Cellular mechanisms responsible for the inotropic action of insulin on failing human myocardium.

BACKGROUND: An increase in intracellular calcium transients is responsible for the positive inotropic effect of insulin on human myocardium, but the mechanisms involved in this increase in [Ca2+]i remain unclear.
METHODS: We studied isolated trabeculae or cardiomyocytes from end-stage failing hearts of 38 patients undergoing heart transplantation. The effect of insulin on isometric twitch force (37 degrees C, 0.5 Hz) and L-type Ca2+ current (whole-cell voltage clamp) was assessed.
RESULTS: Crystalline insulin increased the contractile force in a dose-dependent manner (0.01 to 10 micromol/liter), with a maximum increase of 45 +/- 8% (p < 0.05) at 1 micromol/liter. It also increased L-type Ca2+ peak current density by 26 +/- 6% (p < 0.05). This insulin-mediated positive inotropic effect was unchanged in the presence of propranolol (1 micromol/liter). Positive inotropy was partially independent of glucose. L-type Ca2+ channel blockade (diltiazem, 5 micromol/liter), and sarcoplasmic reticulum (SR) Ca2+-release channel blockade (ryanodine, 0.1 micromol/liter) did not affect the inotropic response to insulin. However, blockade of SR Ca2+-ATPase (cyclopiazonic acid, 10 micromol/liter), inhibition of Na+-H+ exchange (HOE642, 10 micromol/liter), and inhibition of Na+-Ca2+ exchange (SEA0400, 1 micromol/liter) partially prevented the inotropic response to insulin.
CONCLUSIONS: Positive inotropy of insulin was not related to catecholamine release and subsequent stimulation of beta-adrenergic receptor, but it may enhance the activity of SR Ca2+-ATPase and trans-sarcolemmal Ca2+ entry, mainly via reverse-mode Na+-Ca2+ exchange and insulin-mediated activation of Na+-H+ exchange. We hypothesize that these changes in [Ca2+]i might be secondary to the activation of reverse-mode Na+-Ca2+ exchange, presumably via elevated intracellular Na+ concentration.