Aldosterone: A Mediator of Myocardial Necrosis and Renal Arteriopathy*

Abstract

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 Nomega-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/angiotensin II induced vascular damage through mechanisms apparently independent of its effects on systolic blood pressure.

Overt Diabetic Nephropathy and Mineralocorticoid Receptor Antagonism

“…14 Likewise, in the stroke-prone hypertensive rat on a high sodium intake, aldosterone infusion during ACE inhibition with captopril was associated with proteinuria and malignant nephrosclerosis, 15 whereas in a hypertensive rat model subjected to angiotensin II and N-nitro-L-arginine methyl ester (L-NAME) infusion, renal and cardiac damage was prevented by aldosterone removal through adrenalectomy or administration of eplerenone. 13 Moreover, in the streptozotocin-induced diabetic rat with increased renal protein excretion, administration of spironolactone markedly attenuated urinary protein excretion and prevented early renal injury, indirectly indicating involvement of aldosterone in this process of renal injury. 16 Similar findings were obtained in the streptozotocin-induced diabetic rat and the db/db (a rodent model of type 1 diabetes) mouse when eplerenone was used as a mineralocorticoid receptor antagonist.…”

“…Experimental studies suggest the involvement of both mechanisms. 12,13,[30][31][32] In a study reported by Dworkin et al, haemodynamic factors were responsible for the glomerular injury in rats with deoxycorticosterone-salt-induced hypertension. 32 Sechi et al.…”

“…12,13 In the rodent remnant kidney model, infusion of aldosterone during losartan administration was associated with hypertension, proteinuria and glomerulosclerosis. 14 Likewise, in the stroke-prone hypertensive rat on a high sodium intake, aldosterone infusion during ACE inhibition with captopril was associated with proteinuria and malignant nephrosclerosis, 15 whereas in a hypertensive rat model subjected to angiotensin II and N-nitro-L-arginine methyl ester (L-NAME) infusion, renal and cardiac damage was prevented by aldosterone removal through adrenalectomy or administration of eplerenone.…”

“…14 Likewise, in the stroke-prone hypertensive rat on a high sodium intake, aldosterone infusion during ACE inhibition with captopril was associated with proteinuria and malignant nephrosclerosis, 15 whereas in a hypertensive rat model subjected to angiotensin II and N-nitro-L-arginine methyl ester (L-NAME) infusion, renal and cardiac damage was prevented by aldosterone removal through adrenalectomy or administration of eplerenone. 13 Although the synthesis and release of aldosterone by the adrenal gland is in part under the control of angiotensin II, escape of aldosterone has been reported to occur in a substantial proportion of patients with diabetic nephropathy treated with ACE inhibitors or angiotensin II receptor antagonists. 21,22 This aldosterone escape is not harmless as it has been shown to be associated with an enhanced excretion of urinary albumin and an enhanced decline of renal function.…”

Mineralocorticoid Receptor Antagonist Pretreatment to MINIMISE Reperfusion Injury After ST‐Elevation Myocardial Infarction (The MINIMISE STEMI Trial): Rationale and Study Design

“…It is known to regulate a number of pathophysiological pathways important to post‐MI HF, including inhibition of nitric oxide activity,10 acute endothelial dysfunction,11 increased vascular tone,12 vascular smooth muscle cell and cardiomyocyte necrosis,13, 14 myocardial hypertrophy and fibrosis,15, 16 apoptosis,17 and unfavorable LV remodeling 18. Consequently, a number of landmark clinical studies have highlighted the significant benefits of aldosterone antagonist therapy on clinical outcomes post‐MI 19, 20, 21…”