Mechanisms for aldosterone and spironolactone-induced positive inotropic actions in the rat heart.

Previously, we reported that aldosterone and spironolactone have inotropic effects in the isolated perfused heart. To address the mechanisms underlying these inotropic effects, we examined the effects of aldosterone and spironolactone on isolated cardiac myocyte shortening, intracellular calcium ([Ca+2]i), pHi, and calcium-dependent actinomyosin ATPase activity. Aldosterone significantly increased shortening in cardiac myocytes (8.0+/-1.0 versus 16.0+/-1.3%, P<0.01) but neither diastolic [Ca+2]i (61.0+/-1.1 versus 66.0+/-4.4 nmol/L) nor peak systolic [Ca+2]i (302+/-11 versus 304+/-17 nmol/L) was affected. Spironolactone-increased shortening was also not coupled with changes in peak systolic calcium; however, diastolic calcium was significantly increased by spironolactone. Aldosterone, but not spironolactone, increased pHi from 7.23+/-0.03 to 7.59+/-0.02 (P<0.01); this was completely blocked by coadministration of 100 micromol/L of ethyl-isopropyl amiloride (EIPA), an inhibitor of the Na+/H+ exchanger (P<0.01). Consistent with this finding, aldosterone increased cytosolic sodium concentration ([Na+]i) from 9.2+/-0.15 to 11.4+/-0.2 mmol/L and produced a leftward shift in the pCa ATPase curve (pCa=5.82+/-0.02 versus 6.35+/-0.02, P<0.01) without affecting maximal myosin ATPase activity. Conversely, spironolactone, but not aldosterone, significantly increases maximal actomyosin ATPase activity (837+/-59 versus 355+/-52 nmol inorganic phosphate (P(i)) x min(-1) x g tissue(-1)). Collectively, these data strongly suggest that the inotropic actions of aldosterone and spironolactone are caused by different mechanisms of action. Aldosterone appeared to increase inotropy primarily through increased cytosolic pH, whereas spironolactone increased myosin ATPase calcium sensitivity and diastolic calcium concentration.

Rapid effects of aldosterone and spironolactone in the isolated working rat heart.

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 (P<0.01). Similar to the aldosterone effect, 10 nmol/L spironolactone increased contractility by 41% (P<0.01). 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% (P<0.01). 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.

Regulación de la acción de la aldosterona al nivel del receptor mineralocorticoide / Regulation of the action of aldosterone at level from mineralocorticoid receptor

Se revisan nuevos conceptos acerca de la secreción de aldosterona y de la interacción de la aldosterona con el receptor mineralocorticoide así como el papel de la enzima 11b-hidroxisteroid dehidrogenasa tipo 2(11b-HSD-2) en la protección del receptor mineralocorticoides contra la acción de los glucocorticoides endógenos. Alteraciones en la actividad de esta enzima causan hipertensión arterial en humanos y animales de experimentación. En vista del papel crítico que esta enzima juega en la reabsorción de sodio y el volumen sanguineo en este estudio se investiga la regulación del gen de la 11b-HSD-2 en el riñón de la rata Dahl, un modelo experimental de hipertensión genética sensible al sodio dietético y se muestra que el sodio dietético aumenta la expresión del gen en el riñón de estas ratas.