Rapid Effects of Aldosterone and Spironolactone in the Isolated Working Rat Heart

Abstract

Abstract-Chronic administration of aldosterone promotes myocardial fibrosis in rats. The Randomized Aldactone Evaluation Study reported that the aldosterone antagonist spironolactone improved outcome in patients with congestive heart failure, suggesting a deleterious effect of aldosterone in the heart. Aldosterone has been shown to have rapid nongenomic effects in different tissues including the heart. However, the hemodynamic actions of aldosterone and spironolactone are not well characterized. In this study, we examined the hemodynamic effects of aldosterone and its receptor antagonist, spironolactone, in the isolated rat heart by use of the Langendorff-Neely technique. Perfusion with 10 nmol/L aldosterone increased contractility by 45% within 2 to 4 minutes (PϽ0.01). Similar to the aldosterone effect, 10 nmol/L spironolactone increased contractility by 41% (PϽ0.01). Furthermore, 100-fold molar excess of spironolactone did not block the aldosterone effect. Perfusion of aldosterone plus spironolactone resulted in the highest increase in contractility 106% (PϽ0.01). The threshold response for aldosterone occurred within physiological concentrations (0.5 to 1 nmol/L), and maximal contractility was achieved with 10 nmol/L aldosterone. For spironolactone, the threshold and maximal contractile responses occurred at concentrations readily achieved with clinical dosing, 0.1 to 0.5 nmol/L and 1.0 nmol/L, respectively. These data demonstrate that aldosterone and spironolactone have rapid, positive inotropic actions on the myocardium. Moreover, addition of spironolactone to aldosterone increased contractility beyond the maximal responses elicited by each agent when perfused alone, thus suggesting different pathways of action. Furthermore, the intrinsic inotropic effects of spironolactone might be relevant to the apparent beneficial effect this compound has in patients with congestive heart failure. Key Words: congestive heart failure Ⅲ renin-angiotensin system Ⅲ mineralocorticoids Ⅲ aldosterone Ⅲ fibrosis Ⅲ cardiac function T he renin-angiotensin-aldosterone system represents a compensatory mechanism functioning to improve cardiac output during heart failure. 1 Although initially beneficial, prolonged activation of the renin-angiotensin-aldosterone system may be detrimental. The elevated pressure and increased extracellular fluid volume increases the hemodynamic load on the heart, leading to compensatory cardiac remodeling. 2 Also, aldosterone acting alone or with other humoral factors can increase fibrosis in the heart independent of pressure. [2][3][4][5][6] The Randomized Aldactone Evaluation Study (RALES) demonstrated significant reductions in morbidity and mortality rates when spironolactone, the aldosterone mineralocorticoid receptor antagonist, was included in the treatment of heart failure. 7,8 The rationale for this therapy was based on reports of the ability of aldosterone to activate cardiac fibroblasts and initiate cardiac fibrosis. 2-6,9 -14 Because of the success of spironolactone in RALES, this agent is c...

Mechanisms for Aldosterone and Spironolactone-Induced Positive Inotropic Actions in the Rat Heart

“…As we observed in our earlier report, 6 the additive contractile effect of aldosterone with spironolactone suggests independent mechanisms of action for these agents. This hypothesis is further supported by the results on the current studies, which demonstrated contrasting actions on diastolic intracellular calcium, pHi, calcium-activated myosin ATPase activation, and maximal myosin ATPase activity.…”

“…The concentration of aldosterone used (10 nmol/L) was chosen because it was previously shown to elicit maximal contractility. 6 For spironolactone, although maximal contractility was noted to occur at 1 nmol/L, 1000 nmol/L was chosen to ensure complete blockade of the mineralocorticoid receptor when combined with aldosterone and for direct comparison with our previous work performed on isolated working hearts. 6 …”

“…6,40 After retrograde perfusion for 15 minutes at 80 mm Hg, anterograde perfusion was initiated at a preload of 15 mm Hg and an afterload of 70 mm Hg for the duration of each study.…”

“…Therefore, the objective of the present study was to compare and contrast the responses of aldosterone and spironolactone at the cellular and organ levels to discern the molecular mechanisms underlying the inotropic effects of these agents previously reported. 6 …”

Nongenomic Effects of Aldosterone in the Human Heart

“…The nonrenal actions of aldosterone include inotropic effects in the heart and vasoconstrictor as well as vasodilator effects in various vascular beds. [3][4][5][6][7] Unexpectedly, these effects occurred within minutes rather than hours and could not always be blocked by MR antagonists. Consequently, they are now known as "nongenomic" effects of aldosterone.…”