD A series of experiments was carried out in which pairs of glomerular substances were tested The pairs were Teatinine and anulin inulin and ferrocyanide and ferrocyanide and creatinine No signifi cant differences were detected in the curves fractional excretions or time parameters of the paired substances 61 ·CHRONIC SODIUM CHLORIDE TOXICITY AND THE PROTECTIVE EFFECT OF POTASSIUM CHLORIDE * GEORGER MENEEL , M D and CON O T BALI Departments of Medicine and Pretentue Vedicine and Publıc Health, Vanderbilt Unnersity School of Medicine, Naslaalle Tennessee LEGACY A from evolution is an exceptionally good mechanı m for water and salt retention and for excess potassium excretion (1) From pre recorded hi tory the need for salt 15 indicated in the herbivores great trels to salt licks and the carnivores filling their needs from their natural diet of the flesh of other animals (2) Legacies of history are the salıne wars slavery decapitation and other trong measures (36) Legacies of the 19th century are rich and varied (7) In 1807 Davy isolated potassium and later that same year he isolated sodium also by electrolysis By 1890 Carl Schmidt (8) was reporting determinations of sodium and potassium in the blood in his essay on cholera He and Redtenbacher (7) are commonly credited as the first who paid scientific attention to salt in disea e states but as Gamble (9) has pointed out the honor really lies with the London physician O Shaughnessy twenty years earlier In the ensuing hundred years the merit of alt withdrawal in edema heart failure and hypertension has been dis covered and red covered (10 11) Observations and experiments in the 20th century are more familiar to all of us (1219) Allen (20) in 1922 con sidered low odium dipts important in hypertension and the rice diet of Kempner (21) some thirty years later is an example of the widespread ap plication of such theories Selye (22 23) produced nephroscelrosis like lesions in chicks fed large amounts of salt Sapir tein (24) produced renal lesions and hypertension in rats by providing only salted drinking water The mini mal odium requirements for many laboratory animals have been determined and the need for salt for the gronth of farm animals is well proven Flow ever de pite this knowledge little is known of the actual requirements for mammalia and what if any con titutes a toxic level particularly on the basis of long continued intake Our iny tigations of the possible toxic effects of chronic dietary sodium chloride intially centered on the hypothe is of threshold and the hypothesis of lag Findings early in 1993 focu ed our attention on the possible relation to potassium intake accordingly life span experiments were tarted in which the pota sium to odium ratio on the diet was brought toward ope Supported in part by the Research Labo atory and Rai ortotope Service_Thayer let ns Admin tration Ho plal the Life In uranc Wed cal Res arch Fondo 56 1 and the National In tutut of Health H 1816 65 ·Early Fındıngs In the initial experiment started in 1951 sır groups of thirty five week old male Sprague Dawley rats housed in constant temperature humidity con trolled quarters were placed on complete purified diets identical except for sodium chloride (25) A basic ration of 251 percent purified Ca ein 51 8 percent sucrose 200 percent hydrogenated vegetable oil a complete vitamin mixture and 29 percent mineral mixture (26) without added sodium chloride was prepared SODIUM SPACE mple % NaC1 N 5 Na Space IS E 2 - 4 months ontrol gh salt #ederna gh salt C edema 0 15 7 0 8 4 & 9 8 7 0 & 9 8 7 11 2 23 80 75 26 10 61 57 7 8 10 months »ntrol 0 15 0 2 & 1 1 28 23 1 to 28 ded salt 5 6 10 24 7 to 65 gh salt 70 8 4 & 9 8 40 27 20 67 Fig 1 Sodium space measured with Na'4 and found to contain 0 01 percent NaCl Diets were derived by the addition of powdered sodium chloride intimately mixed The control diet contained 0 15 percent Naci The other five groups received progressively higher pro portions of odium chloride 28 56 70 84 and 98 percent It is worth noting that the salt content of the 28 percent NaCl ration com pares roughly on a weight for nutrient basis with the human intake of about 12 15 grams a day a common e timate of the salt in the diet in this country (27) The rats had free acces to tho e diets and in later experiments 11 20 140 and 21 0 percent NaCl as well as demineralized water When first placed on high odrum chloride marked polydipia and polyuria but only mild anorexia occurred After three days the e rats appeared to be everely dehydrated Two weeks later the rats all looked healthy and were gaining weight regularly In the initial experiment average werght gains for the first twenty Weeks were 353 grams control ration 331 grams 28 percent NaCl 315 grams 56 percent NaCl 310 grams 70 percent NaCl 295 grams 8 4 percent Naci and 274 grams 9 8 percent NaCl (28) The earliest untoward finding (29) was during the third and fourth months when edema developed in 18 percent 66 ·of the rats eating the three highest levels of odium chloride Sudden weight gains of 40 to 160 grams occurred Extracellular water measured with radio active sodium (30) rose from the control level of 24 percent to 58 percent of body weight The e edematous animals were everely anemic and showed lipemia and hy poproteinemia At autopsy there were obvious edema and anemia Other wie microscopically all the ti sues except the kidneys appeared normal In relatively bloodless glomerular tuft, there were foam cells containing large Fug Early glomerular lesion (H & E) Reproduced with the permiss on of the Editors of the Journal of Exper mental Medic ne amounts of fats taining material The tubules exhibited a nephrotic degen eration and contained alo much fat staining material There were les er deposits of lipoid in ome of the arterioles Three edematous animals urrived this pha e rapidly lo t their extra fluid and became extremely emaciated and cachectic Again all tissues seemed es sentially normal in the gross except the kidney A renal lesion similar to that de cribed above but more extensive was ob erved Many glomerular tufts were obliterated Tubular degeneration was extreme No evidence of adrenal failure was found There was widespread arteriolar disea e of all the parenchymatous organs (31) During an eight month period about fifteen percent of the test animals on high alt rations in the fir t and in the sit ucceeding experiments de 67 ·veloped renal failure Among those which did not there was a high incidence of elevated blood pressure In the animals which developed renal failure miassive edema occurred abruptly and sometimes was o extreme that the extracellular fluid (measured with radioactive sodium) accounted for more than one half of the total body weight At this phase the rats were severely anemic hypoproteinemic azotemic lipemic and had elevated blood pressure As I have said three rate in the first experiment lost their extra fluid and entered a state of cachexia Two rats entered this terminal state without developing edema The hearts livers kidneys and adrenal glands usually were hypertrophied The kidneys showed a diffuse degenerative disease in Folving all parenchymal elements The glomeruli were fused and almost blood less due to the accumulation of sudanophılıc lipid and the degeneration of basement membranes There was evere lipid degeneration of the tubular epithelium The arterioles underwent fatly degeneration and sclerosts (32) Blood Pressure Systolic blood pressure measurements were made by the cuff method of herston et al (33) At the end of the ninth month in the first experiment and as early as the second in later experiments reliable reproducible observations were obtained At the minth month of Experiment 1 to our immense astonish ment we found an almost perfectly linear relationship between the average blood pressure (the mean for the group) and the amount of salt in the diet (34) There is quite a bit of scattering The highest group those eating nearly ten percent of salt had a mean systolic blood pressure of about 155 but the levels ranged from about 210 down to something under 130 Three months later scattering is less and the mean blood pressure has gone up considerably in all groups In later experiments (35 38) the association of hypertension and high dietary sodium chloride was evident from the fourth month A total of 622 male and 21 female rats have been subjected to the experimental regimen with increments of NaCl as the sole variable in the purified diet The mean elevations of blood pressure were somewhat less in the female Comparable hypertension was produced seven females by feeding commercial chow with added NaCl Females eating 56 and 98 percent sodium chloride mated with normal males and delisered apparently normal young without developing ymptoms of eclampsia although the number of pregnanciee the sizes of litters and the survival of the young were unfavorably influenced In addition to the early nephrotic syndrome increa ed sodium space and elevations in systolic blood pressure (3941) there was evidence of shortened life pan (42) proportional to the les els of NaCl aduled to the purified diets Other unfavorable physiologic and nutritional threshold and lag effects were noticed (43) Serum cholesterol as measured by the method of Pearson et ol (41) 68 ·r + 54+ 12 240 220 200 180 SYSTOLIC BLOOD PRESSURE MM HG) 160 140 120 11 100L 50 1 300 100 150 200 250 350 SERUM CHOLESTEROL (MG 4) F18 3 Elevated serum cholesterol not exhibited by normoten ire rals SPECIFIC APNORMALITIES no w E A ST SEG ET AD OR IT LIT DE tis TIO LEFT ETR CUL 4 ST PROLOG RN ER L T POLE GED 160 O S DU TO 20 c PERCENT SOD UM CHLORIDE IN TEDET F & D trib tion of letroc rdiographic abnorm lities at 19 month 69 ·Tyrar WOUL DOD SWORTH 0 15% NaC1 AT 20 MONTHS BLOOD PRESSURE 122 SERUM CHOLESTEROL 178 F1g 5 Obese rat on control ration normal electrocardiogram was elevated in young as well as in middle and older aged rats In a blind analysis of 90 electrocardiograms* after nineteen months (corresponding to late middle age) on the experimental regimen the incidence of electrocardio graphıc abnormalities paralleled the degree of hypertension and the concentra tion of NaCl intake Rats eating 14 0 percent NaCl nere dead at fifteen months those on 21 0 percent at nine months Some eightly percent of the group eating 98 percent MaCl (the highest dietary lesel in this analysis) exhibited abnor malities The electrocardiographic abnormalities in these elderly rats cor related well with hypertension and cardiac hypertrophy at gutopsy Maturity Characteristics (15) In the nutritional effects as in the physiologic ne hase consideration of threshold and of lag Early growth and development were adversely affected by the increment of Naci The highest salt diete 140 and 21 0 per 10 ·cent resulted in a high mortality thre hold early in the coure of the experi ment The maximum body weight attained was related to the amount of alt in the diet (46) The mean body weight of the control group was significantly higher than the other groups (P<001) Obesity most pronounced in the control group was observed in animal at all levels up to and including 56 percent NaCl It was not seen among rats eating 70 percent or more of MCI in the diet One grossly obe e control rat neighed over 1000 grams at twenty months His electrocardiogram was within normal limits and his sy tolic blood pressure 122 mm Hg and total pum cholesterol 178 were very near the mean values of the control group The control rats continued to gain weight for seventeen months longer though not significantly than the 28 percent (fifteen months) and 56 percent (sixteen months) In the groups consuming 70 percent or more NaCl the average weight gaining period was significantly horter The mean sy tolic blood pres ure measured durin, the month in which the maximum weight wa attained was significantly MAXIMUM WEIGHT (GRAMS) BLOOD PRESSURE AT MAXIMUM WEIGHT (MM HG) воот 7170 --160 700 -150 -140 600 130 120 NaC1 IN DIET 1 1 500 1 0 110 9 10 2 3 6 7 8 Fig 6 Blood pre sure at masimum weight. higher (P<001) in all groupe eating added alt The blood pressure at maximum body weight is not synonymous with the matimum blood pressure ethibited during the hfe pan This di tinction is important in apprausing the highest levels of salt feeding as the mean maximum blood pres ures attained by these groups were well above the levels exhibited at maximum 71 ·MEAN AND STANDARD ERROR OF THE MEAN LENGTH AT DEATH (CMS) 27 T 26 0.15% TT 26% 56% IT 707 25001% 84/ 9 Oy 24 I NOCI IN DIET 11 23 0 8 9 10 2 3 4 5 6 7 Fug 7 Aserage length at death - Experiment 1 MONTHS ON DIET 10 IL 14 16 10 20 22 24 26 20 1 1 100 30 - LO 2:+56* NICI 0193 NCI (CONTROU 10 PER CENT SURVIVAL 70 . +9. NAC! 2/* nect 14N CI Fug 8 Sorvril carte 72 ·weight The average body length at death mea ured from the tip of the ne to the tail ba e at autopsy folloned the maumum weight attained pattern ie the controls were ignificantly larger than groups eating 70 percent or more of NaCI Longerity (42 43, 45, 46) Twenty one and 140 percent Mall resulted in high mortality early in the cour e of the experiment Decrea ed urvival in the group eating 7098 percent Mall was detectable from the fifth month The other level controls 28 and 56 percent present the e pecially triking feature of identical survival until the fifteenth or itteenth month of expo ure to the diet approximating late maturity or early ene cence It is noteworthy that tho e rats eating 28 and 56 percent Maci the lesels most rea onably related to human consump tion did not die at an exce sive rate until after the seventeenth month. They had been mildly to moderately hypertensive from the ninth month but only this late in life does the lag effect of increa ed dietary salt exact its penalty Considering these experiments on a time schedule adjusted to the human life pan (ten days for rat equal one year for man) benign essential hypertension appears in the third or fourth decade but only in the early fifties is the sur MEAN AND STANDARD ERROR OF THE MEAN LIFE SPAN IN MONTHS 24 23- T 22 TO 15 I 21 20 28% C 56% 30 19 H. 18 70% 98% 17 Buy A NaC1 IN DIET 001% 1 1 16 1 0 2 3 4 5 6 7 8 9 10 Fug 9 Averag adrenal weight - Experiment I 73 ·vival rate noticeably different This is remarkably similar to the pattern the naturally occurring disease follows in the human being Analysis of data on wet organ weights at death must take into account the variations in body weight and the variations in age of the rats at death Animals less than twelve months old at death were considered as young MEAN AND STANDARD ERROR OF THE MEAN ADRENAL WEIGHT (MG/KG) 2204 210F 200H 190 IBOH 170 160H 704 B4% 150 26% M 36% II O 15% 1401 INACI IN DIET 0.01% 1 1 1 7 11 8 O 1 2 3 4 5 6 9 10 Fyy 10 Average Life span - Experiment] thirteen to nineteen months as middle aged and twenty or more months as old Organ weights were expressed as weight of the organs in grams per kilogram of body weight Mean heart weight increased as the dietary salt intake increased the greate t cardiac hypertrophy being evident at the 98 140 and 210 percent NaCl levels These increments were congistent with the increa es in blood pres ure Relative heart weights in rats dying or sacrificed in youth were similar until the NaCl intake was at the 70 percent level After twenty months on the etperimental regimen the increased relative cardiac weight is apparent at the 28 percent level Renal hypertrophy fol lowed a similar pattern The relative adrenal weight changes were less consi tent The smallest relative adrenal weights Here found among the 0 15 percent NaCl control animals and the 28 percent NaCl the greatest at intakes of 70 210 percent NaCl In rats dying during the fir t year Increa ed 74 ·adrenal size was related to amount of dietary salt A conser e relationship was evidenred in tho e dying after twenty month The arteriolosclerotic lesions in the fifteen percent of the rats eating high levels of salt which deseloped the early nephrotic syndrome have been dis cus ed Among the remainder life pan was hortened hypertension developed there was a disturbance of lipid metabolism renal and heart failure occurred all in proportion to the amount of NaCl in the diet The pertrum of hyper tensive cardiova cular renal di ease seen in the human was reproduced rang ing from a clinical course resembling that of mild benign essential hyper tension with minimal shortening of life pan to rapidly progres ire and lethal malignant hypertension Arteriolar lesions (29 31 32 39 40 11) occurred in incidence extent and degree proportional to the increase in dietary sodium chloride and to the everity of the clinical course In the more advanced disease the renal arterioles were uniformly involved Stajnable lipid formed vacuoles in smooth Fox 11 Clom rular lesion tubular Is on an arteriolar DectosReproduced with pe mi son of the Ed tors of the Journal of Eperim nt ! Vedicine mu cle cells some of which were necrotic In many arterioles the ela tic lamma was greatly swollen frayed and inten ely eosinophilze The lumina Here narroned or even occluded Visceral arteriolar lesions were fairly con tant among the e animals and were almot invariably present in the heart pancreas testis and gastrointestinal tract in the less sesere forms of the 75 ·Fug 12 Arteriolar lesion in testes disease the vascular le con both renal and general visceral was less im pressive and less constant usually consisting of medial hypertrophy Potassium Chlorule (47 51) The highly reproducible significant correlations of dietary alt with systolic blood pressure elevations and hortened life span in the rat offered a sensitive measure of pota sium as an antagoni t and po sıble interrelations of dietary eodium and potassium (35) As you recall on 1813 it was postulated that the herbivores' treks to salt licks were motivated not by the lack of odium in the diet but to the Health of potassium (52) The fine report of Thompson and McQuarrie (53) in the early 1930s illustrates the hypertension governing effects of polse juni chloride added to high sodium chloride diets in salt eating children (one as much as sixty four grams daily) They tated in the ca e of one normal control subject the inge tion of fifteen grams of odium chloride every six hours cau ed an increa e in blood pressure from 115/80 to 118/100 mm lig when the gubject was on the simple relatively lon potassium diet Assen to the three diabetic children but Jule or no change when he was taking an ordinary mixed diet containing liberal aniounts of vegetables and meats Priddle (54) in 1913 advocated pota ium as a po sible therapeutic agent in hypertension Experiments bringing the dietary Na ratio toward one were initiated in 1933 Concurrent control group and added NaCl groupa comprised the 76 ·100 IDO PROTECTIVE ACTION OF KOI IN DIETS HIGH IN NOCI SURVIVAL 33 CONTROL RATS 90 90 80 80 BASIC RATION CASEIN 25 / GANE SUGAR 318% VEGETABLE FAT 20 0% MINERAL MIX 2 94 VITAMINS O 2% W LIFE 18 NO 70 701 % SURVIVAL 27% 60 60, 1 SURVIVAL 50 14 BMO 43 RATS DIET A 26 84% Naci 47% KCI NINA DE 50 VELIFE 22 5 MO 40 40 JT RATS DIETA 36 84% Naci 0 66% KCI 30 30 /ra on 20 53 CONTROL RATS 20 CONTROL A 015* NAGI 0667 KCI NG 60 %UFE - 28 NO CONTROL 11% NAGI 66% XC: Na os MONTHS ON DIET 10 10 MONTHS ON DIET O 3 70 15 20 25 30 35 40 5 15 20 25 30 Fox 13 I ft Sunris leur control rals F18 11 Right Survival curves 56 percent NaCl with and 11) out added (i Figur rriro lur with lhe permission of the editors of Annals of Intern Med cine 35 40 13 11 og 18 ·OO @00000 PROTECTIVE ACTION OF KC1 IN DIETS HIGH IN NAGI 90 80 1_SURVIVAL 70 29 601 3 RATS DIET 24 56% Naci 29* KCI NO 0. 50 7 MO 40- J7 RATS 56% NOCI 066* KC 30 ooooo N 010 53 CONTROL RATS 20 101 MONTHS ON DIET o 5 10 IS 20 25 JO 35 40 Fug 25 Survival curves 8 4 percent NaCl with and without added XC) 78 ·pilot experiment 56 percent NaCl + 29 percent AC and 84 percent NaCI + 47 percent Aci were fed to the rat The la t experiment included rations containing 98 percent NaCl and 98 percent Macl + 56 percent Kai Let us look fir t at the protection afforded survival At the 56 percent level of added salt bringing the Ma ratio toward one enabled the con sumers to outlive not only their counterparts but the concurrent control Less dramatic but still significant was the difference at the 84 percent level At 98 percent after early decimation by the nephrosts syndrome (the e animals were probably approaching the total electrolyte limit) the potassium protected rats outlived their counterpart After eight to ten months on the CONTROL A KCONTROL B RATS 8-10 MONTHS ON DIET 156% NOCI 166/EXCESS "PLUS 294KCI EXCES 84% NACI 28 56 EXCESS PLUS 47% KCI EXCESS 98% NaC1 PLUS 56%KCI -4 1-5 -2 -1 O +1 +2 +3 T +4 +5 +6 +7 +8 +9 tio -104 MEQ/KG + 10% (O 33 6) TOTAL EXCHANGEABLE SODIUM, MEQ /KG ABOVE OR BELOW CONTROL AVERAGE OF 33 6 F18 16 Total exchangeable rod um regimer measurements of total body odium by 1 olope dilution in elected rats howed some ci protection at the 84 percent and definite ACI pro tection at the 98 percent level of odium chloride Added potassium chloride had no apparent effect on the modest hyper tension of rats fed at the 56 percent Maci level Blood pres ure elevations were al o present in the groups receiving 84 and 9 8 percent odjurn chloride to which pota ium was added but these did not approach either their 79 ·3 Meneely CR Salt Am J Med 16 ) 1954 4 Smith WR Salt ancient history and religious symbolism Encyclopedia Britannica Ilth Ed 24 87 1911 Vary Press Cambridge 5 Eskew GL Salt the fifth element 1918 J G Ferguson Chicago 6 Hughes E Studies in adminitration and finance 1934 Umv Manchester Press Manchester 7 Chapman, C B Hypertension A Symposium Bell E T Editor Minnesota Press Minneapolis 1951 P 504 8 Schmidt, C Charakteristik der epidemi chen cholera gegenuber verwanderten Transsadation sanomaljeen 18 O Eine physiologi ch chemische Utersuching Leipzig and Mitau 9 Gamble IL Early history of fluid replacement therapy Pedians Il 554 1953 10 Youman JB The horns of a dilemma Am J Me! Il 133 1931 11 Youmans, J B The chromc toxicity of salt (sodium chloride) JM A State Alabama 27 161 19,7 1° Bell ET Ed Hypertension A Symposium 1951 Un Minnesota Press Minneapolis 13 Berk B N and Harmison CR Blood pressure and heart ile in agın rats J Gerontol IO 416 19 5 14 Campbell IL Sodium I lor de as an adjunct to a diet of whole wheat and wi ole milk Am J Physiol 141 310 1946 15 Dahl Land Loye, RA Hvidenc of rel tion hin between sodium (chloride) intake and human essential hypertension Arch Int Med 91 525 1934 16 Fukuda TR L hypertension par le sel chez les lapins et ses relations avec la glande varredate Unjon mel du Cana la 80 1 1931 17 Medeely (R. Relation of sodium intake to blood pressure Tran Im Coll Cardio1 4 2 8 1934 18 Meneely GR Congestive heart failure in the matie heart disease 1oxic action of salt Trang Am ( oi Cardiol 6 102 1956 19 Stein, B R and Barnes A R Severity and Joration of hypertension in relation to amount trophy Am J Med Se J6 661918 I cardiac heper 82 ·20 Allen F M and Sherrill ) W The treatment of arterial hypertension J Metabolic Research 2 429 192" 21 Kempner W Treatment of kidney disea e and hypertensive vascular disease with rice diet N Carolina M J 5 123 1941 2 Selye H., Hall C E and Rowley E M M lignant hypertension produced by treatment with desoxycort costerone acetate and sodium chloride Canad M A J 49 88 1943 23 Selye H and Stone H Role of sod um chloride in production of nephrosclerosis by steroids Proc Soc Exp Bol & Med 52 190 1943 24 Sapirsten LA Brandt WL and Drury DR Production of hypertens on in the rat by subtituting hypertonic sod um chloride for drink ng water Proc Soc Exp Biol & Med 73 87 1950 25 Mencely GR., Tucker R and Darby J Chronic sodium chloride toxicity in the albino rat I Growth on a purified diet containing va tous levels of sodium chloride J Nutrition 48 489 1952 26 Hubbell R B., Mendel L. B and Wakeman AJ A new salt mixture for the in exper ment I dit J Nutrition 14 273 1937 27 Food and Nonton Board Rec dietary allow Rev 19 3 Natl A ad Sc Natl Rese rch Council Pub 309 1953 28 Tuck RG Darby W J and Meneely CR Effect of various levels of dieta y soð um chloride on growth in the rat Proc Am Soc Clin Invest 31 77 1972 29 Mencely GR, Tucker R G. Auerbach S II and Darby WJ Renal damag in rats fed large quantities of sodium hloride Poc Am Soc Clin Invest J Clin Invest 31 670 19 30 M nery J F an 1 Bale WF The penetration of rad oact v sod am rd pho pho v into the extra and intra cellular rh s soft ssue Am J Phyo 1 132 215 1941 31 Auerbach S H Tu ker RC Darby V J and Meneely GR Renal and vascular lesions induced n rats b ah gh salt diet Fed Proc 12 384 1993 32 Mencely GR. Lemley Stone J. Tuck R G. Blake T M. Auerbach S H. Darby J and Goodpa tore E. V Chronic sodium chloride to ity the arterioloscl rota I non Pror Am Soe StodyArt rio Crrelation l481 19 ) 33 Kerst n 11. Brosene v G, Jr., Ablon F and Subbarow Y A new method r the ndirect measurement of blo d pressure in the rat. J Lab Ci n Med 3 1090 1917 34 BIICOT Tucker R G., Darby VJ and Men ly GR Ch on es dium chlorid toe by Variation and correlation within gopps of rats eating ad led salt Proc Am Pby: ol Soc. Am J Physiol 1 9 616, 1954 35 Ball corn! Mencels GR Obser t ons on d tary solum cllo de J im Deteu A soc 33 366 1937 83 ·36 Meneely GR., Auerbach S H., Ball C0T Darby # )., Early WR Iem ley Stone J and Toumans J B Chronic sodium chloride toxicity Long term cardiovasplar and biochemical changes in 488 rats and 21 Jitter mate male beagles Scien Exbibit Proc Am Heart Assoc 29th Ann Scien Seestons P 137 1956 37 Menecls CR Ball COT Darby J Early VR Shapiro J L. Lemley Stone J., Tucher RG and Younans B Salt life span studies of the chronic effects of sodium chloride in the diet of mammalıt Scien Exbubit, Am Coll Cardiol Washington May 1957 38 Meneely GR. Tucker RG Darby w . hory RC Ball COT and Auerbach S U Toxic effects of 10creased sodium chloride Summary of 12 years observations on albino rat 2nd World Congr Cardiol Washington Abs P 531 1934 39 Meneely G R Tucker R G., Darby W J and Auerbach S H Hypertensjon edema and renal failure prodaced in the rat by high salt diet Proc Im Phytol Soc Am J Physol 171 750 1932 40 Dienteely G R Tocker R 6 Darby w j. and Auerbach S H Chronic sodium chloride toxicity in the albino rat II Occurrence of hypertension and a syn Irome of edema and renal failure J Exper Med 98 71 1973 41 Mencely C R. Tucker R G. Darby w j and Auerbach S II Chronic sodium chloride toxicity Hypertension renal and vascular lesione Ann Int Med 39 991 1953 4" Tucker R G. Darby W J Auerbach, S H Ball COT and Meneely GR Effect of dietary NaCl on the longevity of the albino rat XIX Internat i hysiol Copgr Montreal Abs P 838 1933 43 Meneely GR. Tucker R G., Darby W J Ball, C O T., kory RC and AurbacbSH Electrocardiographic changes disturbed loped metabolion and decreased survival rates in rats chronically eating increased sodium chloride I'roe South Soc Clin Re: Am J Mel 16 599 1991 41 Pearson S., tern and McGavock TNI A rapid procedure for the determination of seruin cholesterol J Clin Endocrinol Metab 12 1215 1952 45 Torker R C., Ball CO T. Darby w J, hory RC Youmans J B xod Neneely GR Chron e sodium chloride foricity in the albino rat III Vasurity characteristica survivorship and organ weights J Gerontol 12 189 1997 46 Tucher R G. Darby J and Mencels GR Effect of dietary NaCl on ultimale nze blood pressure an organ weight of rat Fed Proc 13 480 19,4 47 Lemley Stone J, Darby * J and Mencely GR Body sodium and potassium in rato recensing anereste i dietary sodium chloride Fed Proc 16 78 1956 18 Veneely CR, Ball C. O T., Darby J, Lemle Stone J., Tucker R G. an Youmany J B Cladded to diets containing fotic lerels of NaCl hypertension an ) survival Proe, South Soc CIA Res. Am J Med. 2 969 19,7 84 ·49 Mene ly CR Ball COT and Youmans JB Chronic sodium chloride toxicity The protective effect of added potass um cbloride Ann Int Med 47 263 1937 50 Meneely GR Darby W J., Lemley Stone J Tucker RG and Ball COT Survival of rats prolonged by adding potassium chlor de to diets conta o ng toxic levels of sodium chloride Proc Am Phye ol Soc Am J Phys ol 187 617 1936 51 Meneely GR., Darby WJ Lemley Stone I Tucker R G Ball COT and Youmans JB Chronic sodrum chlorde to vicity The protective eff et of ad led potassium chlor de Proc Im Soc Study Arterio Circulation 14 501 1956 52 Bunge, C Physilogische Ch me 3rd Ed 1896 Verlag von F CW Vogel Leipzig 53 Thompson, WH and McQuarrie I Effects of various salts on carbohydrate metabolism an1 blood pres ure in dia betic children Proc Soc Exp Bol & Med 31 907 1933 34 54 Pr ddle WW Obse at ons on the management of hypertension C nad MAJ 25 5 1932 55 Tobian L Jr T188ue cations and water in arte al hypertension Circulation 5 754 1952 56 kaunitz, H Relation of chloride sod m and pota s um intahe to renal and adr n loze Lab Invet 132 1956 DISCUSSION DR HEVRY A SCHROEDER I would like to bring out everal important points First Dr Merrill would like to know the level of sodium and pota sium in the plasma on the e high alt diets Your control chole terol values 130 140 are quite high for the rat in our experience and I wonder what method you used We find them u ually around 100 or less Secondly are not the e lesions merely the nonspecific hypertensive vascular le ions you ee in any form of hypertension? The third point is that I think it hazardou to imply in any way a relation hip between these mot unphy hological experiments and the situation in man Many mea urements have been made on normal diet and urine and we believe five to eight grams per day is a normal intake of odium chloride The measured intake in Japanese is ten grams which is less than the equiva lent of the 28 percent level in your fat etperiments and only a little more than in the American dret There i no evidence measurement wi e that Japane e take larger amounts According to ome old experiment eighteen grams per liter is the mo t a young adult apparently can concentrate in terms of odium chloride Perhaps children can concentrate higher amounts older people concentrate lees In Michigan ome years ago Dr Richard Lyons 85 ·even used thirty grams in young adults and got edema high senous pre sure dyspnea and in some signs of cardiomegaly and pulmonary congestion whereas dogs can concentrate to levels many times higher So I think we do not eat as much salt as is thought by Dr Meneely, probably only four five or six grams If you pour salt from a shaker into a spoon in tead of on food you realize a gram goes a long way in seasoning food DR E D FREIS Some arterioles in the hi tological sectons look like hypertensive changes and some like periarteritis nodosa Selye produced periarteritis nodosa in rats Did you see such lesions? Did you mea ure plasma volume or blood volume in any of these sats on high sodium diets? DR SIMON RODBARD In the experimental series that we reported yesterday we also fed cholesterol to some of the animals on a high salt diet Our results show the addition of salt alone to animals on a normal mash diet changes neither the plasma cholesterol nor the tendency to atherosclerosis in the aorta or in the coronary ves els However addition of salt to the diet of animals receiving cholesterol definitely intensifies the lesions in the e ve el though the plasma cholesterol level unaffected I might also add that saw no changes in the kidney comparable to those reported by Dr Meneely Perhaps this is due to pecies difierence DR SIDVEY FRIEDMAN We find that of odrum is added to the diet in the absence of potasium the animal becomes severely hypotensee In other words odium becomes a hypotensive agent in the complete ab ence of potassium in the diet As Dr Perera suggested rigid restriction of potassium in the diet of essential hypertensive patients produces a moderate reduction in their blood pressure DR GEORCE A PERERA About one quarter of that in the normal diet DR ARTHUR M FISJIBERC I would like to a k Dr Meneely of the hyper cholesterolemia in his experiments always accompanied hypoalbuminemia A great deal of evidence has been brought out here about the role of increased sodium intake in the production of high blood pressure But in treating human hypertensive patients on the ward one often obaerves that during heart failure they develop hyponatremia and nevertheless the hypertension persists at maximum levels A patient may have a erum sodium of 210 215 millequivalents for weeks with the blood pre ure still at 200/120 Thus requires reconcilation with the conception of the relation of codium retention to hypertension DR GEORCE R MENEELY I feel like one of the chola tice of the Middle Ages I think we have rai ed more ghosts than we have laid I do not under tand many of our findings Our rats were given certain levels of sodium chloride they cho - to take cercain amount of Nurd and then certain things happened The erperiment is obviou ly too vast ever to complete the analysis Therefore we can only regard it as a report of what happens in rats given this particular diet 86 ·Obviously our animals were whole animals — they had all their parts The classic example of the extirpation type of experiment concerns the man who said to a flea Jump flea jump The flea jumped and he noted down that the flea can hear commands Aiter pulling the flea , legs off he yelled Jump and the flea did not jump He then put down Removal of legs from fleas makes them deaf Dr Friedman we have never seen the blood pres ure drift down in high salt eating animals — it always drifts up That the e rats wait eventeen months to manifest their difference from the controls suggests that whatever is going on is a slow process Dr Schroeder the blood levels of odium and potassium are essentially normal We do have some rather detailed analy es of organ sodium and potassium The method of cholesterol level determination is that of Pearson and associates This tandard rat diet 13 high in fat and our rats get more calories from fat than we wish I am sure the vascular le ions are nonspecific I do not think there is periarteritis We have not seen cellular infiltrate around the small arteries These experiments may be unphysiological They are of course on rats I know nothing about man Adequate figures for human intake of salt are some of the most needed and least known Mly Japane e figure up to thirty grams of salt was pure hearsay It is e sential to find out how much salt people are eating Our odium space findings are complicated In waterlogged nephrotic rats odium spaces ranged up to fifty or ixty percent of body weight with non edematous high salt rats having larger sodium spaces than controls As hfe goes on the control sodium paces go down somewhat while the others stay about the same Meanwhile the non salt eating rats become obese This may account for the differences Venous pres ure goes up in rats that develop heart failure Dr Rodbard I am very interested to hear about the salt and cholesterol effects Our dogs are not becoming hypertensive but they are showing changes in cholesterol With regard to the coincidence of hypoalbuminemia and hyper cholesterolemia that is seen in the edematous rats *Pea son Stern S and MrGauach Th Ar pd poceda e for the dete m nation of serum cholesterol J Clin Endoer nol Metab 19 1245 1952 ·REPORT OF THE COMMITTEC ON INSTRUMENTAL TECHNIQUES DR V F HAMILTON (Chairman) DR 11 D GREEN DR ERIC OGDEN Criteria for the auscultatory measure oj arterial pressure In the last report of the American Heart Association Blood Pressure Com mittee (Circulation 5 503 1951) it was suggested that the cufl pressure at which sound was first heard as the pre sure within the cuff was reduced be read as the systolic arterial pressure in the appendıx it was noted that the conclusion arrived at by four teams of workers after more than 100 comparisons with direct manometry is that the estimate of sy tolic pre sure thus determined was too low by about three mm Hg This correction was not made in the com mittee recommendations and has not been discussed insofar as we are aware in the recent literature The criterion suggested for the measurement of diastolic pressure however has received criticism because if for no other reason it has broken with tradition The report cited above advises that the diastolic reading be recorded at the pressure level in the cuff where all sound stops as the pressure is grad ually lowered This is about 8 mm Hg below where sound mulles or fades and I found on comparison to be within a millimeter or two on the average of the true diastolic pressure It is carefully pointed out that under hemodynamic conditions in which no cessation of sounds occurs the level of mulling hould be recorded as a que tionable diastolic reading This recommendation has been criticised as being unnecesarily complex and resulting in confusion in clinical reports in which the older (mufling) and the suggested criteria are not clearly distinguished It cems doubtful to the committee that any serious harm will be wrought by the effort for greater accuracy indicated by the report Hemodynamıc conditions (anemia hyperthyroidism aortic regurgitation) in which cessation of sound does not occur offer many other diagnostic signs than the auscultatory one On the other hand the true level of diastolic pressure in hypertension Is both uniquely important and more accurately measured by the cessation rather than by the muffling of sound Until contradiction of data supporting thus report is available and/or a theoretical basis is found for under tanding the mechanism by which the horotkoff sounds are produced it is suggested that the blood pressure pamphlet remain unrevised Blood Pressure Morms It was suggested that your committee concern it ell with blood pre ure norms and minimal hypertenerse levels The competence of the committee does not extend to cover the broad tatı fical and clinical insight needed to cover thi« que tion adequately 88 ·Technical difficulties and ambiguities hould be in mind when comparisons are made with published or intuitively established norms Thus on new born infants agreement with directly mea ured umbilical systolic pre ure is to be had by palpation only when the arm cuff is 25 cm wide The conventional pediatrician s cuff gives figures 20 25 mm Hg too low Unfortunately the published figures were obtained mostly with too wide a cuff and therefore are too low The opposite is true when cuff pressures are taken with standard arm rufts in obese persons with large arms or in the thigh It is best to look skeptically at cuff figures obtained on people with unusually large or small arms The former are probably too high the latter too low Ballistorurdiography This is a subject that is presently being con dered by another committee of the American Heart Association Fenous occlusion plethysmography is a technique which has been accepted Intuitively because it seems reasonable The history of physiological method ology confronts us with many programs which defaulted as soon as adequate Examination of methodology was made Much time has been given to getting and interpreting results by the venous occlusion method it is highly desirable that this method be compared with other directly calibrated methods Skin temperature can be an inder to blood flow only if environmental con ditions such as humidity air motion air temperature and other factors can be thoroughly known and interpreted The evaluation of the method again can come only from careful comparative experiments with a calibrated method for measuring blood flow Errors which might stultify the re ults obtained by the injection method for measuring blood flow through the lungs and other areas or by the Fick procedure must receive careful attention in the present rapidly changing of knowledge in this field Intrarascular manometry The u e of a catheter or other flexible connection between a pressure trans ducer and the cavity who e infernal pre sure is to be mea ured 13 at best a make hift It is usually difficult and often impossible to place a catheter so that is intracardiac motion will not introduce pres ure changes of inertial origin which cannot be damped out without tultifying the record Certing a good intracardiac record of pre sute is a matter of good luck rather than good management with present equipment Telling a good record from a bad one 14 a problem that requires con iderable in ight and for which a rule of thumb 19 not at present available It rems that we are awaiting the marketing of one of the everal propo ed tran ducers that ran be made independent of all hydraulic columns by having its electrical parts on the end of the catheter Hazards involved in this approach among others are that the tran ducer may werk loose and come off inside whether this hazard 1 greater than that of having a knot form 89 ·in an ordinary catheter is questionable It may be hard to establish a stable known zero with certain models of intracardiac transducers but a recently developed model overcomes this difficulty by allowing simultaneous external registration of mean pressure through the lumen of the gauge The agreement of investigators as to the hydrostatic level to which pressures should be referred is a goal to be sought A good case can be made for the hydrostatic level that is basic to the function or role of the pressure concerned Thus pressures in the renous system which bll the right ventricle should be considered in relation to the height of the night ventricle or the apex beat and pressures whose role 19 to distend and cause filtration in the capillary bed should be considered in relation to the mean height of the capillaries themselves However the investigator refers his pressures both he and the edstors of Journals hould be urged to see to it that the frame of reference hould be explıcıtly stated so that another inse tigator may calculate his results to a comparable frame of reference Thus when venous pressures are under con sideration a figure of say 10 cm H O is quite meaningless Additional data hould be given I) landmark for zero 2) the position of the animal or sub Ject (prone supine or lateral) and 3) the dimensions of the chest It hould al o be realized that in practically all atuations including cal culating real tance to flow the arterio venous pressure difference 19 im portant while arterial pressure alone may be meangingless In studying factors which produce congestion and capillary filtration transmural pressure 19 important and may in the pre ence of appreciable ambient pressures be quite different from intraluminal pre cures The low ambient pressure in the thorax and the high ambient pressure during the contraction of the walls of the uterus or of the abdomen hould be pecified where relevant REPORT OF COMBUTTEE ON CHEMOTHERAPY IN HYPERTENSION DRY VE\DLOWITZ (Chairman) DRJ BORDLEY JII DR SW ITOOBLER DR E D FREIS DR C TUOVAS The purpo e of this report 13 to indicate the present tatus of chemotherapy for hypertension with the full realization that the field 19 controver ial and still developing No statement as to indications for do age or value of any therapeutic agent is therefore meant to be dogmatic or final Antihyperten ive treatment with drugs 19 often used in a wide spectrum of hypertensive disea e The chief objective of such treatment is the prevention of subsequent structural vascular di case with consequent organ impairment chielly in the brain the eyes the heart or the kidneys A secondary objective is the amelioration of such symptoms as may properly be attributed to the hyperten ion especially various grades of hypertensive encephalopathy and of left ventricular failure 90 ·There is considerable agreement concerning contra indications to drug therapy but a wide divergence of opinion as to indications Uremia with severe nitrogen retention is generally con idered to be a contra indication to treatment with mild nitrogen retention antihypertensive treatment may improve renal function in some cases but this hould be carefully followed with daily blood urea nitrogen determinations There are erceptions to this blanket rule especially if the blood urea nitrogen be elevated on the basis of an intercurrent reversible proces uch as pyelonephritis loner nephron nephrosis or congestive heart failure Hypertension in the aged is usually con sidered not to be amenable to aggre sive treatment although again this is true only of the hypertension is largely systolic and hence on an arterio clerotic basis Some elderly patients in whom it can be demonstrated that the hypertension is neurogenic or with evident vascular acceleration may be treated Hyperten sion secondary to renal and vascular diseases such as acute and chronic glo merulonephritis amyloid contracted kidneys polycy tic kidneys lupus ery thematosus periarteritis nodo a diabetes mellitus Goldblatt kidney coarcta tion of the aorta etc are ordinarily not considered amenable to antihyper tensive treatment There are many exceptions to this rule however and each case therefore deserves evaluation If the hypertension is excessive therapeutic trial 13 justified Acute coronary occlusion or acute cerebrovascular accident are generally contraindications whereas residuals of the e events are not necessarily contraindications to antihypertensive treatment Angina pectoris may be im proved or made worse by treatment and each case must be evaluated separately There is some agreement as to indications for treatment but also large areas of dr cord Most observers are agreed that the accelerated form or the so called malignant pha e of es ential hypertension must be treated vigorously nearly all workers also favor vigorous treatment of hypertensive crises or encephalo pathy e pecially if relatosely uncomplicated by urema There is a wide drier gence of opinion however as to whether uncomplicated e ential or primary hypertension hould be treated at any age There are some who believe that since such people may be asymptomatic for many years and never develop accelerated hypertension they hould not be ubjected to the hazard expense and dis comfort of treatment whereas others believe that all hyperten ion accelerates vascular disease and that early treatment is therefore important Most workers in the field are agreed that except where treatment hould be prompt and vigorou as in malignant hypertension some form of rauwolfia derivative is the drug of choice with which to begin antihyperten use treatment The results are generally better with reference to the hyperten son than if a more general sedatne uch as phenobarbital 19 v ed There is little difference between the various forms of rauwolfia drug provided the do age is tandard ized and adjusted in each case The ugge ted initial do e of re erpinte for example is 025 mg three times daily Doses greater than this are not of additional value and increa e the side actions whereg maller do es (01 to 020 mg once daily) often can be employed for maintenance of effect If the 91 ·rauwolfia drugs are not effectile in any given case they should be withdrawn but effective reductions in blood pressure can be achieved with rauwolfia alone in many cases of hypertension Side actions of the rauwolfia drugs consist of occasional diarrher and nau ea nasal tufiness blurring of vi ion fluid reten tion with edema un teady gazt a tendency toward frightening dreams and mot important depressive pay chosia The latter reaction which may be preceded by agulation and insomnia is often a late eftect following four months to three years or more of rauwolfia therapy It is always a contraindication to continuing therapy The other symptoms can be met by dosage adjustments and in the case of nasal obstruction by supplementation with ante histaminic drugs and vasocon tricire no e drops Occasionally peptic ulcer is produced or activated by rauwolfia drugs and this may be manifested by pain or by a tarry stool or hematenesis In uch cases the drug should ordinarily be discontinued Epile py is considered a contraindication to rauwolfia on theoretical grounds but clinical evidence of its harmfulness ly as yet incomplete Veratrum derivatives may be used to supplement rauwolfia on occasion but have been found by many observers not to be very useful for this purpo e If there is tachycardia and a contraindication to rauwolfia veratrum is useful as a substitute It has the disadvantage of the rapid development of tolerance and of the «de actions of nau ea and vomiting which often appear clo e to the therapeutic do e level As a prototype the oral do e of protoveratrine A and B 19 04 mg spaced six hours apart with the added precaution that no food be ingested for four hours after any single do e Dosage may be increased gradu ally until there is either a satisfactory reduction of blood pressure or the appearance of nausea and vomiting Hydralazine is a useful supplement to rauwolha and may also be given independently There are many side actions of the drug including headache nau ea vomiting drug fever ra h and Nud retention The most serious side action is a lupus erythemato us like reaction with arthropathy kin eruption feser and a poutie L E. cell te Thıs 19 less commonly seen if a dosage of 400 mg daily is not exceeded and rarely occurs on a dose of 200 m, daily or less Many de actions can be avoided if the do age begins at 10 mg three times a day and is thereafter gradually increased and if rauwolfia is admını tered for qeveral weeks prior to the exhibition of hydralazine Angina pectoris is a con traindication to the u e of hy dralazine and tachycardia and even angina itself may be induced by the drug in ome cases The ganghon blocking druge may also be u ed independently or in combina tion with other drugs There eems to be little choice between the sarıous prepar atrons mecamylamine chlorı ondamine or pentolinjum Mecamylamine has the adiantage of complete ab orption after oral adminitration but the disadvantage of prominent aide effecta due to parasympathetic blockade Do age of these drugs should begin quite low and be gradually incres ad The initial twice daily do e of mecamylamine is 25 mg of pentolinium 20 mg and of chlos isondamine 25 mg with gradual increa e in amount and/or frequency until 92 ·an adequate effect is achieved or until intolerable side actions preclude further increase Coarse tremor and psychosis have been side effects of very large doses of mecamylamine given to patients already in uremia or with cerebrovascular disease Successful use of the ganglion blocking agents requires detailed knowledge and pecial effort Dosage must be titrated to the individual requirements of each patient Some physicians prefer to use home blood pressures in the standing position for this purpose since office blood pressures are often falsely high whereas others do not favor home blood pre surpy because of the anxiety they create and the inconvenience involved If office blood pressures are used it 18 better that they be taken by the office assistant or nur e both in the erect and in the supine positions If it is suspected that they are falsely high the attempt to reduce the erect blond pressure to completely normotensive levels need not be pressed The complaint of dizziness or faintne s on standing relieved by recumbenry 19 usually a good indication that dosage should be reduced regardless of the recorded office blood pressure This symptom however must ometimes be distinguished from the dizziness produced by the hypertension or by labyrın thune di ease Dosage may require adjustment because of increa ed reactivity to the drug which is induced by hot weather the ingestion of alcohol or by acute salt loss The physician needs to be familiar with the common side effects of sympa thetic blockade such as postural syncope or faintness chilling in a cold environ ment increased susceptibility to heat stroke and of parasympathetic blockade such as dry mouth di turbance in visual accommodation gastrointe tinal atony impotence and difficulty in emptying the urinary bladder A rare pecular type of interstitial pneumonia has been attributed by some workers to hexamethonium whereas others believe this to be uremic pneumonitis not related to the ad ministration of the drug Many of the e side effects do not occur with careful dosage regulation and when they do occur they are often transient Some of the side effects can be circumvented by the use of parasympathomimetic agents such as pilocarpine and neostigmine Cathartics and enemata are almost always necessary to combat the constipation often seen In fact constipation is so common that catharties are usually given with the initiation of treatment The degree of success achieved with the ganglion blocking agents depends in large measure on the kill and patience of the physician and the intelligence and fortitude of the patient Other drugs which are often used in the management of hypertension are the barbiturates and the tranquilizers including thorazine meprobamate and their derivatives They are useful for allaying anxiety e pecially if there is a contraindication to rauwolfia but produce little if any lowering of blood pressure per se Mercurial and other diuretics are u elul upplements to the low sodium diet especially for the treatment as well as the prevention of left ventricular failure 93 ·and any of the drugs discu sed in this report may be used in conjunction with the 200 mg low sodium diet provided the blood urea nitrogen concentration is checked frequently and the silent des elopment of renal insufficiency is avoided A recent development has been the discovery that chlorothiazide a diuretic and potent saluretic agent will reduce blood pressure in hypertensive but apparently not in normotensive indıviduals Experience with this drug is still too limited to nake definitive claims for it The drug will however potentiate the action of ganglion blocking agents One half gram on arising and at bedtime is the ordinary maintenance dose Although chlorothiazide appears to have promise the possibility of sodium chloride or potassium depletion or pro gressive azotemia must be kept in mind In addition enough time has not elapsed to judge the effects of this agent in the treatment of hypertension or to be certain of the absence of long term foric effects Hypertensive encephalopathy requires special treatment with drugs whether it occurs in pregnancy as eclampsia or in the patient with advanced hyperten ion There is ome que tion in eclampsia whether uch treatment increa es fetal mortality Antihypertensive therapy is usually begun at once especially if the blood urea nitrogen level is below 60 Since there is often psychic obfu cation barbiturates are contraindicated Because vomiting is common drugs should ordinarily be given dissolved in five percent glucose and water solution by in travenous drip Those most commonly used for this purpose are protoveratrone and trimethaphan (Arfonado) An alternative procedure of continuous measure ment of blood pressure is impractical is to gne five mg of reserpine intra muscularly When the ensorium has become clear and vomiting has stopped transition to oral treatment may be effected During drug infusion blond pres ure hould be brought down to no lower than 170/90 by adju ting the do e of the drug and the rate of infusion The committee wishes to emphasize that no two cases of hypertension are alike and that therapy must be considered an individual etperiment in each case Thorough clinical evaluation before treatment is mandatory especially in the «cvere ca es It hould al o be remembered that the u e of drugs 19 only one a pect of the total treatment of hypertension REPORT OR COMMITTEE ON SURGICAL TREATMENT OF HYPERTENSION DR EDWARD FREIS Chairman DR WILLIAV COLDRING DR LEITII CRIVISOS The urgical treatment of hyperten son includes procedures aimed at eradica tion of primarı etiologic proce es uch a (1) untiateral renal di ea e circu latory i chemia or hypopla 1a (2) adrenal hyperfunction due to cortical adenoma carcinoma or hyperpla ia (3) pheochromocy toma and (4) coarcta tion of the aorta In the e conditions urgical intersention indicated providing 91 ·the patient s general condition permits and the damage has not become so far advanced as to preclude successful results of such intervention There is marked variability of opinion concerning the value of sympathectomy in hypertension However most of the long term follow up reports in the literature suggest some prolongation of life The difficulty in a truly definitive evaluation of reports is the lack of adequate control series followed concom itantly with the treated series Comparison of surgical results with various series treated medically by other individuals in different locations and at other times always is open to some question The ability to select favorable from unfavorable ponders prior to surgery is the main problem Sympathectomy probably 13 be t indicated for patients under the age of fifty to fifty five who exhibit evidence of acceleration but without marked renal impairment (phenol sulphenphthalein excretion greater than fifteen percent in fifteen minutes and no azotemia) The operation definitely is not indicated for patients with nitrogen retention They have not tolerated surgery well and those who survive the postoperative period rarely have shown evidence of retrogression of their di ea e Patients with a slowly progressive hypertension could have sympathectomy as an elective procedure It is the prevailing opinion that an adequate trial of antı hypertensive drug therapy including the use of ganglionic blocking agents hould be undertaken prior to advising surgery However if the trial is unsuccessful in controlling blood pres ure levels or in arresting the progress of the di ea e as hown by failure of clearing of hemorrhages exudates or papilledema in the optic fundi episodes of hypertensive encephalopathy or increasing cardiomegaly and albuminuria sympathectomy may be recommended Some authorities believe that if a patient does not respond to blocking agents he also will not re pond to sympathectomy Others believe that this is not always the ca e and also that there are patients who do not cooperate well enough for a long term medical program to be effective The mot practical type and extent of sympathectomy will vary with the training and experience of the surgeon and the everity of the di ea e Splanchnicectomy includes removal of the lower thoracic and the upper or all lumbar ganglia with the planchnie neries and with or without removal of the celiac ganglia Total sympathectomy includes this and al o removal of the stellate and upper thoracic ganglia to denervate the cardiopulmonary area and the upper body This produces slowing of the heart rate Vasocon tractor path ways through the econd and third lumbar ganglia usually are not removed The purpose is to avoid incapacitating postural hypoten von As determined by sweat and kin resistance tests ome return of ympathetic nervous activity occure a year or more after operation Removal of intermediate ganglia uch as the illac and the tellate minimizes functional regeneration In general the more extensise the ympathectomy the more likely it is that there will be a la ling and significant reduchon in blood pre ure However the length of the period of po toperative di ghality and the occurrence of 93 ·complications of surgery also may be increased in proportion to the ettent of sympathectomy This increased risk and disability may be justified in rapidly advancing or in chronic and intractable cases Total adrenalectomy for hypertension has not been sufficiently well evaluated to warrant use other than as an experimental procedure It has not yet been proved that survival is any greater The same may be said for the combined procedures of sympathectomy and total or partial adrenalectomy The evidence available indicates that these procedures also have been unsuccessful in the presence of marked renal impairment The principal disadvantage of sympathectomy is the inability to select with any assurance the patients who will achieve long term reduction of blood pressure However postural hypotension and relief of symptoms is more frequent than reduction of supine pressure Since the advent of more effective antihypertensive agents the numbe of sympathectomies done in most medical centers has decreased markedly One advantage of the surgical approach however is that it does not require meticulous and îndefinitely protracted medical management such as is required with either dietotherapy or treatment with most antıhypertensive agents Whatever lasting protection is achieved by sympathectomy is not entirely dependent on the patients will to cooperate the protection obtained with a medical regimen lasts only as long as the patient desires to continue his treatment There is also some evidence to suggest that after ympathectomy the patients blood pressure may become more re ponsive to the various forms of medical treatment A few authorities do not believe that mere reduction of blood pressure erther by sympathectomy or by the use of antihypertensive drugs has been proved to be of any real value either in preventing complications or prolonging life Since long term tatistically definitive controlled studies are lacking it 18 im possible to settle this issue one way or the other Nevertheless the majority opinion of this council 13 that hypertension accelerates vascular changes and that as a rule reduction of blood pressure promotes increased longevity Thus if a patient is a candidate for sympathectomy if he fails to respond to antihypertensie drug therapy or will not tolerate a long term medical regimen and if he is willing to accept surgery for its po gible benefit sym Pathectomy may be advised REPORT OF COMMITTEE ON CPIDEMIOLOGY OT HYPERTENSION DR KENNETH KOHLSTAEDT, Chairman DR ANTHUR FISIBERG DR LFUN WATERS DR ARTIIUR MERRIIL DR EDWARD WEISS The application of epidemiological methods to the study of hypertension offers an opportunity to obtain information that will be u eful in eatabli hing the cause of primary diastolic hypertengion and thereby aid in eliminating this 96 ·di order Studies hould not be undertaken without guidance of persons trained in epidemiology In considering areas for future inte tigation this committee propo es that the factors be divided into three categories on the basis of need for information and practicability of study 1 In the fir t group are a number of problems which in our opinion have already received adequate con ideration and concerning which it is doubtful that additional tudies would be of value Race-It is well known that hypertension is frequent and often severe in the Negro It is difficult to separate race from heredity and environment in the course of an epidemiological study It is likely that in the future racial back ground will become less important Obesity-In the past being overweight has been considered a cause per se of high blood pressure The committee wishes to point out that errors in measuring arterial pressure by the auscultatory method on the very large upper arm of obese persons may have been responsible for the establishment of this concept The reduction in blood pressure attributed to lo s of weight mav actually have been due to improved accuracy in recording pressure when the circumference of the arm was decreased The fale correlation of obesity and hypetension can be eliminated by wrapping the cuff of the sphygmomanometer around the forearm and pstimating the tolic pre sure by palpating pulsation of the radial artery as pressure within the cuff is decrea ed Body build and height and use of alcohol or tobacco - In the opinion of the committee there is sufficient evidence to justify the conclusion that none of these are concerned in the genesis of primary diastolic hypertension Food--At the present time there is no evidence that food it elf is a factor in elevated arterial pres ure There is no basis in fact for the once popular belief that red meat was harmful to persons with hypertension Thysical erercise-Moderate physical exerci e is not considered harmful for patients with primary diastolic hypertension The committee does not be lieve that investigation of physical activity de erves further consideration in an epidemiological studs 2 The econd category 13 compo ed of factors that may be important but which hould be difficult to study The effect of agen-Although evidence has hown that there is a difference between blood pres ure in children and in adults and that there is a tendency for arterial pre ure (e pecially systolic pressure) increa ( a the individual grow older a tudy of age in relation to the development of primary dia tolic hyperten un would require numerous longitudinal tudies (observations et tending rer a prolonged period) This form of investigation 19 very co thy The committee believes that ob ervations made by Hamilton Pickering Rob erts and Sowry (Clin Sc 13 37 1931) indicate the problems to be expected in obtaining information regarding the relation hip between age and blood pre ure The data presented by the e investigators do not warrant the con 97 ·clusion that primary diastolic hypertension may be a phenomenon of aging rather than of diaease The relationship between age and blood pressure is ad mittedly a very complex problem that would be difficult to study by epidem hological methods The role of emotional stress-A personality pattern characteristic of primary diastolic hypertension has not been defined There is insufficient evidence to support the concept that emotional stress cau es hypertension A study of the role of emotions in the elevation of blood pressure would be a formidable undertaking Normotensive controls would be needed Ade quate tests for emotional factors are not known and even if they were it is doubtful if a ufficient number of trained persons would be available to con duct them 3 In a third category the committee considered the factors that are believed to be important in the genesis of hypertension and that should recere priority Heredity and environment deserve the immediate attention of investigators The measurement of blood pressure in relatives of patients with primary di astolic hypertension can be done without great expen e and of properly my ecuted a great deal of useful information could be obtained in a short time Another worth while study would be the recording of blood pre sure in a large number of twins Measurement of blood pressure in large populations al o might shed light on the relation of sex to the pathogenesis of hypertension A tudy of environmental factors would be more difficult than problema re lated to heredity An epidemiological investigation of carefully controller could be of great value in elucidating the effect of environment on the oc currence of hypertension At this time the role of odium as an environ mental factor in the genesis of primary diastolic hypertension is of paramount importance Although epidemiological tudies of the dietary habits of a pop ulation are difficult a thorough inve ligation of the relation of both the o dium and pota sium content of food and water to the incidence of high blood pressure and va cular damage would provide a great deal of u eful informa tion It is the opinion of the committee that the evaluation of tests for hyperrero truity of the vasomotor ay tem could be the subject of study There are no ah factory ones available at the pre ent time The committee hopes in ve tigators will give attention to this problems Time did not permit a full di cu ton and review of this report at the November 1937 meeting of the Medical Advisory Council It hoped the epidemiology of hyperten ion may receive further consideration at future meeting The committee wi hea to thank Dr John W Ferrer Associate Medical Director of the American Heart Asociation for hie help in provadong info mation 98

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LNGFAY FOR HYPERTENSION AND RELATED ( ARDIOVASCULAR
DISEASES Keith S Crimson MD
THE WAY TO A MAN HEART George A Perera ID
105
Tue 1 SEFUI VESS OF Drucs IY THE TREATMENT OF
HIT PERTENSION Harriet i Dustan ND
107
COINCIL FOR HIGH BLOOD PRI STRE RESEARCH
MENICA HEART ASSOCIATION NOVEMDER 1997

·SURGERY FOR HYPERTENSION AND RELATED CARDIOVASCULAR DISEASES KEITH S GRIMSON, MD Department of Surgery Duhe Untersity School of Medicine Durham, NC The earliest form of surgery for high blood pressure was a limited sym pathectomy - splanchnicectomy The sympathetic nerves activate or regulate the blood ves els and blood flow throughout the body The splanchnic branches in particular supply the abdominal viscera Splanchnicectomy had been first theoretically considered by French physici ins It had then been per formed in this country by Adson Peet and other surgeons between 1930 and 1935 Surgical research on high blood pressure and interest in the sym pathetic nervous system was in part a logical outgrowth of studies on low blood pressure or shock stimulated by the high mortality rate among the wounded between 1914 and 1918 Cardiovascular dtscoveries and their ap plication to clinical problem have continued steadily until now cardio vascular surgery is almost a pecialty In general there are two types of surgical approach to hypertension One is the removal of nerves organs or glands whose normal function is detrı mental to a hypertensive patient The other attempts repair or replacement of diseased or worn out structures of the body All operations are ba ed upon knowledge of structure and function of the body and of the merhanisms cau ing high blood pressure The cause of hypertension is differently emphasized by the followers of two classical schools of thought One began here in Cleveland in 1933 when Dr Harry Goldblatt demonstrated that partial obstruction of the arteries to the kidneys cau ed hypertension in dogs Dr Irvine Page carried on some experiments to demonstrate that the culprit was angiotonio a substance released into the blood stream by the obstructed kidney Surgically this conrept has led through various research steps to clinical application in the occa ional cure of hypertension by the removal of one di eased kidney Within the lat two years several groups have used v rays of the arteries to the kidney to lemonstrate small points of obstruction and have repaired the defect or have removed one kidney Re_ults are not always encouraging Why not remove both kidneys for patients with renal hypertension? Fır i the patient would pot live long Second Dr Arthur Grollman and others have shown that an insufficiency of kidney tis ue can al o cause high blood pressure the so called renoprıval hypertension This in a sen e is the opposite of the Gold blatt theory Similar difficult problems have to be faced in experimental and clinical attempts to bring a new blood supply to a kidney Interruption of the nerves to the kidney has not helped Re earch 14 continuing but as yet there is no reliable surgery on the kidneys for mo ! Patient with this form of high blood pres tire 100 ·The second classical school of thought centers around the work of Profes sor C Heymans and his proof that hypertension could be cau ed in dogs by dividing the nerves from certain pressure sensitive areas of the arteries of the neck and heart The e normally act as governors to keep blood pressure down to normal levels in anger frustration etc in patients with this common form of hyperten on the buffering mechanism till functions although reset at a higher pres ure level Te do not yet know how to readjust the pressure setting However removal of all of the sympathetic nerves in animals with this neurogenic hypertension restores blood pressure to normal by di con necting the nerve wiring circuit at its mo t accesible point Is it neces ary to disconnect the sympathetic nervous sy tem completely? Many experiments indicate that it is Half a sympathectomy does little in animals The sympathetic nerves to the head and heart are ju t as important in the maintenance of neurogenic hyperten ion as are tho e to the kidneys and abdominal viscera The operations of Ad on and Peet and their ubsequent modification by Smithwick in 1939 were planchnicectomies focu ed on the Lidneys and abdominal viscera only The e operations effect some relief of symptoms and an occasional definite reduction of blood pres ure Many surgeons now em ploy modifications of the original procedure but still limit their operation to a planchnicectomy Because of training with Heymans experiments in animals and a behet that neurogenic components of the hypertensive disease process are important ating and perpetuating factors Itarted total sympathectomy in 1910 This operation includes denervation of the upper body and thoracic viscera as well as the planchnic area Results among 220 patients o treated have been encouraging with maintained reduction of blood pressure to about normal in a third reduction but not to normal in a third and relief of symptoms and apparent increased life expectancy for most These resulta added to tho e from the u e of new drugs which uppre s the sympathetic ganglia demonstrate the significance of the neurogenic component of hyper tension Even the present popularity of the so-called tranquilizing drugs 18 evidence of the There seems to be no doubt that suppression of the sym pathetic nerves by drugs or urgery is at present the most practical way of benefiting patients with hyperten son Removal of the adrenal glands is another form of urgery directed at re ducing blood pressure by interfering with tructures which have apparently normal function Patients with lo s of thee glands by di ea e uffer from low blood pre ure and may require Cort one to keep them alne Experi mentally and clinically it is difficult to produce a compromise or balance between the evils of high and tho e of low blood pres ure If the adrenal are totally removed and then adequate do es of Corts one are given hyper tension return For this and other rea on total adrenalectomy has not become popular Research in this field continues For the pre ent the ac cepted form of adrenalectoms is the removal of a rare tumor a pheochromocy 101 ·toma which secretes adrenalın and does cause a hypertension that can be corrected For the last five years Dr Harold Zantel and his associates have felt it necessary to remove part of the adrenal glands to reinforce the effecta of splanchnicectomy Removal of ninety five percent of the adrenals may be too much for one patient not enough for the next This leaves most patients in constant need of medical supervision and Cortisone This operation has met with limited trial and popularity Sympathectomy renal surgery and adrenalectomy have been the main surgical approaches to hypertension by altering normal function Repair or replacement of body structures is usually directed toward a main complication of hypertension hardening of the arteries or arterio clerosis Common causes of death from high blood pressure are damage to the brain heart and kidneys by coexisting arterio clerosis which is accelerated by the high pressure Today the recognition of the importance of low fat diet and of the use of sitosterols such as Cytellin in the prevention and management of arteriosclerosis probably will improve results of all forms of treatment of hypertension and will minimize these complications The arteries to the brain can be damaged by arteriosclerotic obstruction of the flow of blood (minor strokes) by sudden occlusion from a blood clot (thrombosis) or by rupture and hemorrhage Dr Champ Lyons and others have demonstrated small segments of occlusion of the carotid arteries in the neck and have removed the e segments replacing them by cloth tubes or by arteries from an artery bank Also the obstructions can be cleared out from within the artery - thrombo endarterectomy This benefits patients having repeated small trokes Patients loving consciousness with the sudden development of a thrombosis within the skull have been given injections of novocain into the upper sympathetic ganglia to try to reduce spasm of collateral Ses els and improve circulation Thic minor operative procedure may have helped some patients However there is evidence that the blood vessels of the brain enclo ed as they are in a hard skull have little sympathetic control Probably one of the mo t important relatively new des elopments has been the u e of cerebral angiograms to demon trate by ray the presence of small aneuryams or ruptured sessels in patients who have had a cerebral hemorrhage and are about to have another Neuro urgeons can operate in the nech ap plying a clamp to decrease pres ure and then operate within the kull to remove clip or tie off these aneurysms The coronary arteries to the heart can also gradually occlude or «uddenly thrombo e causing di ability or death to our hypertensive patients Mo! of the re earch and the clinical advances in cardiac urgery today have been in the field of congenital abnormalities in children and in treatment of val sular di eases usually rheumatic in origin The lechniques for heart lung pump for topping and starting hearts and for operating upon open blood less heart chambere are available for the management of coronary disea e However there is an as ociated mortality r k even in voung patients with 102 ·out coronary disease and to the best of my knowl dge this type of cardiac surgery has not been applied to the greater risk patient - the older man with coronary insufficiency and angina Early urgical efforts with coronary disea e both experimental and clinical consisted of introducing irritating substances to cause inflammatory reactions in the sac or pace about the heart which is called the pericardium Al o tried were the attachment of lung abdominal omental fat or other structures to the heart in the early stages of healing inflammatory tue at the site of a foreign substance is vascular Later it tends to become relatively a va cular car tu cue Dr Claude Beck in Cleveland has long worked with the blood flow through the coronary sinus and has devised several operation designed to develop intercoronary communications to increase blood flow His latest operation is a simplification of the earlier ones designed to reduce mortality risk le abrades the walls of the heart and its pericardial sac in stalls powdered asbestos and partially ligates the coronary sinus This pro cedure has been tested both in animals and in man Another operation de veloped several years ago by Dr Arthur Vineberg of Montreal is the moving of the internal mammary artery from its location beneath the breat bone or sternum into a tunnel in the wall of the heart Experiments indicate that new arteries can branch out from this tran planted ves el A direct approach to clean out or replace obstructed segments of coronary arteries was reported from Minneapolis by Doctors Absolan Aut Varco and I illeher in 1936 Early this year Dr Charles Bailey of Philadelphia reported removal of the thickened lining of a coronary artery in two patients He used a pecial instrument to scrape or ream out the depo its which clog it These operation require a general anesthetic and surgery on the surface of the beating heart A procedure which does not was developed by Dr Robert Glover of Philadelphia within the last few years This is the hgation of the internal mammary artery The artery is easily acce sible for ligation Becau e of its implicity thi operation has been employed frequently but there is extensive debate about rationale and results Experimentally a great deal of work is progressing along all of these lines Why is it then that I can a k for a show of hands by physicians in thi room and probably find an overwhelming majority who do not advi e any surgery for the great majority of coronary patients? There are several medical reasons but the mot important seems to be that it is hard to know whether there is any improvement after urgery or at leat ufficient improvement to warrant the operative n k Perhaps ninets percent of good rik patient survive their initial myocardial infarction With improved methods of medical treatment more than one half of the ur vors live longer than five years and one third ten year Mans patient live to beyond the ten years and would be considered a good re ult had they had an operation Surgical patient are neces arily elected and therefore 103 ·constitute a omen hat different population from tho e receiving medical management I can only say that a popular operation for coronary insuficiency has not yet evolved and that generally accepted proof of the value of this surgery has not yet been presented However I can as ure you that this is a problem which is receiving extensive investigation and increasing clinical trial My medical colleagues here are probably wondering whether I have over looked the role of surgery of the autonomic nervous sy tem in the treatment of patients with coronary insufficiency The subconscious vegetative or avtonomic nervous sy tem has two main divisions One is the sympathetic The other is the parasympathetic with its vagus nerves to the heart The vagus nerves slow the rate of the heart The sympathetic nerves accelerate the heart and also conduct pain ensations from the heart All of my sympathectomized hyperten 15e patients have a slow heart rate and should experience no cor onary pain It has been reassuring to ob erse that these completely sym pathectomized patients who without surgery should have had a high rate of coronary difficulty and angina have instead a low incidence of cardiac trouble I woh I could persuade more of my surgical colleagues to include this cardiac denervation with their splanchnicectomies for hypertension It is today a generally accepted theory that occasional patients disabled by evere angına can be relieved by ympathetic denervation of the heart Several urgeons have removed both the vagus and sympathetic to the heart as the e nerves join in the cardiac nerve plexus Tere again the balance be tween rik and benefit is difficult to e tablih The large t artery of the body the aorta and its largest branches can ob truct or dılate and form aneurysms in patients with hypertension as well as arterio clero Successful replacements and clean out procedures have been desi ed and are commonly applied Greater difficulty is encountered in the main arteries to the legs and arms but percentages of succes, are en couraging The maller arteries of the body such as the coronary arterie are eldom uccessfully treated by direct arterial surgery Generally as the ize of blocked arteries derrea es from the aorta out through its branches to the extremities a regional sympathectomy becomes the operation of choice Replacement of organs is a difficult problem I know of no one who has uggested replacing the brain Some Rus ian cient ts po tulated and tried in animals replacement of the heart Sub titution of a kidney 13 more logical and American The artifical kidney a des eloped by Dr Willem Kolff and Dr Jack Leonard of Cleveland Dr John Verrill in Bo ton and others have proved a practical method for upporting patient with temporary renal fail ure Until two years ago the transplantation of the human kidney from a healthy individual or body to a patient has met with failure or only tem porary urval jut as happens in dog Two years ago Dr Joseph Murray and Dr Hartnell Harri on of Bo ton succesfully tran planted a normal kid ney from a normal identical twin to his brother who was dying becau e of 10+ ·lo s of function of his kidney This arhtesement has again stimulated re earch directed toward the immunologiral and other aspects of t1 sue trang plantation in an effort to make this feat poible for patients who are not identical twin The barrier which has prevented successful organ transplants from one per un to another nou is cracked and weakened although still trong THE WAY TO A MANS HEART GEORGE A PERERA, UD Department of Medicine, Columbia Unuersity College of Physicians and Surgeons, New York Meie loch A few years ago a verlthy banker approached me and said I have read all the scientific and medical Isterature and am convinced it is possible for you to keep me alive until I am 110 year old His financial offer for such a program was moet tempting but I turned him down He presents what is today a growing epidemic of fear and anxiety There are few who choo e to temember that life is fatal and that the only really successful way to prevent old age 18 to commit suiride when one 19 young There is considerable talk about nutrition and vitarains and how they produce bigger and better babie healthier children brager hoes and taller basket ball players On reaching adult life in contradi tnction one is ad vised to do without wine women and son, in order to stay alue and avord heart disease When you go to a urgeon to have a gall bladder or other spare part removed the good doctor thinks about a lot of things lle a ks himself whether an operation will relieve symptoms and whether it will cure the trouble What are the rı kg'llow much will the patient be disabled? Are there other ways of olving the problem? Is the patient willing to go through an operative procedure Will he cooperate? What are the psychological con sequences > The same can be true of drets of carried to extremes they too can induce restrictions and alter the way of life be expensive and produce all sorts of emotional adju iments In fact similar ta drugs or surgery they can cause harm through nutritional deficiencies and in other ways The title of this talk ! The Way to a Man 9 Heart I do not know whether a young lady is taught how to cook these days but that supposedly used to be tbe way she got her man If he cooks too well it is and that she will get her mans in urance Cupids arrow becomes transformed to the barbed arrow of dret delnering its (ing through too much salt too many calories or too much fat The e are the ingredients which have recensed much attention in the fields of hypertension and athero elproaja I should like to conduce you briefly and air a lew representatxe eramples of medical knowledge and lack of knowledge The will not be a complete tory but jut a few tales abrut salt ole ity and fat As ome of you heard this morning there is con desable es denre that if we reduce the amount of salt in our dret deleterious effect of high blood pressure may be lessened Lowered alt intake may lower the pre ure leve a little in ome patient 105 ·relieve symptoms and help a few of the complications Diets that are sery restricted may lower the amount of cholesterol in the body But now let us ask ourselves a few questions It is not established that taking away the salt in the diet cures the patient In fact it is rather hard to convince ourselves that the life of the patient is lengthened to any material extent There is little knowl edge yet of the mechanisms by which low salt diet exerts beneficial effects When the lesel of cholesterol drops in the blood where does the cholesterol go? There is a remote possibility that it may go into the walls of the blood vessels just the place we should like to avoid When the cholesterol decrea es after a low salt diet certain other fatty substances in the circulation are in creased There are many remaining questions as you can see What about being over weight? You have heard this story before Doctor do not like their patients to be over weight No one recommends that you go upstairs carrying a lot of suitca es and if these are built in suitcases you hould logically make the load less by cutting down your weight We know that certain complications of disea e are more difficult to treat in patients who are over weight and that mild forms of diabetes may be cured by werght reduction A few have sugge ted that decreasing the weight may have some small bearing on blood pressure levels Finally there is some evidence that there is a greater amount of athero clerosis percentage wise in people who are over weight as compared to tho e who are thin But once again there are a lot of questions For example we have no convincing proof that weight reduction will modify processes already present in our own hypertensive clinic fat patients seem to live longer than thin ones Much more study 1 needed Finally what of the role of fat in the diet? There does seem to be a rela tron hıp of some sort at lea t on a tatı tical basis Letween groups of per on who eat a lot of fat and tho e who eat le Disorders associated with high chole terol levels in the blood eem to be tho e giving rise to hardening and scarring of arteries - athero clerosis Animals fed cholesterol will develop athero clero is in their blood ve el And there are hundreds of tattical studies ranging from Bantus to E kimoes contrasting the incidence of athero sclerosis among different races nations and even occupational groups But what of proteins and carbohydrates? Some tudies have hown that protein may not be innocuous in fact we peak of lipo protein fat molecules that hook up with protein molecules in our circulation Other studies show that it is almo é impossible to predict the individuals future on the basis of the chole ferol level the size of fat molecule or anything else In fact of one takes a diabetic or hyperten le population few differences can be een in average values although the range of variety is omwhat greater in tho e with di ease And for every theory there is a counter theory For example the Ban tus appear to have lea heart di ea e but thes are often thuin may hase Iner di ea e and may have sitamin deficiencie Perhaps other factors than diet are respon ible F kimoes rarels lose to a ripe old age one has to be careful 106 ·about making comparisions of groups of people unle s they are contrasted from the standpoint of being the ame age One doctor in Great Britain honed that deaths from heart di ease declined a little bit before fat ra tioning was introduced and then rose just after the fat rationing became more trict You are familiar with the line that one man s porson is another s meat And so I would like to raise another problem Ma s tati tics are very important They give us clues Ultimately it is the individual that should concern us If there is more heart di ea e in the United States does it mean that an entire population is more prone or that a few of us are more sus ceptible? This is another unanswered que hon but one which may be very important Someday we would like to know how to di tingui h the usceptible one so that he can be treated instead of an entire population Furthermore psychological disturbances increa e when we impo e restrictions on entire populations A year or two ago there was a meeting about the epidemiology of heart di ease and hypertension The conclusion was reached that there is more hardening of the arteries in men than in women that there is more in older folk than in younger ones and that there is an association of some sort be tween fat in the dret and the prevalence of coronary artery di ea e All other reported as ociations remain hypothetical Until more knowledge is available we can only try to approach a balance The American diet is rather hgh in fat It makes good sen e to lower its fat content by hying away from butter and chee e and the fat on the margins of roa t beef It seems to me we must retain a clear distinction between what we know and what is still a continuing experiment This is not a plea for discarding any of the guins we have made or for throwing in the sponge it is more a plea for retaining certain attitudes o that we can advance at a faster pace What we really need to do is to devi e and carry out more definitive tudie to find continued support for the right kind of investigation We are still at the bevinning and much needs to be done to elucidate the various pathways to a man s heart THE USEFULNESS OF DRUGS IN THE TREATMCNT OF HYPERTENSION HARRIET P DUSTAN YD Research Dirision Cleeland Clinic Foundation and the Frank r Bunts Educational Institute Clereland, Ohio The treatment of any di ea e aims to cure or failing thi to relieve it ymptoms and prevent its complications If the di ea e one which runs a rapid and predictable cour e such as an acute infection the result of treatment can be evaluated in short order in contra t it may take year of patient effort to a the effectivene of a gren treatment of a chronic 107 ·illness such as essential hyperten ion with its relatively unpredictable cour e In those hypertensive patients whose treatment is aimed at the prevention of symptoms and complications that hare not developed the results of preventne treatment can only be appreciated in general terms Such preventive treatment is commonly used because mo ! physicians belteve that a significant degree of sustained hypertension will eventually have sequelae in the form of strokes or heart attacks which are cau ed in part at least by the blood pressure Hence while potent antihypertensive drugs have been widely u ed for the past seven or eight years the course of e ential hypertension is so variable and usually so prolonged that many more years must pass before we can know whether these drugs are really as effective as they seem to be now Still at the pre ent time we can as es with confidence the effechieness of these agents of me limit the consideration to that group of patients who suffer from a rapidly advancing form of the di ease so called malignant or accelerated hypertension This disease has a relatisely brief and predictable cour e Untreated it is rapidly fatal for nearly all such patients For erample in 1939 Keith Wagener and Barker summarized the clinical courses of 1-16 patients with malignant hypertension more than fifty percent of the e were dead within six months some eighty percent had died by the end of the fir 1 year only two percent were alle at the end of the fourth year At that time le s than twenty years ago no really effective treatment was avail able thus a comparison of their surunal with that of patients with malignant hypertension treated by modern methode can serve as an inder of what lias been our recent accompli hment The aim of treatment in hypertension is with due care to lower and maintain dia tolic blood pre aure at normal or nearly normal levels thug abating the symptoms and complication of the small blood vessel (arteriolar) disease characteristic of hypertension and presenting the complications of Jarge blood sessel disease (arterio clerosis) which is almost always accelerated by hypertension When we compared our group of inty one malignant hypertensive patients whom we had treated during a fire rear period with that group reported about twenty years ago by heith Wagener and Barker we found thirty per cent of our patients died during the fir t year of treatment as opposed to cighty percent of theirs It is important to realize that this thirty percent includes thore patients who died in 1932 when we had little kill in the use of these antihyperten ne drugs and little variety in their election as well as tho e who died in 1957 when we had con derably more erperience and a wider elechon of druge Jence our experience in 19.2 was understandably less gratifying than our more recent re ulte At the end of five yeire thirty percent of our group was till alive while the comparable datum for the untreated group was tuo percent ome 108 ·Thus modern treatment is definitely helpful in malignant hypertension this becomes more obvious when one examines the cau es of death in the twenty eicht patients who died during treatment Ten advanced cases died of kidney failure and even of a peculiar pneumonia that complicated one kind of treatment Five patients died of myocardial infarction four of cerebral hemorrhage and one of a ruptured aortic aneurysmn The cau e of death of one patient is unknown Mone of the patients died of heart failure which was previously an important cause of death of tho e who died of kidney failure all had extensive kidney di ea before treatment was started In short treatment has so changed the course of this type of hyperten ive di ease that patients no longer die of the effects of small blood ves el dı ease from the e they usually recover Some do o only to die months or years later of the complications of large blood vessel disease -- arteriosclerosis There 19 no one drug for the treatment of malignant hypertension Any of the antihypertensive drugs may be useful as long as the diastolic blood pressure is well controlled This is the important point dia tolic blood pren sure must be maintained at normal levels or as near normal levels as possible of the disease is to be well treated The choice of a drug should be made ac cording to the eserity of the hyperten we di ea e and the respon e of the patient If the patient is very ill and requires rapid blood pressure control a ganglion blocking agent is usually chosen if a few more days or weeks of hypertension will not be harmful to the patient hydralazine or re erpine may be tried for although the e drugs may not be so promptly effective they are not so difficult to administer In each in tance the goal is the reduction of dia tolic blood pres ure to normal levels not often is this goal achieved but we always strive for it Even though modern treatment of hypertension is effective many problems remain We know o little about the fundamental mechanisms of the di ea e that our treatments are non pecific furthermore they are clumsy for the patient and are often associated with troublesome and ometimes dangerou side effects Because we do not understand the ba ic mechanı ms we cannot predict the type of treatment which will be effective for a particular patient Perhaps each of the drugs will lower his blood pres ure perhaps none will or perhaps a combination of drugs will be the mot helpful La although We have accomplished a good deal in the treatment of severe and progreise hyperten use di ea e ne are faced with the problem of the arteriosclero is which lias been accelerated by the pre exi ting hypertension We are jut beginning to face up to this problem epling mean for its prevention or cure We hope that it will fade in Importance ac treatment becomes more Specific prompt and la ting as a re ult of learning what are the baaic mech anim of the di ea e in all its sarjous form 109

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