The renin-angiotensin-aldosterone system: a specific target for hypertension management.
Angiotensin II plays a central role in the regulation of systemic arterial pressure through its systemic synthesis via the renin-angiotensin-aldosterone cascade. It acts directly on vascular smooth muscle as a potent vasoconstrictor. In addition, it affects cardiac contractility and heart rate through its action on the sympathetic nervous system. Angiotensin II also alters renal sodium and water absorption through its ability to stimulate the zona glomerulosa cells of the adrenal cortex to synthesize and secrete aldosterone. Furthermore, it enhances thirst and stimulates the secretion of the antidiuretic hormone. Consequently, angiotensin II plays a critical role in both the acute and chronic regulation of blood pressure through its systemic endocrine regulation. A potent neurohormone that regulates systemic arterial pressure, angiotensin II also affects vascular structure and function via paracrine and autocrine effects of local tissue-based synthesis. This alternate pathway of angiotensin II production is catalyzed in tissues via enzymes such as cathepsin G, chymostatin-sensitive angiotensin II-generating enzyme, and chymase. Intratissue formation of angiotensin II plays a critical role in cardiovascular remodeling. Upregulation of these alternate pathways may occur through stretch, stress, and turbulence within the blood vessel. Similar processes within the myocardium and glomeruli of the kidney may also lead to restructuring in these target organs, with consequent organ dysfunction. Additionally, angiotensin II may increase receptor density and sensitivity for other factors that modulate growth of vascular smooth muscle, such as fibroblast growth factor, transforming growth factor beta-1, platelet-derived growth factor, and insulin-like growth factors. Atherosclerosis may also be related, in part, to excessive angiotensin II effect on the vessel wall, which causes smooth muscle cell growth and migration. It also activates macrophages and increases platelet aggregation. Angiotensin II stimulates plasminogen activator inhibitor 1 and directly causes endothelial dysfunction. Other postulated effects of angiotensin II on vascular structure that could promote atherogenesis include inhibition of apoptosis, increase in oxidative stress, promotion of leukocyte adhesion and migration, and stimulation of thrombosis. Inhibition of angiotensin II synthesis with an angiotensin-converting enzyme inhibitor has been demonstrated to be beneficial in modifying human disease progression. This is clearly apparent in clinical trials involving patients with diabetic nephropathy, postmyocardial infarction, or advanced degrees of systolic heart failure. Thus, angiotensin II is an excellent target for pharmacologic blockade. Not only does it play a pivotal role in both the acute and chronic regulation of systemic arterial pressure, but it also is an important modulator of cardiovascular structure and function and may be specifically involved in disease progression. Modification of angiotensin II effect may therefore serve a dual purpose. Not only will blood pressure reduction occur with less stretch, stress, and turbulence of the vascular wall, but there will also be less stimulation, either directly or indirectly, for restructuring and remodeling of the cardiovascular tree.
Weir
M R
MR
Department of Medicine, University of Maryland School of Medicine, Baltimore, USA. mweir@umppal.ab.umd.edu
Dzau
V J
VJ
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II