Mechanisms of inotropic responses of the isolated rat hearts to vanadate

In view of the invariable development of insulin resistance in different types of cardiovascular diseases, considerable attention has been focused on vanadate because of its ability to exert insulin-like effects in the body. Since vanadate, like insulin, has been shown to exert a beneficial effect in diabetic cardiomyopathy, this study was undertaken to examine the mechanisms of its action on the heart. Vanadate, at 5-10 microM concentrations, produced a positive inotropic effect in the isolated perfused rat heart, whereas at higher concentrations (20 microM), it decreased the contractile force development. The positive inotropic effect of 10 microM vanadate was not affected by the pretreatment of animals with reserpine as well as the presence of propranolol or phenoxybenzamine in the perfusion medium. The increase in contractile force development due to vanadate at low (0.3-0.6 mM) concentrations of Ca2+ was markedly augmented, but this agent produced a negative inotropic action at high concentrations of Ca2+ (2.0-3.0 mM). Preperfusion of hearts with verapamil enhanced the positive inotropic effect of vanadate whereas hearts preperfused with ouabain, low sodium or amiloride showed negative inotropic effects of vanadate. Vanadate was found to inhibit sarcoplasmic reticular Ca(2+)-pump and sarcolemmal Ca(2+)-pump as well as Na(+)-K(+)-ATPase activities but the sarcolemmal effects were evident at lower concentrations in comparison to that on the sarcoplasmic reticulum. The actions of vanadate on membrane Ca2+ transport and ATPase systems were specific since this agent exerted no effect on sarcolemmal Na(+)-Ca2+ exchange or myofibrillar ATPase activities. In isolated cardiomyocytes suspended in buffer containing 0.5 or 1.0 mM Ca2+, vanadate increased the intracellular concentration of Ca2+; this increase in intracellular Ca2+ was more pronounced at 0.5 mM Ca2+. These results indicate that increased intracellular concentration of Ca2+ due to inhibition of sarcolemmal Na(+)-K(+)-ATPase and sarcolemmal Ca(2+)-pump may be the primary mechanism of the positive inotropic action of vanadate in the heart. It is suggested that vanadate may serve as an inotropic agent and that this mechanism may contribute towards its beneficial effects on cardiac dysfunction in different cardiovascular diseases.