The best known regulator of blood pressure and determinant of target organ damage from hypertension is the renin-angiotensin-aldosterone system. Overexpression of renin and its metabolic products predisposes to increased blood pressure and even frank hypertension, as well as target organ damage. Renin reacts with angiotensinogen to produce the decapeptide angiotensin I, which is biologically inactive. Angiotensin I is cleaved by a variety of enzymes, including angiotensin converting enzyme (ACE) and other proteolytic enzymes, e.g. the serine protease chymase, to generate angiotensin II, an octapeptide that is responsible for most of the known biological activity of the system. In addition, non-renin-enzymes, including tonin and cathepsin, are capable of generating angiotensin II directly from angiotensinogen. The angiotensin peptides, angiotensin I and II, are susceptible to digestion at a number of sites by angiotensinases. The resultant peptide fragments are found in the circulation and have functions that may be distinct from those of angiotensin II. For example, angiotensin III (the 2-8 peptide) has functions identical to those of angiotensin II, while angiotensin IV (the 3-8 peptide) may bind selectively to a novel receptor (AT4) and stimulate release of plasminogen activator inhibitor-1 (PA1-1), a potent anti-thrombolytic, and the (1-7) peptide may bind to the AT3 receptor to stimulate vasodilation and potentiate bradykinin. The biological significance of these novel peptides has yet to be fully elucidated.
Angiotensin II elevates blood pressure by a variety of mechanisms, including direct vasoconstriction, potentiation of sympathetic nervous system activity at both central and peripheral levels, stimulation of aldosterone synthesis and release with consequent sodium and fluid retention by the kidney and stimulation of arginine vasopressin release. In addition, angiotensin II has a variety of actions that damage blood vessels directly. For example, it stimulates NADH and NADPH activity, raising the oxidative potential of vascular tissue. Angiotensin II also plays a role in the vascular injury response, stimulating leukocyte adhesion to the site of injury and favoring superoxide and peroxynitrite formation and proliferation and migration of various cell types toward the luminal site of injury. The events that follow cause cellular components of the arterial wall to transform their phenotypes, resulting in atherosclerotic plaque or fibrous neointima formation. Angiotensin II and some of its constituent peptides also stimulate synthesis of the antithrombolytic agent, PAI-1, suggesting that activation of the renin-angiotensin-aldosterone system predisposes to atherosclerosis and thromboembolic events, including heart attack and stroke.
Pharmacological agents that antagonize the renin-angiotensin-aldosterone system at the level of ACE, the angiotensin II receptor, and more recently, the aldosterone (mineralocorticoid) receptor, have come into prominence in the treatment of hypertension, heart failure and postmyocardial infarction cardiac remodeling. These agents are highly effective in lowering blood pressure and, particularly in the case of the angiotensin II receptor antagonists, are extremely well tolerated. The major questions asked regarding the clinical utilization of the angiotensin receptor antagonists and the ACE inhibitors are: Do they have clinical benefits beyond blood pressure lowering? Are their advantages sufficient to justify their high cost? Is one class superior to the other with respect to preventing target organ damage and cardiovascular events? Are the therapeutic effects of the two classes additive or synergistic? Clinical trial evidence to date is inconclusive on these points.
Additional long-term controlled clinical trials are needed to clarify the benefits and risks of cardiovascular outcomes associated with blood pressure reduction induced by antihypertensive agents that antagonize components of the renin-angiotensin-aldosterone system in patients with multiple cardiovascular risk factors. The ongoing NHLBI-sponsored Antihypertensive and Lipid Lowering to Prevent Heart Attack (ALLHAT) trial is the largest of these ongoing trials, including over 42,000 high-risk hypertensive subjects with diverse ethnic backgrounds. ALLHAT is comparing ACE inhibitor or calcium channel blocker therapy to a diuretic based regimen with respect to prevention of major cardiovascular disease outcomes. This massive trial should provide important answers to many of these pressing questions. For the rest, we need more fundamental information about the biology of the renin-angiotensin-aldosterone system in human subjects.
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