- Email: [email protected]
The integrated effects of angiotensin II
The Integrated Effects of Angiotensin II Robert J. Cody, MD In recent years, a prodigious amount of information has been gathered regarding the relation5hip between vascular biology and the mechanisms underlying cardiovascular disease. Activation of elements of the reninangiotensin system (RAS) appear to play an important role in the development and progreuion of conditions such as hypertension, coronary artery disease, and heart failure. Indeed, converging lines of evidence indicate that angioten5in-converting enzyme (ACE) regulates a delicate balance among a multitudeof factors responsible for vascular tone, cellular growth promotion and inhibition, and pro- and anti-inflammatory effects. Be-
cause angiotensin II inhibits fibronectin, stimulates expression of pla5minogen activator inhibitors, and degrades bradykinin, thereby impairing production of nitricoxide, ACE and the RAS are also involvedin thrombosis and fibrinolysis. The favorable effects of ACE inhibition on endothelial function and, potentially, on cardiovascular morbidity and mortality are believed to result not only from angiotensin II suppression but also its consequent bradykinin preservation and nitric oxide production. © 7997 by Excerpta Medica, Inc. Am J Cardio11997;79 (SA):9-11
he renin-angiotensin system (RAS) is intiT mately involved in the control of blood pressure and fluid and electrolyte homeostasis.' Compo-
THE RENIN-ANGIOTENSIN SYSTEM Research has shown that the RAS is highly complex . Early investigation into the interplay between renin and aldosterone demonstrated that the RAS utilizes a variety of homeostatic controls to maintain normal blood pressure and electrolyte status." The first of these controls to be investigated were polypeptide vasoactive hormones. including A II. Since the circulating components of the RAS produce A II. which acts on remote target tissues (e.g .• blood vessels. adrenal glands. and kidneys). the RAS was perceived to be primarily a neuroendocrine system. ':' More recent information demonstrates that a local tissue RAS also exists; because components of the tissue RAS exert direct effects on local tissue. this system may be described as autocrine/paracrine. Over the long term. the combined function of the RAS may affect cardiovascular function and structure.' ACE occurs predominantly on the endothelium. Thus. the tissue RAS may be intimately involved in the progression of cardiovascular disease. Regulation of vascular tone. from a structural and functional standpoint. is thought to occur via local tissue RAS in the central nervous system. vasculature. adrenal system, heart. and kidneys. 10,11
nents of the RAS have been implicated in early and late metabolic changes that lead to coronary artery disease and heart failure." The RAS has long been known to be a key regulator of hypertension; this finding led to the development of angiotensin-convert ing enzyme (ACE) inhibitors as antihypertensive agents.' In the last decade. the results of clinical and experimental studies with ACE inhibitors suggest that these agents may also produce beneficial effects in coronary artery disease and improve cardiovascular outcomes." In addition to their blood pressure-lowering effects. ACE inhibitors have been shown to reduce vascular hypertrophy. attenuate atherosclerosis. and influence coronary ischemia and reperfusion injury. Furth~r more. clinical studies have found that ACE Inhibitors may be useful across the continuum of coronary artery disease"; in patients with moderate-to-severe heart failure. ACE inhibitors combined with diuretics and/or digoxin have been sh~wn to improve clinical signs and symptom.s. ~x ercise tolerance. and New York Heart ASSOCIatIOn functional class.l" Similarly. ACE inhibitors have been shown to delay the symptomatic onset of heart failure and clinical progression of this dis- EFFECTS OF ANGIOTENSIN II ease in patients with milder symptoms.":" When developing therapeutic strategies for paThese findings . as well as advances in vascular tients with coronary artery disease, the effects of A II biology, suggest that alterations in ACE activ.ity- are vital considerations. Although a vast amount of particularly at the tissue level-are important In the literature has been published about A II. some condevelopment and progression of cardiovascular dis- troversy remains regarding the various activities ease ." This article reviews the RAS. with an empha- modulated by A II and their relative importance.': " sis on the integral effects of angiotensin II (A II) and Va5occtivity: One of the most potent endogenous the benefits that may occur by blocking the forma- vasoconstrictors. A II affects blood pressure by acttion of A II with ACE inhibitors. ing on a variety of organ systems. In left ventricular dysfunction. elevated plasma levels of A II can impede blood flow. reducing card iac output and reFrom the Division of Cardiology , Departme,nt, of MediCine, The ?h,o gional flOW . I , 12 In addition, A II stimulates cell Sta te University Hospita ls, College o f MediCine, Columbus, Ohio growth and modulates the activity of other vasoacAddress for reprints. RobertJ C ody, foIU) , Dlvi sio n of Cardiology, The Ohio Stale University Hospitals, 61 1 Means Hall, 1654 Upham tive substances .":" Supranormal levels of plasma A II are also associated with progressive fibrosis. enDrive, Col umbus, Ohlo 432 10 © 1997 by Excerpta Medica, Inc. All right. reserved,
0002.9149/97/$17,00 PII 50002.9149(97)00123-9
9
dothelial cell dysfunction, thrombosis, and atherogenesis . 13.14 Fibrosis: An increase in plasma levels of A II and/ or aldosterone can lead to it fibrous tissue respon se, independent of the hemodynamic state." In animal models, administration of A II was associated with disruption of endothelial function , thickening of the vessel wall, and increased fibrosis." These findings suggest that elevated A II levels in conjunction with increased aldosterone levels are directly responsible for causing microendothelial lesions that increase coronary artery permeability," which may allow diffusion of growth factors into the myocardial interstitium. The increase in fibrous tissue (and collagen levels) contributes to greater myocardial wall stiffness, creating a feedback loop involving ventricular filling defects, cardiac decompensation, and a further increase in RAS activity.'? Fibrous tissue appears to accumulate when collagen stimulators (e.g., A II, aldosterone, and endothelins) are relatively abundant in proportion to collagen inhibitors (e.g., bradykinin, prostaglandins, and glucocorticoids).w Inhibition of fibrinolysis: Study of the thrombolytic and fibrinolytic pathways has revealed that A II inhibits fibronectin and stimulates expression of plasminogen activator inhibitors. 14.17 The effect of A II on plasminogen activator inhibitor may be crucial; in animal models, overexpression of plasminogen activator inhibitor increases the incidence of venous occlusions, resulting in peripheral ischemia and necrosis. In humans, the activity of A II in the vascu lature may impair fibrinolysis and possibly contribute to thrombus formation. 14 Activity in congestive heart failure: Angiotensin II contributes to congestive heart failure by directly stimulating the adrenals to release aldosterone, thereby exacerbating sodium and water retention. I Consequently, pulmonary and systemic venous congestion develop, contributing to increased vascular stiffness. I Depending on the concentration and preparation of A II as well as the experimental model utilized, A II has positive inotropic effects. IS For instance, an increase in A II in the myocardium produces a positive inotropic effect by acting on cardiac rnyocytes and impairing diastolic relaxation.' This direct action may be important in the process of cardiac hypertrophy andlor myocardial remodeling. Angiotensin 11stimulated sympathetic activity can also exert a positive inotropic effect and may be a factor in the occurrence of arrhythmia in the presence of ischemia or advanced heart failure.' Notably, Studer et al'" showed that patients with end-stage heart failure have increased ACE activity compared with healthy subjects. These investigators used a polymerase chain reaction to amplify and investigate the gene expression of major A II-forming enzymes (ACE and chymase) in the left ventricle. Compared with nonfailing hearts, the amount of ACE transcription was increased 3-fold in patients with chronic heart failure (4.2 :!: 2.5 vs 12.8 ± 6 x 105 10
THE AM ERICAN JOURNAL OF CARDIOlOGY41
TABLE I
Possible Benefits of Ang iotensin-Converting Enzyme (ACE) Inhibition
Left ventricular structural and functional effects Decreased transmural wall stress Decreased compensatory dilatation and compensatory increase of end-diostolic and end-systolic volume Improved coronary flow distr ibut ion in surface and transmurol planes Hemodynamic effects Reduced vascular resistance Reduced inotropic stimulation Absence of chronotropic stimulation Neurohormonal and paracrine effects Decreased circulating and tissue effects of ang iotensin" Diminished aldosterone and prevention of secondary sodium (and volume) retention Decreosed circulatory catecholam ines, improved bororeceptor function and restoration of sympathetic-parasympathetic balance Dimin ished bradykinin degradation Other effects Blockade of cell growth effects of angiotensin" Potential direct cellular effects of ACE (a carboxypeptidase) (Reprinted with permission fromAm Fom PhyJic,on')
relative ratio units, p <0.0005) . There was no difference in chymase gene expression between normal and failing hearts, indicating that the expression of ACE is due to activation of the cardiac RAS .
ANGIOTENSIN II RECEPTORS The physiologic effects of A II in cardiovascular disease appear to be mediated by binding to receptors in the plasma membrane of various tissues. I The best characterized receptor, the AT] subtype, is thought to regulate the activity of A II on the lungs, vascular smooth muscle cells, liver, brain, and kidneys. I The function of the AT 2 receptor is less well known; this subtype may affect fetal tissue, the brain, and reproductive tissue, and it may modulate other beneficial activities." The distinctly different mechanisms of action of A II in various effector tissues are thought to be related to multiple angiotensin receptor subtypes. I Angiotensin II exerts its effects at the cellular level through phosphorylation of the AT 1A receptor. 2 I
ROLE OF ACE INHIBITORS IN BLUNTING EFFECTS OF ANGIOTENSIN II Although the mechanisms by which ACE inhibition may ameliorate atherogenesis remain to be established, the available data indicate that the beneficial effects of ACE inhibition extend beyond the simple lowering of plasma A II levels (Table I). The RAS not only controls electrolyte balance, fluid volume, and systemic blood pressure, it also influences endothelial function and vascular structure. By affecting vasoactive substances that interact with the endothelium (e.g., angiotensin and bradykinin), ACE appears to playa critical role in defining the balance between vasoconstriction/growth promotion and vasodilation/growth inhibition.v' :"
VOl. 79 ISAI
MARCH 6 . 1997
Inhibition of A II conversion and preservation of nitric oxide production are considered to underlie the favorable effects of ACE inhibition on endothelial function and, potentially, on cardiovascular events. Both A II and nitric oxide are involved in the balance of thrombosis and fibrinolysis via changes in platelet aggregation, plasminogen activator inhibitor, and tissue plasminogen activator, as well as changes in the matrix synthesis of plaques." Numerous large clinical studies in patients with heart failure and in those with coronary artery disease and left ventricular dysfunction have documented reductions in cardiovascular morbidity and mortality.v" Therefore, unless specific contraindications exist, ACE inhibition is recommended for treatment of heart failure in patients with left ventricular dysfunction." The optimal management of myocardial infarction remains to be clarified; however, it may include ACE inhibitors as adjuncts to conventional measures such as aspirin use and .a-adrenergic blockade.
SUMMARY In recent years, research has begun to elucidate the role of the RAS in cardiovascular disease, ineluding the effects of ACE and its activity, i.~., A ~I generation and bradykinin degradation affecting mtric oxide production. The systemic RAS exhibits endocrine function, manifested by the release of renin and the subsequent chain of events leading to acute restoration of circulatory homeostasis, whereas the tissue RAS demonstrates autocrine/paracrine function, manifested by the direct action of RAS components on tissue. Multiple lines of research indicate that the activity of the RAS is maintained in a delicate equilibrium. The action of ACE, which catalyzes A II conversion and stimulates the ?reakdown of bradykinin, may contribute to cardiovascular disorders such as hypertension, heart failure, and coronary artery disease through mechanisms i!1volving thrombus formation, inflammation, fibrosis, and atherogenesis. These data, as well as ongoing clinical and scientific research. help to underscore how the role of ACE inhibitors in the spectrum of cardiovascular disease is far greater than initially envisioned.'
1. Cody RJ. The clinical potential of renin inhibitors and angiotensin antagonists. Drugs 1994;47:586-598. 2. Dzau VJ. Tissue renin-angiotensin system in myocardial hypertrophy and failure. Arch Intern Med 1993; I 53:937 -942. 3. Cody RJ. Renin system inhibition: Beginning The Fourth Epoch. Circulation 1992;85:362-364. 4. Dzau VJ. Angiotensin-converting enzyme as a multimechanistic factor in CAD. J Myocard Ischemia 1995;7(suppl 1):6-14. S. Cody RJ. ACE inhibitors: myocardial infarction and congestive heart failure. Am Fam Physician 1995;52:1801-1806. 6. Cody RJ. ACE inhibitors: mechanisms. pharmacokinetics. and clinical trials in heart failure. Cardiol Rev 1994;3:145-156. 7. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685-691. 8. Kleber FX. Niemoller L. Doering W. Impact of converting enzyme inhihnion on progression of chronic heart failure: results of the Munich Mild Heart Failure Trial. Br Heart J 1992;67:289-296. 9. Laragh JH. The renin system and the Impact of ACE inhibition for understanding. diagnosis. and treatment of hypertension. In: Sonnenblick EH. Laragh JH. Lesch M. eds. New Frontiers in Cardiovascular Therapy: Focus on Angiotensin Converting Enzyme Inhibition. Princeton. NJ: Excerpta Medica. 1989:83-116. 10. Weber MA. Neutel JM. Smith DHG. Circulatory and extracircularory effects of angiotensin-eonverting enzyme inhibition. Am Heart J 1992;123:14141420. 11. Fabris B. Chen B. Pupic V. Perich R. Johnston CI. Inhibition of angiotensinconverting enzyme (ACE) in plasma and tissue. J Cardiovasc Pharmacol 1990; 15(suppl 2):S6-S 13. 12. Kang PM. Landau AJ. Eberhardt RT. Frishman WHoAngiotensin II receptor antagonists: a new approach to blockade of the renin-iangrotensln system. Am Heart J 1994;127:1388- 1401. 13. Ollivier J-P. Bouchet VA. Prospects for cardioreparation. Am J Cardiol 1992;70(suppl C):27C-36C. 14. Feener EP. Northrup JM. Aiello LP. King GL. Angiotensin II induces plasminogen activator inhibitor-I and ·2 expression in vascular endothelial and smooth muscle cells. J Clin Invest 1995;95'1353-1362. 1S. Weber KT. Brilla CG. Pathological hypertrophy and cardiac interstitium: fibrosis and renin-angiotensin-aldosterone system. Circulation 1991;83: 1849-1865. 16. Weber KT. Sun Y. Guarda E. Structural remodeling in hypertensive heart disease and the role of hormones. Hypertension 1994;23(pt 2):869877.
17. van Leeuwen RTJ. Kol A. Andreotti F. Kluft C. Maseri A. Sperti G. Angiotensin II increases plasminogen activator inhibitor type I and tissue-type plasminogen activator messenger RNA in cultured rat aortic smooth muscle cells. Circulation 1994;90:362-368. 18. Feolde E. Vigne P, Freltn C. Angiotensin AT, receptors mediate a positive inotropic effect of angiotensin II in guinea pig atria. Eur J Pharmacol 1993;245:63-66. 19. Studer R. Reinecke H. MUller B. Holtz J. Just H. Drexler H. Increased angiotensin-I converting enzyme gene expression in the failing human heart Quantification by competitive RNA polymerase chain reaction. J Clin Invest 1994;94:301-310. 20. Peach MJ. Dostal DE. The angiotensin II receptor and the actions of angiotensin II. J Cardiovasc PharmacoI1990;16(suppI4):S25-S30. 21. Kai H. Griendling KK. Lassegue B. Ollerenshaw JD, Runge MS. Alexander RW. Agonist-induced phosphorylation of the vascular type 1 angiotensin II receptor. Hypertension 1994;24:523-527. 22. Konstam MA. Dracup K. Baker OW. Bottorff MB. Brooks NH. Dacey RA. Dunbar SB. Jackson AB. Jessup M. Johnson Je. Jones RH. Luchi RJ. Massie BM. Pit! B. Rose EA. Rubin U. Wright RF. Hadom DC. Heart Failure: Evaluation and Care of Patients with Left- Ventricular Systolic Dysfunction. AHCPR Publication 94-0612. Rockville, MD: Agency for Health Care Policy and Research. Public HeaJth Service. US Department of Health and Human Services. June 1994.
A SYMPOSIUM' ACE INHIBITION
11
cause angiotensin II inhibits fibronectin, stimulates expression of pla5minogen activator inhibitors, and degrades bradykinin, thereby impairing production of nitricoxide, ACE and the RAS are also involvedin thrombosis and fibrinolysis. The favorable effects of ACE inhibition on endothelial function and, potentially, on cardiovascular morbidity and mortality are believed to result not only from angiotensin II suppression but also its consequent bradykinin preservation and nitric oxide production. © 7997 by Excerpta Medica, Inc. Am J Cardio11997;79 (SA):9-11
he renin-angiotensin system (RAS) is intiT mately involved in the control of blood pressure and fluid and electrolyte homeostasis.' Compo-
THE RENIN-ANGIOTENSIN SYSTEM Research has shown that the RAS is highly complex . Early investigation into the interplay between renin and aldosterone demonstrated that the RAS utilizes a variety of homeostatic controls to maintain normal blood pressure and electrolyte status." The first of these controls to be investigated were polypeptide vasoactive hormones. including A II. Since the circulating components of the RAS produce A II. which acts on remote target tissues (e.g .• blood vessels. adrenal glands. and kidneys). the RAS was perceived to be primarily a neuroendocrine system. ':' More recent information demonstrates that a local tissue RAS also exists; because components of the tissue RAS exert direct effects on local tissue. this system may be described as autocrine/paracrine. Over the long term. the combined function of the RAS may affect cardiovascular function and structure.' ACE occurs predominantly on the endothelium. Thus. the tissue RAS may be intimately involved in the progression of cardiovascular disease. Regulation of vascular tone. from a structural and functional standpoint. is thought to occur via local tissue RAS in the central nervous system. vasculature. adrenal system, heart. and kidneys. 10,11
nents of the RAS have been implicated in early and late metabolic changes that lead to coronary artery disease and heart failure." The RAS has long been known to be a key regulator of hypertension; this finding led to the development of angiotensin-convert ing enzyme (ACE) inhibitors as antihypertensive agents.' In the last decade. the results of clinical and experimental studies with ACE inhibitors suggest that these agents may also produce beneficial effects in coronary artery disease and improve cardiovascular outcomes." In addition to their blood pressure-lowering effects. ACE inhibitors have been shown to reduce vascular hypertrophy. attenuate atherosclerosis. and influence coronary ischemia and reperfusion injury. Furth~r more. clinical studies have found that ACE Inhibitors may be useful across the continuum of coronary artery disease"; in patients with moderate-to-severe heart failure. ACE inhibitors combined with diuretics and/or digoxin have been sh~wn to improve clinical signs and symptom.s. ~x ercise tolerance. and New York Heart ASSOCIatIOn functional class.l" Similarly. ACE inhibitors have been shown to delay the symptomatic onset of heart failure and clinical progression of this dis- EFFECTS OF ANGIOTENSIN II ease in patients with milder symptoms.":" When developing therapeutic strategies for paThese findings . as well as advances in vascular tients with coronary artery disease, the effects of A II biology, suggest that alterations in ACE activ.ity- are vital considerations. Although a vast amount of particularly at the tissue level-are important In the literature has been published about A II. some condevelopment and progression of cardiovascular dis- troversy remains regarding the various activities ease ." This article reviews the RAS. with an empha- modulated by A II and their relative importance.': " sis on the integral effects of angiotensin II (A II) and Va5occtivity: One of the most potent endogenous the benefits that may occur by blocking the forma- vasoconstrictors. A II affects blood pressure by acttion of A II with ACE inhibitors. ing on a variety of organ systems. In left ventricular dysfunction. elevated plasma levels of A II can impede blood flow. reducing card iac output and reFrom the Division of Cardiology , Departme,nt, of MediCine, The ?h,o gional flOW . I , 12 In addition, A II stimulates cell Sta te University Hospita ls, College o f MediCine, Columbus, Ohio growth and modulates the activity of other vasoacAddress for reprints. RobertJ C ody, foIU) , Dlvi sio n of Cardiology, The Ohio Stale University Hospitals, 61 1 Means Hall, 1654 Upham tive substances .":" Supranormal levels of plasma A II are also associated with progressive fibrosis. enDrive, Col umbus, Ohlo 432 10 © 1997 by Excerpta Medica, Inc. All right. reserved,
0002.9149/97/$17,00 PII 50002.9149(97)00123-9
9
dothelial cell dysfunction, thrombosis, and atherogenesis . 13.14 Fibrosis: An increase in plasma levels of A II and/ or aldosterone can lead to it fibrous tissue respon se, independent of the hemodynamic state." In animal models, administration of A II was associated with disruption of endothelial function , thickening of the vessel wall, and increased fibrosis." These findings suggest that elevated A II levels in conjunction with increased aldosterone levels are directly responsible for causing microendothelial lesions that increase coronary artery permeability," which may allow diffusion of growth factors into the myocardial interstitium. The increase in fibrous tissue (and collagen levels) contributes to greater myocardial wall stiffness, creating a feedback loop involving ventricular filling defects, cardiac decompensation, and a further increase in RAS activity.'? Fibrous tissue appears to accumulate when collagen stimulators (e.g., A II, aldosterone, and endothelins) are relatively abundant in proportion to collagen inhibitors (e.g., bradykinin, prostaglandins, and glucocorticoids).w Inhibition of fibrinolysis: Study of the thrombolytic and fibrinolytic pathways has revealed that A II inhibits fibronectin and stimulates expression of plasminogen activator inhibitors. 14.17 The effect of A II on plasminogen activator inhibitor may be crucial; in animal models, overexpression of plasminogen activator inhibitor increases the incidence of venous occlusions, resulting in peripheral ischemia and necrosis. In humans, the activity of A II in the vascu lature may impair fibrinolysis and possibly contribute to thrombus formation. 14 Activity in congestive heart failure: Angiotensin II contributes to congestive heart failure by directly stimulating the adrenals to release aldosterone, thereby exacerbating sodium and water retention. I Consequently, pulmonary and systemic venous congestion develop, contributing to increased vascular stiffness. I Depending on the concentration and preparation of A II as well as the experimental model utilized, A II has positive inotropic effects. IS For instance, an increase in A II in the myocardium produces a positive inotropic effect by acting on cardiac rnyocytes and impairing diastolic relaxation.' This direct action may be important in the process of cardiac hypertrophy andlor myocardial remodeling. Angiotensin 11stimulated sympathetic activity can also exert a positive inotropic effect and may be a factor in the occurrence of arrhythmia in the presence of ischemia or advanced heart failure.' Notably, Studer et al'" showed that patients with end-stage heart failure have increased ACE activity compared with healthy subjects. These investigators used a polymerase chain reaction to amplify and investigate the gene expression of major A II-forming enzymes (ACE and chymase) in the left ventricle. Compared with nonfailing hearts, the amount of ACE transcription was increased 3-fold in patients with chronic heart failure (4.2 :!: 2.5 vs 12.8 ± 6 x 105 10
THE AM ERICAN JOURNAL OF CARDIOlOGY41
TABLE I
Possible Benefits of Ang iotensin-Converting Enzyme (ACE) Inhibition
Left ventricular structural and functional effects Decreased transmural wall stress Decreased compensatory dilatation and compensatory increase of end-diostolic and end-systolic volume Improved coronary flow distr ibut ion in surface and transmurol planes Hemodynamic effects Reduced vascular resistance Reduced inotropic stimulation Absence of chronotropic stimulation Neurohormonal and paracrine effects Decreased circulating and tissue effects of ang iotensin" Diminished aldosterone and prevention of secondary sodium (and volume) retention Decreosed circulatory catecholam ines, improved bororeceptor function and restoration of sympathetic-parasympathetic balance Dimin ished bradykinin degradation Other effects Blockade of cell growth effects of angiotensin" Potential direct cellular effects of ACE (a carboxypeptidase) (Reprinted with permission fromAm Fom PhyJic,on')
relative ratio units, p <0.0005) . There was no difference in chymase gene expression between normal and failing hearts, indicating that the expression of ACE is due to activation of the cardiac RAS .
ANGIOTENSIN II RECEPTORS The physiologic effects of A II in cardiovascular disease appear to be mediated by binding to receptors in the plasma membrane of various tissues. I The best characterized receptor, the AT] subtype, is thought to regulate the activity of A II on the lungs, vascular smooth muscle cells, liver, brain, and kidneys. I The function of the AT 2 receptor is less well known; this subtype may affect fetal tissue, the brain, and reproductive tissue, and it may modulate other beneficial activities." The distinctly different mechanisms of action of A II in various effector tissues are thought to be related to multiple angiotensin receptor subtypes. I Angiotensin II exerts its effects at the cellular level through phosphorylation of the AT 1A receptor. 2 I
ROLE OF ACE INHIBITORS IN BLUNTING EFFECTS OF ANGIOTENSIN II Although the mechanisms by which ACE inhibition may ameliorate atherogenesis remain to be established, the available data indicate that the beneficial effects of ACE inhibition extend beyond the simple lowering of plasma A II levels (Table I). The RAS not only controls electrolyte balance, fluid volume, and systemic blood pressure, it also influences endothelial function and vascular structure. By affecting vasoactive substances that interact with the endothelium (e.g., angiotensin and bradykinin), ACE appears to playa critical role in defining the balance between vasoconstriction/growth promotion and vasodilation/growth inhibition.v' :"
VOl. 79 ISAI
MARCH 6 . 1997
Inhibition of A II conversion and preservation of nitric oxide production are considered to underlie the favorable effects of ACE inhibition on endothelial function and, potentially, on cardiovascular events. Both A II and nitric oxide are involved in the balance of thrombosis and fibrinolysis via changes in platelet aggregation, plasminogen activator inhibitor, and tissue plasminogen activator, as well as changes in the matrix synthesis of plaques." Numerous large clinical studies in patients with heart failure and in those with coronary artery disease and left ventricular dysfunction have documented reductions in cardiovascular morbidity and mortality.v" Therefore, unless specific contraindications exist, ACE inhibition is recommended for treatment of heart failure in patients with left ventricular dysfunction." The optimal management of myocardial infarction remains to be clarified; however, it may include ACE inhibitors as adjuncts to conventional measures such as aspirin use and .a-adrenergic blockade.
SUMMARY In recent years, research has begun to elucidate the role of the RAS in cardiovascular disease, ineluding the effects of ACE and its activity, i.~., A ~I generation and bradykinin degradation affecting mtric oxide production. The systemic RAS exhibits endocrine function, manifested by the release of renin and the subsequent chain of events leading to acute restoration of circulatory homeostasis, whereas the tissue RAS demonstrates autocrine/paracrine function, manifested by the direct action of RAS components on tissue. Multiple lines of research indicate that the activity of the RAS is maintained in a delicate equilibrium. The action of ACE, which catalyzes A II conversion and stimulates the ?reakdown of bradykinin, may contribute to cardiovascular disorders such as hypertension, heart failure, and coronary artery disease through mechanisms i!1volving thrombus formation, inflammation, fibrosis, and atherogenesis. These data, as well as ongoing clinical and scientific research. help to underscore how the role of ACE inhibitors in the spectrum of cardiovascular disease is far greater than initially envisioned.'
1. Cody RJ. The clinical potential of renin inhibitors and angiotensin antagonists. Drugs 1994;47:586-598. 2. Dzau VJ. Tissue renin-angiotensin system in myocardial hypertrophy and failure. Arch Intern Med 1993; I 53:937 -942. 3. Cody RJ. Renin system inhibition: Beginning The Fourth Epoch. Circulation 1992;85:362-364. 4. Dzau VJ. Angiotensin-converting enzyme as a multimechanistic factor in CAD. J Myocard Ischemia 1995;7(suppl 1):6-14. S. Cody RJ. ACE inhibitors: myocardial infarction and congestive heart failure. Am Fam Physician 1995;52:1801-1806. 6. Cody RJ. ACE inhibitors: mechanisms. pharmacokinetics. and clinical trials in heart failure. Cardiol Rev 1994;3:145-156. 7. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685-691. 8. Kleber FX. Niemoller L. Doering W. Impact of converting enzyme inhihnion on progression of chronic heart failure: results of the Munich Mild Heart Failure Trial. Br Heart J 1992;67:289-296. 9. Laragh JH. The renin system and the Impact of ACE inhibition for understanding. diagnosis. and treatment of hypertension. In: Sonnenblick EH. Laragh JH. Lesch M. eds. New Frontiers in Cardiovascular Therapy: Focus on Angiotensin Converting Enzyme Inhibition. Princeton. NJ: Excerpta Medica. 1989:83-116. 10. Weber MA. Neutel JM. Smith DHG. Circulatory and extracircularory effects of angiotensin-eonverting enzyme inhibition. Am Heart J 1992;123:14141420. 11. Fabris B. Chen B. Pupic V. Perich R. Johnston CI. Inhibition of angiotensinconverting enzyme (ACE) in plasma and tissue. J Cardiovasc Pharmacol 1990; 15(suppl 2):S6-S 13. 12. Kang PM. Landau AJ. Eberhardt RT. Frishman WHoAngiotensin II receptor antagonists: a new approach to blockade of the renin-iangrotensln system. Am Heart J 1994;127:1388- 1401. 13. Ollivier J-P. Bouchet VA. Prospects for cardioreparation. Am J Cardiol 1992;70(suppl C):27C-36C. 14. Feener EP. Northrup JM. Aiello LP. King GL. Angiotensin II induces plasminogen activator inhibitor-I and ·2 expression in vascular endothelial and smooth muscle cells. J Clin Invest 1995;95'1353-1362. 1S. Weber KT. Brilla CG. Pathological hypertrophy and cardiac interstitium: fibrosis and renin-angiotensin-aldosterone system. Circulation 1991;83: 1849-1865. 16. Weber KT. Sun Y. Guarda E. Structural remodeling in hypertensive heart disease and the role of hormones. Hypertension 1994;23(pt 2):869877.
17. van Leeuwen RTJ. Kol A. Andreotti F. Kluft C. Maseri A. Sperti G. Angiotensin II increases plasminogen activator inhibitor type I and tissue-type plasminogen activator messenger RNA in cultured rat aortic smooth muscle cells. Circulation 1994;90:362-368. 18. Feolde E. Vigne P, Freltn C. Angiotensin AT, receptors mediate a positive inotropic effect of angiotensin II in guinea pig atria. Eur J Pharmacol 1993;245:63-66. 19. Studer R. Reinecke H. MUller B. Holtz J. Just H. Drexler H. Increased angiotensin-I converting enzyme gene expression in the failing human heart Quantification by competitive RNA polymerase chain reaction. J Clin Invest 1994;94:301-310. 20. Peach MJ. Dostal DE. The angiotensin II receptor and the actions of angiotensin II. J Cardiovasc PharmacoI1990;16(suppI4):S25-S30. 21. Kai H. Griendling KK. Lassegue B. Ollerenshaw JD, Runge MS. Alexander RW. Agonist-induced phosphorylation of the vascular type 1 angiotensin II receptor. Hypertension 1994;24:523-527. 22. Konstam MA. Dracup K. Baker OW. Bottorff MB. Brooks NH. Dacey RA. Dunbar SB. Jackson AB. Jessup M. Johnson Je. Jones RH. Luchi RJ. Massie BM. Pit! B. Rose EA. Rubin U. Wright RF. Hadom DC. Heart Failure: Evaluation and Care of Patients with Left- Ventricular Systolic Dysfunction. AHCPR Publication 94-0612. Rockville, MD: Agency for Health Care Policy and Research. Public HeaJth Service. US Department of Health and Human Services. June 1994.
A SYMPOSIUM' ACE INHIBITION
11