Aldosterone : A Mediator of Myocardial Necrosis and Renal Arteriopathy *

To determine the role of aldosterone in mediating cardiovascular damage, we performed ablation/replacement experiments with aldosterone in a rat model of cardiac injury. Administration of angiotensin II and N-nitro-L-arginine methyl ester (L-NAME; nitric oxide synthesis inhibitor) to male rats drinking 1% saline caused hypertension, severe biventricular myocardial necrosis, proteinuria, and fibrinoid necrosis of renal and cardiac vessels. Removal of aldosterone by adrenalectomy or through administration of the selective aldosterone antagonist eplerenone markedly reduced the cardiac and renal damage without significantly altering blood pressure. Aldosterone infusion in adrenalectomized, glucocorticoid-replaced L-NAME/angiotensin II-treated animals restored damage. Thus, we identified aldosterone as a critical mediator of L-NAME/angiotensine II induced vascular damage through mechanisms apparently independent of its effects on systolic blood pressure. (Endocrinology 141: 3871–3878, 2000) T RENIN-ANGIOTENSIN-ALDOSTERONE system (RAAS) is a major regulator of the cardiovascular system. Abnormal activation of this system has been postulated to participate in the occurrence of end-organ damage in hypertensive patients (1, 2). Supporting this concept are clinical studies showing that treatment of hypertensive patients with either angiotensin-converting enzyme (ACE) inhibitors (3, 4) or angiotensin II type I (AT1) receptor antagonists (5, 6) provides significant protection against cardiovascular morbidity and mortality. Animal studies also demonstrate a significant contribution of ACE inhibitors and AT1 receptor antagonists in preventing renal (7–10), cerebral (7, 8, 11), and cardiovascular (8, 12) injury. Thus, it has been proposed that abnormal activation of the RAAS represents a cardiovascular risk factor (13). Although many studies have investigated the role of angiotensin II (Ang II) in mediating cardiovascular damage, relatively little attention has been paid to the role of aldosterone, the end product of the RAAS. However, there are data to suggest that aldosterone may play an important role in the pathogenesis of cardiovascular disease that is independent of Ang II. Patients with primary aldosteronism, in which Ang II levels are usually very low, have a higher incidence of left ventricular hypertrophy (14), albuminuria (15), and stroke (16, 17) than do patients with essential hypertension. A recent study performed in patients classified with New York Heart Association class III and IV cardiac failure showed a 30% reduction in morbidity and mortality with the addition of the aldosterone antagonist spironolactone to conventional therapy including ACE inhibitors, loop diuretics, and digoxin (18). This decrease occurred with an average dose of spironolactone (26 mg/day) that did not have significant hemodynamic effects. Experimental animal data support a role for aldosterone in mediating cardiovascular injury in the kidney and brain. In the stroke-prone spontaneously hypertensive rat (SHRSP), a genetic model of spontaneous hypertension, administration of either spironolactone (19) or an ACE inhibitor (7, 8, 20) greatly attenuated renal and cerebral vascular damage (20, 21). Likewise, in the remnant kidney hypertensive rat, administration of aldosterone reversed the renal protection given by blockade of the RAAS with combined ACE inhibition/AT1 receptor antagonist treatment (22). Thus, in the kidney and brain, aldosterone may have deleterious effects on the vasculature that may be independent of other components of the RAAS. An important pathological effect of aldosterone in the heart has been reported in experimental models of mineralocorticoid hypertension. In these studies prolonged (6to 8-week) exposure to aldosterone was associated with the development of myocardial fibrosis (23, 24). Although a direct effect of aldosterone on collagen deposition was initially proposed, in vitro studies have not consistently demonstrated an effect of aldosterone in modulating collagen gene expression (25, 26). Thus, the mechanisms by which aldoReceived April 12, 2000. Address all correspondence and requests for reprints to: Gail K. Adler, M.D., Ph.D., Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: gadler@partners.org. * Parts of this manuscript were presented in abstract form at the American Society of Hypertension Meeting, New York, NY, 1999, and at the 53th Scientific Conference of the Council for High Blood Pressure Research, American Heart Association, Orlando, Florida, 1999. This work was supported by NIH Research Grants HL-35522 and HL-63423, American Heart Association (New York State Affiliate) Grant-in-Aid 9859133, and funds donated by Searle, Monsanto (St. Louis, MO). † Supported by a postdoctoral fellowship grant from the American Heart Association-New England Affiliate (9920264T). 0013-7227/00/$03.00/0 Vol. 141, No. 10 Endocrinology Printed in U.S.A. Copyright © 2000 by The Endocrine Society