MECHANISMS OF INOTROPIC RESPONSES OF THE ISOLATED RAT HEARTS TO VANADATE

In view of the invariable development of insulin resistance in differe nt types of cardiovascular diseases, considerable attention has been f ocussed on vanadate because of its ability to exert insulin-like effec ts in the body. Since vanadate, like insulin, has been shown to exert a beneficial effect in diabetic cardiomyopathy, this study was underta ken to examine the mechanisms of its action on the heart. Vanadate, at 5-10 mu M concentrations, produced a positive inotropic effect in the isolated perfused rat heart, whereas at higher concentrations (20 mu M), it decreased the contractile force development. The positive inotr opic effect of 10 mu M vanadate was not affected by the pretreatment o f animals with reserpine as well as the presence of propranolol or phe noxybenzamine in the perfusion medium. The increase in contractile for ce development due to vanadate at low (0.3-0.6 mM) concentrations of C a2+ was markedly augmented, but this agent produced a negative inotrop ic action at high concentrations of Ca2+ (2.0-3.0 mM). Preperfusion of hearts with verapamil enhanced the positive inotropic effect ofvanada te whereas hearts preperfused with ouabain, low sodium or amiloride sh owed negative inotropic effects of vanadate. Vanadate was found to inh ibit sarcoplasmic reticular Ca2+-pump and sarcolemmal Ca2+-pump as wel l as Na+-K+-ATPase activities but the sarcolemmal effects were evident at lower concentrations in comparison to that on the sarcoplasmic ret iculum, The actions of vanadate on membrane Ca2+ transport and ATPase systems were specific since this agent exerted no effect on sarcolemma l Na+-Ca2+ exchange or myofibrillar ATPase activities, In isolated car diomyocytes suspended in buffer containing 0.5 or 1.0 mM Ca2+, vanadat e increased the intracellular concentration of Ca2+; this increase in intracellular Ca2+ was more pronounced at 0.5 mM Ca2+. These results i ndicate that increased intracellular concentration of Ca2+ due to inhi bition of sarcolemmal Na+-K+-ATPase and sarcolemmal Ca2+-pump may be t he primary mechanism of the positive inotropic action of vanadate in t he heart, It is suggested that vanadate may serve as an inotropic agen t and that this mechanism may contribute towards its beneficial effect s on cardiac dysfunction in different cardiovascular diseases.