931
A PHYSIOLOGICAL BASIS FOR THE TREATMENT OF ESSENTIAL HYPERTENSION* MICHAEL A. WEBER, M.D., and JOHN H. LARAGH, M.D. Cardiovascular Center The New York Hospital-Cornell Medical Center New York, New York
DURING the last two decades our approach to hypertension has changed radically and we are now aware that hypertension probably is the principal factor in the genesis of most cardiovascular disease. Heart disease and stroke, both closely related to hypertension, are the most important causes of death and disability in the United States. The magnitude of the challenge facing physicians has been highlighted by estimates that between 12 and 25% of adults are hypertensive. An important impetus to more aggressive treatment has come from various studies, such as the Veterans Administration Cooperative Study,1 which document that the lowering of blood pressure substantially reduces the incidence of stroke, heart failure, and renal insufficiency among hypertensive subjects. Two other developments have made it possible to meet the problem. First, during the last 10 or 15 years the advent of a new generation of drugs that are effective and palatable has allowed treatment of many patients who would have found the severe side-effects of previous drugs intolerable. Second, and perhaps more important, breakthroughs in understanding of circulatory physiology, particularly hormonal regulation of blood pressure, have enabled us to propose rational and specific approaches to treatment. Thus, the physician now can prescribe individualized therapy based on the definition of mechanisms that are sustaining the high blood pressure. MECHANISMS IN ESSENTIAL HYPERTENSION
Investigators have advanced several hypotheses to explain essential hypertension. These explanations are based on abnormalities in the central *Presented as part of a meeting on Advances in Primary Care held by the Committee on Medical Education of the New York Academy of Medicine June 6 to 10, 1977.
Vol. 54, No. 10, November 1978
9329
3
M
M. A. WEBER AND J. H..LRG LARAGH A. WEE N
and sympathetic nervous systems and the intrinsic properties of the heart and arterial circulation. Changes in the metabolism of mineralocorticoid hormones and even prostaglandins also have been cited as possible causes or participating mechanisms in the genesis of hypertension. Hypotheses dealing with these factors and others are all potentially attractive, but as yet we have insufficient data to incorporate these ideas into the clinical management of hypertensive patients. One consistently advanced explanation for essential hypertension is that elevated blood pressure is sustained by an excessive volume of sodium and water. In the sense that hypertension can result only when the capacity of the arterial system is relatively too small for the volume it is required to accommodate, this thesis has a certain logical force. Indeed, it is the basis for the now popular "stepped-care" approach to treating hypertension, in which all patients receive potent diuretic therapy as the cornerstone of their treatment. Unfortunately, this approach presumes, without justification, a homogeneity within the hypertensive population. It fails to take into account that in some patients volume factors are normal or even reduced and that, instead, their hypertension is sustained entirely by an excessively vasoconstricted state (i.e., reduced capacity) of the arterial circulation; in such patients the indiscriminate use of diuretics not only may fail to prove helpful, but may actually be counterproductive. THE RENIN-ALDOSTERONE Axis
During the last few years an improved understanding of the reninangiotensin-aldosterone axis has provided the most workable elucidation of the characteristics of essential hypertension. By employing a technique called "renin profiling" it is now possible to classify patients with essential hypertension into different groups according to etiologic mechanism and to provide them with appropriate, specific, and individual treatment. A schema of the renin-angiotensin-aldosterone system is shown in Figure 1. The enzyme renin is synthesized and stored in the juxtaglomerular cells of the kidney, which are sensitive to changes in renal blood pressure; reductions in blood flow stimulate the secretion of renin and increases in blood flow inhibit it. Through the macula densa-a specialized portion of the distal convoluted tubule in close apposition to the juxtaglomerular cells-and perhaps through other mechanisms as well, the secretion of renin is influenced strongly by the overall state of sodium balance; sodium depletion increases the secretion of renin, and sodium loading decreases it. Bull. N.Y. Acad. Med.
933
OF HYPERTENSION TREATMENT TREATMENT OF HYPERTENSION
933~~~~~~-
VASOCONSTRICTION-VOLUME HYPOTHESIS AND THE RENIN AXIS RENIN
ANGIOTENSIN
I
ANGIOTENSIN II A LDOSTERONE
SODIUM VASOCONSTRICTION
L
---
VOLUME
------
--OBLOOD PRESSURE |--
-Negative feedback
Fig. 1. The renin-angiotensin-aldosterone axis and its regulation of the vasoconstriction and volume components of blood pressure. Dotted lines signify negative feedback pathways. Reproduced by permission from Laragh, J. H.: Modern system for treating high blood pressure based on renin profiling and vasoconstriction-volume analysis: A primary role for beta blocking drugs such as propranolol. Am. J. Med. 61:797-810, 1976.
The third important factor influencing the secretion of renin is the sympathetic nervous system, which stimulates the release of renin through beta-adrenergic receptors located directly on the juxtaglomerular cells. Once in the circulation, renin's sole effect is to act on angiotensinogen (renin substrate), an alpha-glycoprotein produced in the liver, to split off the decapeptide, angiotensin I. Angiotensin I has little or no direct action of its own, but during passage through the pulmonary circulation is acted upon by a hydrolytic converting enzyme that breaks off a dipeptide fragment to produce the octapeptide hormone, angiotensin II. Angiotensin II has two principal actions. The first is direct vasoconstriction on the arterial circulation. Angiotensin II is an exceptionally potent Vol. 54, No. 10, November 1978
934
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M. A. WEBER AND J. H. LARAGH
pressor hormone, at least several times more powerful by weight than norepinephrine in producing vasoconstriction. The second major action of angiotensin II is to stimulate secretion of the mineralocorticoid hormone aldosterone from the adrenal cortex. In turn, aldosterone acts in the distal convoluted tubule of the kidney to promote reabsorption of sodium and water. Thus, as Figure 1 shows, the renin-angiotensin system can increase blood pressure in two ways: direct vasoconstriction and sodium and water retention. By these actions that regulate both the capacity of the arterial circulation and the volume of circulating plasma, the renin-aldosterone axis plays an integral part in the overall control of blood pressure. RENIN AND HYPERTENSION
The role of renin as a participant in hypertensive mechanisms and as an indicator of the pathophysiological characteristics of hypertension now is well established. Studies in man and in animal models document the seminal role of the renin axis in high blood pressure states through what is now called the vasoconstriction-volume analysis.2 In essence, three key explanations have been advanced: In patients whose plasma levels of renin are inappropriately high the renin-angiotensin system, through its direct vasoconstrictor actions, is considered the principal factor sustaining the hypertension; in patients whose renin levels are suppressed, excessive salt and water retention provides the main force for sustaining the high blood pressure; and in patients whose renin levels seem normal both vasoconstrictor and volume factors are involved in producing the hypertension. Before these hypotheses could be tested it was necessary to find a reliable method to establish whether a patient in fact had a high, normal, or low-renin status. The chief difficulty in attaining this goal was that plasma renin levels vary considerably according to the state of sodium balance; therefore, it would be invalid simply to use the renin measurements themselves to classify patients. This problem was solved by a nomogram,3 based on observations of many normotensive volunteers in whom the appropriate relation between plasma renin levels and sodium balance could be established (Figure 2). The 24-hour urinary excretion of sodium was used as the monitor of salt balance; this not only is convenient, but portrays the level of sodium ingestion with great accuracy in almost all subjects. By reference to the nomogram a patient can immediately be classified into the appropriate renin subgroup: high, if the renin measureBull. N.Y. Acad. Med.
a,3p\o8
A PHYSIOLOGICAL BASIS FOR THE TREATMENT OF ESSENTIAL HYPERTENSION* MICHAEL A. WEBER, M.D., and JOHN H. LARAGH, M.D. Cardiovascular Center The New York Hospital-Cornell Medical Center New York, New York
DURING the last two decades our approach to hypertension has changed radically and we are now aware that hypertension probably is the principal factor in the genesis of most cardiovascular disease. Heart disease and stroke, both closely related to hypertension, are the most important causes of death and disability in the United States. The magnitude of the challenge facing physicians has been highlighted by estimates that between 12 and 25% of adults are hypertensive. An important impetus to more aggressive treatment has come from various studies, such as the Veterans Administration Cooperative Study,1 which document that the lowering of blood pressure substantially reduces the incidence of stroke, heart failure, and renal insufficiency among hypertensive subjects. Two other developments have made it possible to meet the problem. First, during the last 10 or 15 years the advent of a new generation of drugs that are effective and palatable has allowed treatment of many patients who would have found the severe side-effects of previous drugs intolerable. Second, and perhaps more important, breakthroughs in understanding of circulatory physiology, particularly hormonal regulation of blood pressure, have enabled us to propose rational and specific approaches to treatment. Thus, the physician now can prescribe individualized therapy based on the definition of mechanisms that are sustaining the high blood pressure. MECHANISMS IN ESSENTIAL HYPERTENSION
Investigators have advanced several hypotheses to explain essential hypertension. These explanations are based on abnormalities in the central *Presented as part of a meeting on Advances in Primary Care held by the Committee on Medical Education of the New York Academy of Medicine June 6 to 10, 1977.
Vol. 54, No. 10, November 1978
9329
3
M
M. A. WEBER AND J. H..LRG LARAGH A. WEE N
and sympathetic nervous systems and the intrinsic properties of the heart and arterial circulation. Changes in the metabolism of mineralocorticoid hormones and even prostaglandins also have been cited as possible causes or participating mechanisms in the genesis of hypertension. Hypotheses dealing with these factors and others are all potentially attractive, but as yet we have insufficient data to incorporate these ideas into the clinical management of hypertensive patients. One consistently advanced explanation for essential hypertension is that elevated blood pressure is sustained by an excessive volume of sodium and water. In the sense that hypertension can result only when the capacity of the arterial system is relatively too small for the volume it is required to accommodate, this thesis has a certain logical force. Indeed, it is the basis for the now popular "stepped-care" approach to treating hypertension, in which all patients receive potent diuretic therapy as the cornerstone of their treatment. Unfortunately, this approach presumes, without justification, a homogeneity within the hypertensive population. It fails to take into account that in some patients volume factors are normal or even reduced and that, instead, their hypertension is sustained entirely by an excessively vasoconstricted state (i.e., reduced capacity) of the arterial circulation; in such patients the indiscriminate use of diuretics not only may fail to prove helpful, but may actually be counterproductive. THE RENIN-ALDOSTERONE Axis
During the last few years an improved understanding of the reninangiotensin-aldosterone axis has provided the most workable elucidation of the characteristics of essential hypertension. By employing a technique called "renin profiling" it is now possible to classify patients with essential hypertension into different groups according to etiologic mechanism and to provide them with appropriate, specific, and individual treatment. A schema of the renin-angiotensin-aldosterone system is shown in Figure 1. The enzyme renin is synthesized and stored in the juxtaglomerular cells of the kidney, which are sensitive to changes in renal blood pressure; reductions in blood flow stimulate the secretion of renin and increases in blood flow inhibit it. Through the macula densa-a specialized portion of the distal convoluted tubule in close apposition to the juxtaglomerular cells-and perhaps through other mechanisms as well, the secretion of renin is influenced strongly by the overall state of sodium balance; sodium depletion increases the secretion of renin, and sodium loading decreases it. Bull. N.Y. Acad. Med.
933
OF HYPERTENSION TREATMENT TREATMENT OF HYPERTENSION
933~~~~~~-
VASOCONSTRICTION-VOLUME HYPOTHESIS AND THE RENIN AXIS RENIN
ANGIOTENSIN
I
ANGIOTENSIN II A LDOSTERONE
SODIUM VASOCONSTRICTION
L
---
VOLUME
------
--OBLOOD PRESSURE |--
-Negative feedback
Fig. 1. The renin-angiotensin-aldosterone axis and its regulation of the vasoconstriction and volume components of blood pressure. Dotted lines signify negative feedback pathways. Reproduced by permission from Laragh, J. H.: Modern system for treating high blood pressure based on renin profiling and vasoconstriction-volume analysis: A primary role for beta blocking drugs such as propranolol. Am. J. Med. 61:797-810, 1976.
The third important factor influencing the secretion of renin is the sympathetic nervous system, which stimulates the release of renin through beta-adrenergic receptors located directly on the juxtaglomerular cells. Once in the circulation, renin's sole effect is to act on angiotensinogen (renin substrate), an alpha-glycoprotein produced in the liver, to split off the decapeptide, angiotensin I. Angiotensin I has little or no direct action of its own, but during passage through the pulmonary circulation is acted upon by a hydrolytic converting enzyme that breaks off a dipeptide fragment to produce the octapeptide hormone, angiotensin II. Angiotensin II has two principal actions. The first is direct vasoconstriction on the arterial circulation. Angiotensin II is an exceptionally potent Vol. 54, No. 10, November 1978
934
934
M. A. WEBER AND J. H. LARAGH
pressor hormone, at least several times more powerful by weight than norepinephrine in producing vasoconstriction. The second major action of angiotensin II is to stimulate secretion of the mineralocorticoid hormone aldosterone from the adrenal cortex. In turn, aldosterone acts in the distal convoluted tubule of the kidney to promote reabsorption of sodium and water. Thus, as Figure 1 shows, the renin-angiotensin system can increase blood pressure in two ways: direct vasoconstriction and sodium and water retention. By these actions that regulate both the capacity of the arterial circulation and the volume of circulating plasma, the renin-aldosterone axis plays an integral part in the overall control of blood pressure. RENIN AND HYPERTENSION
The role of renin as a participant in hypertensive mechanisms and as an indicator of the pathophysiological characteristics of hypertension now is well established. Studies in man and in animal models document the seminal role of the renin axis in high blood pressure states through what is now called the vasoconstriction-volume analysis.2 In essence, three key explanations have been advanced: In patients whose plasma levels of renin are inappropriately high the renin-angiotensin system, through its direct vasoconstrictor actions, is considered the principal factor sustaining the hypertension; in patients whose renin levels are suppressed, excessive salt and water retention provides the main force for sustaining the high blood pressure; and in patients whose renin levels seem normal both vasoconstrictor and volume factors are involved in producing the hypertension. Before these hypotheses could be tested it was necessary to find a reliable method to establish whether a patient in fact had a high, normal, or low-renin status. The chief difficulty in attaining this goal was that plasma renin levels vary considerably according to the state of sodium balance; therefore, it would be invalid simply to use the renin measurements themselves to classify patients. This problem was solved by a nomogram,3 based on observations of many normotensive volunteers in whom the appropriate relation between plasma renin levels and sodium balance could be established (Figure 2). The 24-hour urinary excretion of sodium was used as the monitor of salt balance; this not only is convenient, but portrays the level of sodium ingestion with great accuracy in almost all subjects. By reference to the nomogram a patient can immediately be classified into the appropriate renin subgroup: high, if the renin measureBull. N.Y. Acad. Med.
a,3p\o8
