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

Abstract

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 +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 + /H ⁺ exchanger ( P + ] _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 i ) · min ⁻¹ · 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.