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Introduction to first part of the Hypertension Symposium
MAY
The
American
Journal
31,
1976
of Medicine VOLUME NUMBER
60 6
Introduction to First Part of the Hypertension Symposium Biochemistry of the Renin Axis Prostaglandins, lndomethacin and Renin Angiotensin Blockade Beta-Blockers as Antirenin Drugs
JOHN H. LARAGH, M.D New York, New York
This latest Symposium on Hypertension is in response to the great interest expressed in our first one which appeared conjointly in The American Journal of Medicine and The American Journal of Cardiology in 1972 and 1973. These symposia have been made possible by William Grace, the Editor in Chief and by Louis Le Jacq, the publisher. The format they have adopted provides the opporturiity for a monthly Journal to treat a timely and lively subject with depth. This blend of recent research and related state of the art reviews by recognized experts helps to place new ideas in a broader frame of scientific reference. High blood pressure is a subject most aptly suited to this type of Symposium approach. Over the past 20 years there has been an explosive growth in our understanding of the physiologic problem and at the same time an increasing awareness of its great relevance as a public health problem. That the lively current status of high blood pressure research has produced findings of considerable immediate and practical value is well exemplified by the papers chosen for the two sections of this Symposium. In the first paper of the Symposium, Leonard Skeggs and his longstanding colleagues at the Veterans Adminisfration Hospital in
From the Hypertension and Cardiovascular Center, New York Hospital, Cornell Medical Center, 525 East 68th Street, New York, New York 10021. Requests for reprints should be addressed to Dr. John H. Laragh.
Cleveland have put together in one place a review and synthesis of their many major contributions to our understanding of the biochemistry of the renin-angiotensin system. For sure, no other single group has contributed so much in this area. Their efforts have included the lsolation, identification and synthesis of both forms of angiotensin, discovery of the converting enzyme and of fhe tetradecapeptide substrate. More recently, their work has clarified our understanding of the
733
INTRODUCTION TO THE HYPERTENSION SYMPOSIUM-LARAGH
physiologic conditions for converting enzyme activity, revealed the different forms of substrate and of, possibly, different chemical forms of renin. Thus, this piececomprises a basic source for all physicians concerned with treating hypertensive disease. In the second paper, Ervin Erdos reviews his work in defining the nature of converting enzyme, its tissue locations and its biologic activity, not only in removing dipeptide bonds from angiotensin I, but also in cleaving bradykinin. This has particular practical value, since intravenous compounds which specifically interfere with the converting enzyme are now available for human use and have great diagnostic and therapeutic promise. The manuscript by Detlev Ganten and his colleagues masterfully reviews our present knowledge of other enzymes, which are biochemically similar to kidney renin, but which exist. in practically all extra renal tissues of most mammals. This set of observations seems extremely important to me for the data suggest that the formation of angiotensin may comprise part of a fundamental biologic cellular process involved in functions other than blood pressure regulation. For example, brain angiotensin may prove to be an important mediator or transmitter of neural activity. Norman Hollenberg and his associates have presented their analysis of the variations in the renal circulation that may occur in hypertensive disease, particularly the differences in intrarenal distribution of flow, and the possible relevance to the pathogenesis of hypertension. Moreover, they have been able to demonstrate significant relationships between renal blood flow and the plasma ienin patterns observed in different hypertensive patients. ~Altogether, these observations provide a new basis for analyzing and interpreting the pathogenetic role of the kidneys in most hypertensive patients. The report by Marshall Fichman and his associates seems of very special relevance. This paper describes, for the first time, their original discovery that the drug indomethacin, commonly used for treatment of arthritis, has a unique, powerful and dramatic effect in correcting the biochemical abnormalities of Bartter’s syndrome. This discovery, which has been independently observed by another group in Europe [l], has shown that indomethacin, presumably by inhibiting the generation of prostaglandin in the kidney, can produce sustained renal sodium retention in patients with Barber’s syndrome and consequent to this, a complete correction of the elevated plasma renin and aldosterone levels. These data are most exciting. They lead to new avenues of research in the control of sodium excretion and of renin release since they suggest that prostaglandin generation may be a key mediator of one or both of these processes. The data are also in agreement with the hypothesis that Bartter’s syndrome, at least in some
734
May 31, 1976
The American
Journal of Medicine
Volunie
instances, is in fact a sodium losing state [2] and, therefore, it is reasonable that indomethacin therapy might be applicable to other such conditions. Accompanying and complementing Dr. Fichman’s report is an article by Dr. James Lee and his associates reviewing, from their close personal experience, the possible role of renal prostaglandins in the regulation of blood pressure and sodium water balance. Of particular interest, are their new findings that indomethacin administration can block the natriuretic action of certain commonly used sulfonamide diuretics. These findings, in particular, ,support the discovery of Fichman and associates that indomethacin, presumably by inhibition of prostaglandin synthesis, can retard renal sodium loss. In the latter half of this symposium, the theme changes to blockade of the renin system. Two papers are presented describing the current status of the use of the octapeptide, saralasin, which has been described as a competitive antagonist of angiotensin. Depressor responses to the intravenous administration of the drug have usually been interpreted as evidence for angiotensin excess as a factor in the particular hypertensive state. in the first paper, Streeten and his colleagues from Syracuse present a comprehensive review of their extensive experience using the saralasin test to identify renin-dependent (i.e., angiotensinemic) forms of hypertension in man. Their testing approach is based on the observation [3] that the depressor action of the drug is enhanced after sodium depletion with induction of reactive hyperreninemia. Their experience presents clear guidelines for the use of the drug in this way. In the following paper by Case and his associates of our group, no prior treatment with diuretics was used in an attempt to reveal basal excesses of endogenous angiotensin as a factor in the hypertension. Another feature of this study was a comparison of saralasin testing with renin profiling using the renin-sodium index as a means to evaluate patients. It was found that saralasin testing will most reliably identify a renin factor in patients with high renin levels, that it usually fails to recognize a possible renin factor in patients with “normal” renin levels and that paradoxic pressor responses were very common in patients with low renin levels. Altogether, the data suggest that saratasin has intrinsic agonist properties in man and that it acts as a weaker false transmitter rather than a true antagonist. Because of this inherent property, the drug underestimates the renin factor in hypertensive patients. Our present view is that although prior sodium depletion may reveal more renin-dependent patients at the time of study, these positive tests may merely expose reactive hyperreninemia and need not necessarily point to de novo renin dependent hypertension. These two reports describing the limitations and usefulness of saralasin testing suggest that perhaps another type of agent will
60
INTRODUCTIONTO THE HYPERTENSIONSYMPOSIUM-LARAGH
be more valuable for identifying a renin factor in the hypertension of human subjects. Hopefully, the converting inhibitor, SQ20881 [4], will fulfill this requirement since it has no agonist action. Following logically after a consideration of peptide blockers of angiotensin, is a series of eight papers which characterize, analyze and discuss the antihypertensive action of propranolol and several related beta-blocking drugs. Much of this experience is contributed by our European colleagues, since no betablocker has been officially approved for treatment of hypertension in the United States, even though propranolol is now widely used in this way. The grouping begins with Peter Lewis’ review of the experimental evidence on propranolol’s mechanism of action to lower blood pressure. Lewis favors a basic action of betablockers to reduce sympathetic nerve output via sensory input to the brain from a cardiac receptor system. Whether or not this is the case, it seems likely that the motor limb of the reaction involves a dampening of the renin secretion by the kidney, probably transmitted over to the autonomic nervous system. The succeeding paper by Stumpe and his associates describes fascinating and well done physiologic studies which characterize the hemodynamic effects of propranolol and of another beta-blocker, pindolol. This study is especially exciting in its design. By administering propranolol in the evening, Stumpe and coworkers have demonstrated for the first time an acute and immediate antihypertensive action of intravenous propranolol. Moreover, these workers give important new information on the diurnal variation of plasma renin levels in hypertensive patients, information that disconcertingly suggests that blood pressure patterns may not closely parallel plasma renin levels. Whatever the case, their experience confirms strongly the idea [5] that the response to beta-blockade in patients with high renin levels is much better than in those with low renin levels. Another paper from the same institution, by Vetter and his associates, provides a brief clinical interlude describing the unusual problem of pheochromocytoma. In these patients, high renin levels were observed that could be markedly curtailed by using an alpha-blocking drug. Their experience suggests that increased renin levels in these patients are determined by the ratio of the abnormal catecholamine excretion levels. The experience tends to broaden our ideas concerning the neurogenic control of renin secretion. The immediately following paper by Drs. Atterhog, Dun& and Pernow from Stockholm describes the hemodynamic changes associated with antihypertensive benefits of administration of another beta-blocking agent, pindolol, which is widely used in Europe although not available in this country. The key changes are a
decrease in heart rate, a decrease in peripheral vascular resistance and an increase in vascular capacitance working to retard venous return. Their data suggest that although a decrease in cardiac output may be an early factor in lowering blood pressure, later on changes in systemic resistance seem to be more important. The beta-blocking drug experience is amplified further in two subsequent papers by Ross Lorimer and his associates from Glasgow and by Joel Menard and his group from Paris. The former paper presents clinical guidelines for the use of propranolol and some of its major contraindication. It describes an important bonus that may accompany propranolol therapy: a reduction in the hypertensive reaction to stress. Thus, betablockers suppress the blood pressure flings in hypertensive patients even when they may not normalize ambient readings. Menard and his associates have used a cardioselective beta-blocking drug, acebutolol, in their studies. Their observations seem especially relevant since they demonstrate that a beta? or cardioselective type of beta-blocker is equally as antihypertensive as those having both beta, plus beta:, blocking activities. Moreover, beta1 blocking drugs seem to lower renin levels just as effectively as they lower blood pressure levels. The use of cardioselective beta blocking drugs has special promise since, theoretically at least, they eliminate the risk of inducing bronchial asthma in susceptible patients. From a theoretic point of view, Menard and his associates have also provided strong confirmation of the idea that renin-sodium profiling can predict or anticipate which patients will respond to beta-blocking drugs. Similar impressions are derived from a subsequent study by Karlberg and Tolagen, who convincingly demonstrate that beta-blocking drugs are especially effective in patients with high renin levels. Perhaps of equal relevance, they confirm that propranolol is almost without antihypertensive effectiveness in patients with low renin levels who instead responded very nicely to volume depleting agents. Altogether, this burgeoning experience suggests a key role in the future for renin profiling as a baseline definition procedure to predict which patients will respond to beta-blocking drugs and to identify those who will respond instead to diuretic therapy as a first approach. Despite the overwhelming evidence presented herein for the value and uniqueness of beta-blocking drugs for treating high blood pressure and the close relationship between their effectiveness and the underlying renin activity, the last paper by Drayer and his colleagues from our group defines a surprising caveat. We have discovered that propranolol can actually produce paradoxic hypertension in certain patients with essential
May 31, 1976
The American Journal 01 Medicine
Volume 60
735
INTRODUCTIONTO THE HYPERTENSIONSYMPOSIUM-LARAGH
hypertension. The pressor responses to propranolol mostly occurred in patients with low renin levels but were observed occasionally in patients with normal renin levels. The analysis of the data suggest that the effect is related to an underlying volume factor combined with a failure of the drug to fully suppress renin and aldosterone at a time when unopposed alphasympathetic activity becomes dominant. This paradoxic response can perhaps be anticipated by baseline renin profiling and anticipated in patients exhibiting undue weight gain.
The package presented herein is large, but perhaps it will be more digestable if studied as coherent subsets. Undoubtedly, the biochemistry of the renin axis, the possible role of prostaglandin, the clinical physiology of angiotensin blocking drugs and of beta-blocking drugs all have much in common. In their overlap and dynamic interrelationships these areas may bring us around full circle to a better understanding of the chemical messengers involved in cybernetics of blood pressure control. Automatically, then, this will lead us to even more specific, simpler and effective therapy.
REFERENCES 1.
2.
3.
736
Verberkmoes R, Clement J, Michielson P, Van Damme 5: Bartter’s syndrome with hyperplasia of renomedullary interstitial cells. Successful treatment with indomethacin (abstract 558). Program of the Vlth International Congress of Nephrology, Florence, Italy. 1975. Cannon PJ, Leeming JM, Sommers SC, Winters RW, Laragh JH: Juxtaglomerular cell hyperplasia and secondary hyperaldosteronism (Bartter’s syndrome). A reevaluation of the pathophysiology. Medicine (Baltimore) 47: 107, 1968. Brunner HR. Gavras H, Laragh JH, Keenan R: Hypertension in
May 31, 1976
The American Journal of Medlclne
4.
5.
Volume 60
man. Exposure of the renin and sodium components using angiotensin II blockade. Circ Res suppl I, p 35. 1974. Gavras H, Brunner HR, Laragh JH; Sealey JE, Gavras I, Vukovitch RA: An angiotensin converting enzyme inhibitor to identify and treat vasoconstrictor and volume factors in hypertensive patients. N Engl J Med 291: 817, 1974. Buhler FR, Laragh JH, Vaughan ED Jr et al.: The antihypertensive action of propranolol. Specific antirenin responses in high and normal renin forms of essential, renal, renovascufar and malignant hypertension. Am J Cardiol 32: 511, 1973.
The
American
Journal
31,
1976
of Medicine VOLUME NUMBER
60 6
Introduction to First Part of the Hypertension Symposium Biochemistry of the Renin Axis Prostaglandins, lndomethacin and Renin Angiotensin Blockade Beta-Blockers as Antirenin Drugs
JOHN H. LARAGH, M.D New York, New York
This latest Symposium on Hypertension is in response to the great interest expressed in our first one which appeared conjointly in The American Journal of Medicine and The American Journal of Cardiology in 1972 and 1973. These symposia have been made possible by William Grace, the Editor in Chief and by Louis Le Jacq, the publisher. The format they have adopted provides the opporturiity for a monthly Journal to treat a timely and lively subject with depth. This blend of recent research and related state of the art reviews by recognized experts helps to place new ideas in a broader frame of scientific reference. High blood pressure is a subject most aptly suited to this type of Symposium approach. Over the past 20 years there has been an explosive growth in our understanding of the physiologic problem and at the same time an increasing awareness of its great relevance as a public health problem. That the lively current status of high blood pressure research has produced findings of considerable immediate and practical value is well exemplified by the papers chosen for the two sections of this Symposium. In the first paper of the Symposium, Leonard Skeggs and his longstanding colleagues at the Veterans Adminisfration Hospital in
From the Hypertension and Cardiovascular Center, New York Hospital, Cornell Medical Center, 525 East 68th Street, New York, New York 10021. Requests for reprints should be addressed to Dr. John H. Laragh.
Cleveland have put together in one place a review and synthesis of their many major contributions to our understanding of the biochemistry of the renin-angiotensin system. For sure, no other single group has contributed so much in this area. Their efforts have included the lsolation, identification and synthesis of both forms of angiotensin, discovery of the converting enzyme and of fhe tetradecapeptide substrate. More recently, their work has clarified our understanding of the
733
INTRODUCTION TO THE HYPERTENSION SYMPOSIUM-LARAGH
physiologic conditions for converting enzyme activity, revealed the different forms of substrate and of, possibly, different chemical forms of renin. Thus, this piececomprises a basic source for all physicians concerned with treating hypertensive disease. In the second paper, Ervin Erdos reviews his work in defining the nature of converting enzyme, its tissue locations and its biologic activity, not only in removing dipeptide bonds from angiotensin I, but also in cleaving bradykinin. This has particular practical value, since intravenous compounds which specifically interfere with the converting enzyme are now available for human use and have great diagnostic and therapeutic promise. The manuscript by Detlev Ganten and his colleagues masterfully reviews our present knowledge of other enzymes, which are biochemically similar to kidney renin, but which exist. in practically all extra renal tissues of most mammals. This set of observations seems extremely important to me for the data suggest that the formation of angiotensin may comprise part of a fundamental biologic cellular process involved in functions other than blood pressure regulation. For example, brain angiotensin may prove to be an important mediator or transmitter of neural activity. Norman Hollenberg and his associates have presented their analysis of the variations in the renal circulation that may occur in hypertensive disease, particularly the differences in intrarenal distribution of flow, and the possible relevance to the pathogenesis of hypertension. Moreover, they have been able to demonstrate significant relationships between renal blood flow and the plasma ienin patterns observed in different hypertensive patients. ~Altogether, these observations provide a new basis for analyzing and interpreting the pathogenetic role of the kidneys in most hypertensive patients. The report by Marshall Fichman and his associates seems of very special relevance. This paper describes, for the first time, their original discovery that the drug indomethacin, commonly used for treatment of arthritis, has a unique, powerful and dramatic effect in correcting the biochemical abnormalities of Bartter’s syndrome. This discovery, which has been independently observed by another group in Europe [l], has shown that indomethacin, presumably by inhibiting the generation of prostaglandin in the kidney, can produce sustained renal sodium retention in patients with Barber’s syndrome and consequent to this, a complete correction of the elevated plasma renin and aldosterone levels. These data are most exciting. They lead to new avenues of research in the control of sodium excretion and of renin release since they suggest that prostaglandin generation may be a key mediator of one or both of these processes. The data are also in agreement with the hypothesis that Bartter’s syndrome, at least in some
734
May 31, 1976
The American
Journal of Medicine
Volunie
instances, is in fact a sodium losing state [2] and, therefore, it is reasonable that indomethacin therapy might be applicable to other such conditions. Accompanying and complementing Dr. Fichman’s report is an article by Dr. James Lee and his associates reviewing, from their close personal experience, the possible role of renal prostaglandins in the regulation of blood pressure and sodium water balance. Of particular interest, are their new findings that indomethacin administration can block the natriuretic action of certain commonly used sulfonamide diuretics. These findings, in particular, ,support the discovery of Fichman and associates that indomethacin, presumably by inhibition of prostaglandin synthesis, can retard renal sodium loss. In the latter half of this symposium, the theme changes to blockade of the renin system. Two papers are presented describing the current status of the use of the octapeptide, saralasin, which has been described as a competitive antagonist of angiotensin. Depressor responses to the intravenous administration of the drug have usually been interpreted as evidence for angiotensin excess as a factor in the particular hypertensive state. in the first paper, Streeten and his colleagues from Syracuse present a comprehensive review of their extensive experience using the saralasin test to identify renin-dependent (i.e., angiotensinemic) forms of hypertension in man. Their testing approach is based on the observation [3] that the depressor action of the drug is enhanced after sodium depletion with induction of reactive hyperreninemia. Their experience presents clear guidelines for the use of the drug in this way. In the following paper by Case and his associates of our group, no prior treatment with diuretics was used in an attempt to reveal basal excesses of endogenous angiotensin as a factor in the hypertension. Another feature of this study was a comparison of saralasin testing with renin profiling using the renin-sodium index as a means to evaluate patients. It was found that saralasin testing will most reliably identify a renin factor in patients with high renin levels, that it usually fails to recognize a possible renin factor in patients with “normal” renin levels and that paradoxic pressor responses were very common in patients with low renin levels. Altogether, the data suggest that saratasin has intrinsic agonist properties in man and that it acts as a weaker false transmitter rather than a true antagonist. Because of this inherent property, the drug underestimates the renin factor in hypertensive patients. Our present view is that although prior sodium depletion may reveal more renin-dependent patients at the time of study, these positive tests may merely expose reactive hyperreninemia and need not necessarily point to de novo renin dependent hypertension. These two reports describing the limitations and usefulness of saralasin testing suggest that perhaps another type of agent will
60
INTRODUCTIONTO THE HYPERTENSIONSYMPOSIUM-LARAGH
be more valuable for identifying a renin factor in the hypertension of human subjects. Hopefully, the converting inhibitor, SQ20881 [4], will fulfill this requirement since it has no agonist action. Following logically after a consideration of peptide blockers of angiotensin, is a series of eight papers which characterize, analyze and discuss the antihypertensive action of propranolol and several related beta-blocking drugs. Much of this experience is contributed by our European colleagues, since no betablocker has been officially approved for treatment of hypertension in the United States, even though propranolol is now widely used in this way. The grouping begins with Peter Lewis’ review of the experimental evidence on propranolol’s mechanism of action to lower blood pressure. Lewis favors a basic action of betablockers to reduce sympathetic nerve output via sensory input to the brain from a cardiac receptor system. Whether or not this is the case, it seems likely that the motor limb of the reaction involves a dampening of the renin secretion by the kidney, probably transmitted over to the autonomic nervous system. The succeeding paper by Stumpe and his associates describes fascinating and well done physiologic studies which characterize the hemodynamic effects of propranolol and of another beta-blocker, pindolol. This study is especially exciting in its design. By administering propranolol in the evening, Stumpe and coworkers have demonstrated for the first time an acute and immediate antihypertensive action of intravenous propranolol. Moreover, these workers give important new information on the diurnal variation of plasma renin levels in hypertensive patients, information that disconcertingly suggests that blood pressure patterns may not closely parallel plasma renin levels. Whatever the case, their experience confirms strongly the idea [5] that the response to beta-blockade in patients with high renin levels is much better than in those with low renin levels. Another paper from the same institution, by Vetter and his associates, provides a brief clinical interlude describing the unusual problem of pheochromocytoma. In these patients, high renin levels were observed that could be markedly curtailed by using an alpha-blocking drug. Their experience suggests that increased renin levels in these patients are determined by the ratio of the abnormal catecholamine excretion levels. The experience tends to broaden our ideas concerning the neurogenic control of renin secretion. The immediately following paper by Drs. Atterhog, Dun& and Pernow from Stockholm describes the hemodynamic changes associated with antihypertensive benefits of administration of another beta-blocking agent, pindolol, which is widely used in Europe although not available in this country. The key changes are a
decrease in heart rate, a decrease in peripheral vascular resistance and an increase in vascular capacitance working to retard venous return. Their data suggest that although a decrease in cardiac output may be an early factor in lowering blood pressure, later on changes in systemic resistance seem to be more important. The beta-blocking drug experience is amplified further in two subsequent papers by Ross Lorimer and his associates from Glasgow and by Joel Menard and his group from Paris. The former paper presents clinical guidelines for the use of propranolol and some of its major contraindication. It describes an important bonus that may accompany propranolol therapy: a reduction in the hypertensive reaction to stress. Thus, betablockers suppress the blood pressure flings in hypertensive patients even when they may not normalize ambient readings. Menard and his associates have used a cardioselective beta-blocking drug, acebutolol, in their studies. Their observations seem especially relevant since they demonstrate that a beta? or cardioselective type of beta-blocker is equally as antihypertensive as those having both beta, plus beta:, blocking activities. Moreover, beta1 blocking drugs seem to lower renin levels just as effectively as they lower blood pressure levels. The use of cardioselective beta blocking drugs has special promise since, theoretically at least, they eliminate the risk of inducing bronchial asthma in susceptible patients. From a theoretic point of view, Menard and his associates have also provided strong confirmation of the idea that renin-sodium profiling can predict or anticipate which patients will respond to beta-blocking drugs. Similar impressions are derived from a subsequent study by Karlberg and Tolagen, who convincingly demonstrate that beta-blocking drugs are especially effective in patients with high renin levels. Perhaps of equal relevance, they confirm that propranolol is almost without antihypertensive effectiveness in patients with low renin levels who instead responded very nicely to volume depleting agents. Altogether, this burgeoning experience suggests a key role in the future for renin profiling as a baseline definition procedure to predict which patients will respond to beta-blocking drugs and to identify those who will respond instead to diuretic therapy as a first approach. Despite the overwhelming evidence presented herein for the value and uniqueness of beta-blocking drugs for treating high blood pressure and the close relationship between their effectiveness and the underlying renin activity, the last paper by Drayer and his colleagues from our group defines a surprising caveat. We have discovered that propranolol can actually produce paradoxic hypertension in certain patients with essential
May 31, 1976
The American Journal 01 Medicine
Volume 60
735
INTRODUCTIONTO THE HYPERTENSIONSYMPOSIUM-LARAGH
hypertension. The pressor responses to propranolol mostly occurred in patients with low renin levels but were observed occasionally in patients with normal renin levels. The analysis of the data suggest that the effect is related to an underlying volume factor combined with a failure of the drug to fully suppress renin and aldosterone at a time when unopposed alphasympathetic activity becomes dominant. This paradoxic response can perhaps be anticipated by baseline renin profiling and anticipated in patients exhibiting undue weight gain.
The package presented herein is large, but perhaps it will be more digestable if studied as coherent subsets. Undoubtedly, the biochemistry of the renin axis, the possible role of prostaglandin, the clinical physiology of angiotensin blocking drugs and of beta-blocking drugs all have much in common. In their overlap and dynamic interrelationships these areas may bring us around full circle to a better understanding of the chemical messengers involved in cybernetics of blood pressure control. Automatically, then, this will lead us to even more specific, simpler and effective therapy.
REFERENCES 1.
2.
3.
736
Verberkmoes R, Clement J, Michielson P, Van Damme 5: Bartter’s syndrome with hyperplasia of renomedullary interstitial cells. Successful treatment with indomethacin (abstract 558). Program of the Vlth International Congress of Nephrology, Florence, Italy. 1975. Cannon PJ, Leeming JM, Sommers SC, Winters RW, Laragh JH: Juxtaglomerular cell hyperplasia and secondary hyperaldosteronism (Bartter’s syndrome). A reevaluation of the pathophysiology. Medicine (Baltimore) 47: 107, 1968. Brunner HR. Gavras H, Laragh JH, Keenan R: Hypertension in
May 31, 1976
The American Journal of Medlclne
4.
5.
Volume 60
man. Exposure of the renin and sodium components using angiotensin II blockade. Circ Res suppl I, p 35. 1974. Gavras H, Brunner HR, Laragh JH; Sealey JE, Gavras I, Vukovitch RA: An angiotensin converting enzyme inhibitor to identify and treat vasoconstrictor and volume factors in hypertensive patients. N Engl J Med 291: 817, 1974. Buhler FR, Laragh JH, Vaughan ED Jr et al.: The antihypertensive action of propranolol. Specific antirenin responses in high and normal renin forms of essential, renal, renovascufar and malignant hypertension. Am J Cardiol 32: 511, 1973.