ANNUAL REVIEWS
Annu. Rev. Med. 1990. 41:377-82 Copyright © 1990 by Annual Reviews Inc. All rights reserved
Further
Quick links to online content
ATRIAL NATRIURETIC
Annu. Rev. Med. 1990.41:377-382. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
FACTOR IN EDEMATOUS DISORDERS Robert J. Cody, M.D.
Department of Medicine, The Ohio State University College of Medicine and Hospital, Columbus, Ohio 43210 KEY WORDS:
heart failure, hypertension, cirrhosis, nephrotic syndrome, natriuretic peptides-atrial.
ABSTRACT
This article provides a brief overview of atrial natriuretic factor (ANF). Considered by many investigators to be the putative "third factor" govern ing sodium excretion, ANF is a peptide actively secreted by the heart, with multiple target organ effectors. As such, ANF represents the first clearly documented cardiac hormone. INTRODUCTION It is
clear from the enthusiasm generated in both basic and clinical spheres, that atrial natriuretic factor (ANF) is a critical link in our understanding of sodium and water regulation. This review summarizes the events leading to the discovery of the hormone ANF, the normal physiology of ANF, and the abnormalities of ANF that characterize edematous disorders. BACKGROUND
Under normal conditions, most of the sodium ingested in the diet is excreted in the urine. A rise or fall in sodium intake is "balanced" by the kidney within a matter of days. Sodium excretion is functionally dependent on the glomerular filtration rate and sodium reabsorption. Glomerular 377 0066-4219/90/0401-0377$02.00
Annu. Rev. Med. 1990.41:377-382. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
378
CODY
filtration rate represents the first factor controlling sodium excrction; thc hormonal control of sodium reabsorption, the second factor, is largely the effect of aldosterone at the distal nephron. A "third factor" had been suspected for several decades, and the rationale for this line of reasoning is summarized elsewhere (1). That changes in atrial tension were somehow closely related to sodium excretion had been suspected for many years, because the atria of the mammalian heart appeared to participate in the regulation of intravascular volume. Very early studies demonstrated that mechanically stretching the atria produced a rapid diuresis, initially attri buted to stimulation of afferent vagal fibers. These observations temporally coincided with the identification of membrane-bound secretory granules in atrial myocytes, which responded to alterations of intravascular volume. Subsequently, deBold and colleagues (2) demonstrated that a crude protein extract from atrial myocytes could induce rapid and reversible increases of sodium and water excretion, establishing a direct link between a cardiac hormone and the kidney. Available evidence suggests that atrial natriuretic factor (AN F), also known as atrial natriuretic peptide (ANP), fulfills the criteria for a third factor.
ANF CONCENTRATION WITHIN THE CIRCULATION
The precursor peptide of ANF (pro-ANF) is a 126-amino-acid residue peptide that is stored in atrial myocytes of mammalian tissue. Structurally related ANF segments have been isolated by many investigators, and the characteristics of the peptide were summarized by Weder et al (5). The circulating form of ANF in humans corresponds to residue numbers 99 to 126, which comprises the C-terminal 28-residue peptide of pro-ANF. Specific ANF receptors have been identified in various target organs, including the kidney, adrenal gland, vascular smooth muscle, and brain (1). Plasma ANF levels respond dynamically to a number of physiologic stimuli. Since ANF is secreted by atrial (and under certain conditions, ventricular) myocytes, the circulatory concentration of ANF is highest in the coronary sinus. ANF binds to particulate guanylate cyclase, which governs the formation of cyclic GMP and thereby provides a plausible cellular messenger for the effects of ANF. The hypothesis that changes in atrial volume or pressure govern ANF release is readily tested by maneu vers that increase or decrease atrial tension. For instance, head-up tilt or lower body negative pressure decreases atrial volume and tension, which in turn decreases ANF secretion; head-down tilt increases atrial volume
Annu. Rev. Med. 1990.41:377-382. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
ANF IN EDEMATOUS DISORDERS
379
and tension (as does immersion in water) and increases ANF secretion. Exercise, which increases atrial pressure and volume, also increases plasma ANF concentrations in both normal subjects and those with edematous diseases. Teleologically it is unlikely that this rise in ANF increases sodium and water excretion, but it may be important in terms of two other target organ responses discussed below: vasodilatation and fluid sequestration. Infusion of saline or other colloids tends to enhance ANF secretion. However, this is not a uniform response and may depend to a certain degree on the myocardial response to volume challenge. Conversely, experimental hemorrhage or sodium depletion reduces ANF secretion. RESPONSE TO EXOGENOUS ANF ADMINISTRATION
Exogenous ANF has been administered to normal subjects and to patients with edematous disorders, in order to evaluate its physiologic effects and determine its potential therapeutic efficacy (1, 3). Commercially prepared ANF is a peptide that can pe degraded by gastrointestinal proteases and so must be administered intravenously. No major physiological differences have been detected among the various commercial preparations of ANF. The first peptide infusions consisted of relatively large, or pharmacologic, doses of ANF. These were administered either as a bolus or as a steady state infusion at one or more doses. In normal subjects, ANF administration has diverse actions (3). The hemodynamic response consists of vasodilatation, reduction of blood pres sure, and variable effects on heart rate and cardiac output. In some subjects there is a marked reduction of heart rate and blood pressure that is not necessarily dose dependent and that has many of the characteristics of a vagal response, including pallor, sweating, and nausea. The renal response is characterized by a prompt increase of sodium and water excretion. A tendency for glomerular filtration rate to increase and renal blood flow to decrease produces a significant net increase of filtration fraction. The observed net diuresis consists of an increase of both free water and osmolar clearance. The hormonal response to ANF infusion includes reduced plasma renin activity and reduced secretion of aldosterone. ANF infusion produces significant hemoconcentration, which is reversible once peptide administration is discontinued. Such hemoconcentration is attributed to an increased vascular permeability. CONGESTIVE HEART FAILURE
In general, patients with congestive heart failure demonstrate the highest plasma levels of ANF (3). However, the range of values is quite broad,
Annu. Rev. Med. 1990.41:377-382. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
380
CODY
and patients with mild congestive heart failure may even demonstrate virtually normal circulating levels. In some studies, comparisons of plasma ANF levels to functional status suggest that ANF is a sensitive marker for congestive heart failure, because the circulating level increases as the severity of heart failure progresses. Despite high circulating ANF levels under basal conditions, heart failure patients can still demonstrate a sig nificant increase of ANF in response to physiological maneuvers, such as exercise, that increase atrial tension. There is a paradox between the high plasma level of ANF and the tendency for sodium retention. Vaso constrictors, such as angiotensin II, may offset the vasodilating effect of ANF. Furthermore, the reduction of glomerular filtration rate and enhanced secretion of aldosterone in heart failure are dominant influences in sodium retention. These offsetting effects may help explain the relatively minimal target organ response to exogenous ANF administration in heart failure, char acterized by a blunted naturesis and diuresis. However, a measurable vasodilating effect suggests that the vascular responsiveness to ANF may be less impaired. Nonetheless, current studies do not support a major therapeutic role for ANF infusion in heart failure patients. HYPERTENSION
The important link between ANF and hypertension is the apparent inability of many hypertensive patients to excrete excess sodium and water. The pathophysiologic mechanism for the sodium-dependent form of hypertension has been difficult to identify beyond obvious etiologies such as primary hypersecretion of aldosterone. Two pathophysiologic scenarios could involve ANF in the sodium retention of hypertension. First, ANF secretion may be relatively low in some hypertensive patients, which would favor a relative retention of sodium and water. Second, ANF secretion may be normal but target organ responses to ANF abnormal, which again would produce sodium and water retention. ANF activity in hypertension can be related to several known patho physiologic factors (4). ANF and renin system activity are of specific interest, in view of the apparent inverse physiological relationship of the two hormonal systems in response to changes in atrial tension, governed by intravascular volume or cardiac disease. The opposing effects of the two hormonal systems on vascular tone and sodium homeostasis were discussed above. While several studies suggest an inverse relationship between the renin system and ANF secretion, other studies have not confirmed these observations. In hypertensive patients with normal renal function, circulating levels of ANF are generally within the normal range.
Annu. Rev. Med. 1990.41:377-382. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
ANF IN EDEMATOUS DISORDERS
381
In patients whose hypertension is secondary to renal vascular disease, increased ANF levels appear related to volume status and atrial distension, rather than to the degree of hypertension or plasma renin elevation. In patients with chronic renal failure, there is a relative increase of atrial natriuretic peptidc, but it is difficult to tell whether this augmented ANF secretion is due to the hypertension per se or to abnormal sodium retention. There may be a specific role for ANF in diabetic glomerulopathy, par ticularly in individuals with hypertension: experimental animal sudies sug gest that renal ANF abnormalities contribute to excessive sodium and water retention in this disorder. There may be an antihypertensive effect on ANF infusion in this population (5). However, the reponse does not conform to standard dose response principles, and it may actually be erratic, with marked and unpredictable blood pressure reduction in some patients. CIRRHOSIS
In patients with cirrhosis, the circulating level of ANF ranges from normal to modestly increased (6). Irrespective of the absolute level, the relative ANF level is apparently low compared to the magnitude of sodium and water retention observed in edematous cirrhotic patients. However, physio logical maneuvers such as head-out water immersion, which produces a central redistribution of blood volume, increase the plasma ANF level. Response to exogenous administration of ANF is also blunted in pati ents with cirrhosis (7). Graded infusions of the peptide can, in some patients, produce very small increases in sodium and water excretion, but it is less than one would anticipate in normal subjects. NEPHROTIC SYNDROME
In both experimental animal and clinical studies of the nephrotic syndrome, the circulating level of ANF is increased, particularly when associated with clinical evidence of sodium and water retention (8). The increase appears to be a compensatory response to abnormal sodium and water handling by the kidney. Data regarding the response to exogenous ANF infusion in this disorder are limited; however, the renal response has been reported in experimental animals (9). ANF THERAPY FOR EDEMATOUS DISORDERS
While a measureable response to ANF infusion can often be demonstrated in edematous disorders, this appears to be more statistical than biologically significant. The observed changes are not necessarily of an order of mag-
382
CODY
nitude to indicate pharmacologic efficacy, particularly compared to other agents such as diuretics and vasodilators. More recently, inhibitors of the endopeptidase responsible for ANF degradation offer an alternative therapeutic approach, with the advantage of being orally active com pounds (10), but the utility of these agents requires further clarification.
Annu. Rev. Med. 1990.41:377-382. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
SUMMARY
Edematous disorders are characterized by enhanced secretion of ANF when there is an increase of atrial tension or central blood volume. This enhancement is seen in patients with congestive heart failure, in most patients with nephrotic syndrome, and in some patients with hypertension. Peripheral edema, and compromised renal function are seen in many patients with cirrhosis. Secretion of ANF is not necessarily increased if central blood volume and atrial pressures are not increased. The effective ness of endogenous ANF, or pharmacologic manipulations that increase plasma levels of ANF, to enhance sodium and water excretion depends on the degree to which renal function is compromised and/or the activation of renal hemodynamic and hormonal mechanisms that oppose the action of ANF. Literature Cited
I. Cody, R. 1., Atlas, S. A., Laragh, 1. H.
2.
3.
4.
5.
6.
1987. Physiological and phar macological studies of atrial natriuretic factor, a natriuretic and vasoactive pep tide. J. Clin. Pharmacal. 27: 927-36 deBold, A. 1., Borenstein, H. B., Veress, A. T., Sonnenberg, H. 1981. A rapid and potent natriuretic response to intra venous injection of atrial myocardial extract in rats. Life Sci. 28: 89-94 Cody, R. 1., Atlas, A. A., Laragh, 1. H., Kubo, S. H., Covit, A. B., et a1. 1986. Atrial natriuretic factor in normal sub jects and heart failure patients: plasma levels and renal, hormonal, and hem odynamic response to peptide infusion. J. Clin. Invest. 78: 1362-74 Cody, R. J. 1989. The pathophysiology of atrial natriuretic peptide in hyper tension. In Contemporary Issues in Neph rology, ed. B. Brenner, J. Stein, pp. 23964. New York: Churchill Livingstone Weder, A. B., Sekkarie, M. A., Takiyyuddin, M., Shork, N. J., Julius, S. 1987. Antihypertensive and hypotensive effects of atrial natriuretic factor in man. Hypertension 10: 582-89 Bonkovsky, H. L., Hartle, D. K., Mellen, B. G., Kutner, M., Galambos,
7.
8.
9.
10.
1. T. 1988. Plasma concentrations of immunoreactive atrial natriuretic pep tide in hospitalized cirrhotic and non cirrhotic patients: evidence for a role of deficient atrial natriuretic peptide in pathogenesis of cirrhotic ascites. Am. J. Gastroenterol. 83: 531-35 Laffi, G., Pinzani, M., Meacci, E., La Villa, G., Renzi, D., et al. 19)19. Renal hemodynamic and natriuretic effects of human atrial natriuretic factor infusion cirrhosis with ascites. Gastro in enterology 96: 167-77 Peterson, C., Madsen, B., Perlman, A., Chan, A. Y., Myers, B. D. 1988. Atrial natriuretic peptide and the rcnal response to hypervolemia in nephrotic humans. Kidney Int. 34: 825-31 Hildenbrandt, D. A., Banks, R. 0. 1988. Effect of atrial natriuretic factor on renal function in rats with nephrotic syndrome. Am. J. Physiol. 254: F210--6 Samuels, G. M. R., Barclay, P. L., Peters, C. J., Ellis, P. 1989. Atri opeptidase inhibitors, a novel class of drug that raises levels of endogenous atr ial natriuretic factor-The preclinical pharmacology of UK-69, 578. J. Am. Call. Cardiol. 13: 75A (Abstr.)
Annu. Rev. Med. 1990. 41:377-82 Copyright © 1990 by Annual Reviews Inc. All rights reserved
Further
Quick links to online content
ATRIAL NATRIURETIC
Annu. Rev. Med. 1990.41:377-382. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
FACTOR IN EDEMATOUS DISORDERS Robert J. Cody, M.D.
Department of Medicine, The Ohio State University College of Medicine and Hospital, Columbus, Ohio 43210 KEY WORDS:
heart failure, hypertension, cirrhosis, nephrotic syndrome, natriuretic peptides-atrial.
ABSTRACT
This article provides a brief overview of atrial natriuretic factor (ANF). Considered by many investigators to be the putative "third factor" govern ing sodium excretion, ANF is a peptide actively secreted by the heart, with multiple target organ effectors. As such, ANF represents the first clearly documented cardiac hormone. INTRODUCTION It is
clear from the enthusiasm generated in both basic and clinical spheres, that atrial natriuretic factor (ANF) is a critical link in our understanding of sodium and water regulation. This review summarizes the events leading to the discovery of the hormone ANF, the normal physiology of ANF, and the abnormalities of ANF that characterize edematous disorders. BACKGROUND
Under normal conditions, most of the sodium ingested in the diet is excreted in the urine. A rise or fall in sodium intake is "balanced" by the kidney within a matter of days. Sodium excretion is functionally dependent on the glomerular filtration rate and sodium reabsorption. Glomerular 377 0066-4219/90/0401-0377$02.00
Annu. Rev. Med. 1990.41:377-382. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
378
CODY
filtration rate represents the first factor controlling sodium excrction; thc hormonal control of sodium reabsorption, the second factor, is largely the effect of aldosterone at the distal nephron. A "third factor" had been suspected for several decades, and the rationale for this line of reasoning is summarized elsewhere (1). That changes in atrial tension were somehow closely related to sodium excretion had been suspected for many years, because the atria of the mammalian heart appeared to participate in the regulation of intravascular volume. Very early studies demonstrated that mechanically stretching the atria produced a rapid diuresis, initially attri buted to stimulation of afferent vagal fibers. These observations temporally coincided with the identification of membrane-bound secretory granules in atrial myocytes, which responded to alterations of intravascular volume. Subsequently, deBold and colleagues (2) demonstrated that a crude protein extract from atrial myocytes could induce rapid and reversible increases of sodium and water excretion, establishing a direct link between a cardiac hormone and the kidney. Available evidence suggests that atrial natriuretic factor (AN F), also known as atrial natriuretic peptide (ANP), fulfills the criteria for a third factor.
ANF CONCENTRATION WITHIN THE CIRCULATION
The precursor peptide of ANF (pro-ANF) is a 126-amino-acid residue peptide that is stored in atrial myocytes of mammalian tissue. Structurally related ANF segments have been isolated by many investigators, and the characteristics of the peptide were summarized by Weder et al (5). The circulating form of ANF in humans corresponds to residue numbers 99 to 126, which comprises the C-terminal 28-residue peptide of pro-ANF. Specific ANF receptors have been identified in various target organs, including the kidney, adrenal gland, vascular smooth muscle, and brain (1). Plasma ANF levels respond dynamically to a number of physiologic stimuli. Since ANF is secreted by atrial (and under certain conditions, ventricular) myocytes, the circulatory concentration of ANF is highest in the coronary sinus. ANF binds to particulate guanylate cyclase, which governs the formation of cyclic GMP and thereby provides a plausible cellular messenger for the effects of ANF. The hypothesis that changes in atrial volume or pressure govern ANF release is readily tested by maneu vers that increase or decrease atrial tension. For instance, head-up tilt or lower body negative pressure decreases atrial volume and tension, which in turn decreases ANF secretion; head-down tilt increases atrial volume
Annu. Rev. Med. 1990.41:377-382. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
ANF IN EDEMATOUS DISORDERS
379
and tension (as does immersion in water) and increases ANF secretion. Exercise, which increases atrial pressure and volume, also increases plasma ANF concentrations in both normal subjects and those with edematous diseases. Teleologically it is unlikely that this rise in ANF increases sodium and water excretion, but it may be important in terms of two other target organ responses discussed below: vasodilatation and fluid sequestration. Infusion of saline or other colloids tends to enhance ANF secretion. However, this is not a uniform response and may depend to a certain degree on the myocardial response to volume challenge. Conversely, experimental hemorrhage or sodium depletion reduces ANF secretion. RESPONSE TO EXOGENOUS ANF ADMINISTRATION
Exogenous ANF has been administered to normal subjects and to patients with edematous disorders, in order to evaluate its physiologic effects and determine its potential therapeutic efficacy (1, 3). Commercially prepared ANF is a peptide that can pe degraded by gastrointestinal proteases and so must be administered intravenously. No major physiological differences have been detected among the various commercial preparations of ANF. The first peptide infusions consisted of relatively large, or pharmacologic, doses of ANF. These were administered either as a bolus or as a steady state infusion at one or more doses. In normal subjects, ANF administration has diverse actions (3). The hemodynamic response consists of vasodilatation, reduction of blood pres sure, and variable effects on heart rate and cardiac output. In some subjects there is a marked reduction of heart rate and blood pressure that is not necessarily dose dependent and that has many of the characteristics of a vagal response, including pallor, sweating, and nausea. The renal response is characterized by a prompt increase of sodium and water excretion. A tendency for glomerular filtration rate to increase and renal blood flow to decrease produces a significant net increase of filtration fraction. The observed net diuresis consists of an increase of both free water and osmolar clearance. The hormonal response to ANF infusion includes reduced plasma renin activity and reduced secretion of aldosterone. ANF infusion produces significant hemoconcentration, which is reversible once peptide administration is discontinued. Such hemoconcentration is attributed to an increased vascular permeability. CONGESTIVE HEART FAILURE
In general, patients with congestive heart failure demonstrate the highest plasma levels of ANF (3). However, the range of values is quite broad,
Annu. Rev. Med. 1990.41:377-382. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
380
CODY
and patients with mild congestive heart failure may even demonstrate virtually normal circulating levels. In some studies, comparisons of plasma ANF levels to functional status suggest that ANF is a sensitive marker for congestive heart failure, because the circulating level increases as the severity of heart failure progresses. Despite high circulating ANF levels under basal conditions, heart failure patients can still demonstrate a sig nificant increase of ANF in response to physiological maneuvers, such as exercise, that increase atrial tension. There is a paradox between the high plasma level of ANF and the tendency for sodium retention. Vaso constrictors, such as angiotensin II, may offset the vasodilating effect of ANF. Furthermore, the reduction of glomerular filtration rate and enhanced secretion of aldosterone in heart failure are dominant influences in sodium retention. These offsetting effects may help explain the relatively minimal target organ response to exogenous ANF administration in heart failure, char acterized by a blunted naturesis and diuresis. However, a measurable vasodilating effect suggests that the vascular responsiveness to ANF may be less impaired. Nonetheless, current studies do not support a major therapeutic role for ANF infusion in heart failure patients. HYPERTENSION
The important link between ANF and hypertension is the apparent inability of many hypertensive patients to excrete excess sodium and water. The pathophysiologic mechanism for the sodium-dependent form of hypertension has been difficult to identify beyond obvious etiologies such as primary hypersecretion of aldosterone. Two pathophysiologic scenarios could involve ANF in the sodium retention of hypertension. First, ANF secretion may be relatively low in some hypertensive patients, which would favor a relative retention of sodium and water. Second, ANF secretion may be normal but target organ responses to ANF abnormal, which again would produce sodium and water retention. ANF activity in hypertension can be related to several known patho physiologic factors (4). ANF and renin system activity are of specific interest, in view of the apparent inverse physiological relationship of the two hormonal systems in response to changes in atrial tension, governed by intravascular volume or cardiac disease. The opposing effects of the two hormonal systems on vascular tone and sodium homeostasis were discussed above. While several studies suggest an inverse relationship between the renin system and ANF secretion, other studies have not confirmed these observations. In hypertensive patients with normal renal function, circulating levels of ANF are generally within the normal range.
Annu. Rev. Med. 1990.41:377-382. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
ANF IN EDEMATOUS DISORDERS
381
In patients whose hypertension is secondary to renal vascular disease, increased ANF levels appear related to volume status and atrial distension, rather than to the degree of hypertension or plasma renin elevation. In patients with chronic renal failure, there is a relative increase of atrial natriuretic peptidc, but it is difficult to tell whether this augmented ANF secretion is due to the hypertension per se or to abnormal sodium retention. There may be a specific role for ANF in diabetic glomerulopathy, par ticularly in individuals with hypertension: experimental animal sudies sug gest that renal ANF abnormalities contribute to excessive sodium and water retention in this disorder. There may be an antihypertensive effect on ANF infusion in this population (5). However, the reponse does not conform to standard dose response principles, and it may actually be erratic, with marked and unpredictable blood pressure reduction in some patients. CIRRHOSIS
In patients with cirrhosis, the circulating level of ANF ranges from normal to modestly increased (6). Irrespective of the absolute level, the relative ANF level is apparently low compared to the magnitude of sodium and water retention observed in edematous cirrhotic patients. However, physio logical maneuvers such as head-out water immersion, which produces a central redistribution of blood volume, increase the plasma ANF level. Response to exogenous administration of ANF is also blunted in pati ents with cirrhosis (7). Graded infusions of the peptide can, in some patients, produce very small increases in sodium and water excretion, but it is less than one would anticipate in normal subjects. NEPHROTIC SYNDROME
In both experimental animal and clinical studies of the nephrotic syndrome, the circulating level of ANF is increased, particularly when associated with clinical evidence of sodium and water retention (8). The increase appears to be a compensatory response to abnormal sodium and water handling by the kidney. Data regarding the response to exogenous ANF infusion in this disorder are limited; however, the renal response has been reported in experimental animals (9). ANF THERAPY FOR EDEMATOUS DISORDERS
While a measureable response to ANF infusion can often be demonstrated in edematous disorders, this appears to be more statistical than biologically significant. The observed changes are not necessarily of an order of mag-
382
CODY
nitude to indicate pharmacologic efficacy, particularly compared to other agents such as diuretics and vasodilators. More recently, inhibitors of the endopeptidase responsible for ANF degradation offer an alternative therapeutic approach, with the advantage of being orally active com pounds (10), but the utility of these agents requires further clarification.
Annu. Rev. Med. 1990.41:377-382. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
SUMMARY
Edematous disorders are characterized by enhanced secretion of ANF when there is an increase of atrial tension or central blood volume. This enhancement is seen in patients with congestive heart failure, in most patients with nephrotic syndrome, and in some patients with hypertension. Peripheral edema, and compromised renal function are seen in many patients with cirrhosis. Secretion of ANF is not necessarily increased if central blood volume and atrial pressures are not increased. The effective ness of endogenous ANF, or pharmacologic manipulations that increase plasma levels of ANF, to enhance sodium and water excretion depends on the degree to which renal function is compromised and/or the activation of renal hemodynamic and hormonal mechanisms that oppose the action of ANF. Literature Cited
I. Cody, R. 1., Atlas, S. A., Laragh, 1. H.
2.
3.
4.
5.
6.
1987. Physiological and phar macological studies of atrial natriuretic factor, a natriuretic and vasoactive pep tide. J. Clin. Pharmacal. 27: 927-36 deBold, A. 1., Borenstein, H. B., Veress, A. T., Sonnenberg, H. 1981. A rapid and potent natriuretic response to intra venous injection of atrial myocardial extract in rats. Life Sci. 28: 89-94 Cody, R. 1., Atlas, A. A., Laragh, 1. H., Kubo, S. H., Covit, A. B., et a1. 1986. Atrial natriuretic factor in normal sub jects and heart failure patients: plasma levels and renal, hormonal, and hem odynamic response to peptide infusion. J. Clin. Invest. 78: 1362-74 Cody, R. J. 1989. The pathophysiology of atrial natriuretic peptide in hyper tension. In Contemporary Issues in Neph rology, ed. B. Brenner, J. Stein, pp. 23964. New York: Churchill Livingstone Weder, A. B., Sekkarie, M. A., Takiyyuddin, M., Shork, N. J., Julius, S. 1987. Antihypertensive and hypotensive effects of atrial natriuretic factor in man. Hypertension 10: 582-89 Bonkovsky, H. L., Hartle, D. K., Mellen, B. G., Kutner, M., Galambos,
7.
8.
9.
10.
1. T. 1988. Plasma concentrations of immunoreactive atrial natriuretic pep tide in hospitalized cirrhotic and non cirrhotic patients: evidence for a role of deficient atrial natriuretic peptide in pathogenesis of cirrhotic ascites. Am. J. Gastroenterol. 83: 531-35 Laffi, G., Pinzani, M., Meacci, E., La Villa, G., Renzi, D., et al. 19)19. Renal hemodynamic and natriuretic effects of human atrial natriuretic factor infusion cirrhosis with ascites. Gastro in enterology 96: 167-77 Peterson, C., Madsen, B., Perlman, A., Chan, A. Y., Myers, B. D. 1988. Atrial natriuretic peptide and the rcnal response to hypervolemia in nephrotic humans. Kidney Int. 34: 825-31 Hildenbrandt, D. A., Banks, R. 0. 1988. Effect of atrial natriuretic factor on renal function in rats with nephrotic syndrome. Am. J. Physiol. 254: F210--6 Samuels, G. M. R., Barclay, P. L., Peters, C. J., Ellis, P. 1989. Atri opeptidase inhibitors, a novel class of drug that raises levels of endogenous atr ial natriuretic factor-The preclinical pharmacology of UK-69, 578. J. Am. Call. Cardiol. 13: 75A (Abstr.)
![[Atrial natriuretic factor].](/assets/img/hold.png)
