Abstract:

The inotropic effect of methoxamine, as well as the α-adrenoceptor population, were measured in cardiac tissue from normal and short-term (3 days) diabetic rats. Methoxamine increased the tension of both normal and diabetic ventricles, but in diabetic ones, the dose-response curve to methoxamine was shifted to the left and the efficacy of the α-agonist was enhanced. This phenomenon was accompanied by an increase in receptor affinity, while the number of α-adrenoceptor sites decreased. Inhibitors of α1-adrenoceptors blocked, in a competitive manner, the positive inotropic effect of methoxamine in both types of ventricles. Inhibition of phospholipase C blocked the ventricular response to the methoxamine in nondiabetic as well as in diabetic hearts. Synthetic diacylglyceride (DAG) potentiated the inotropic action of the α-agonist in normal ventricles and increased the affinity with a decreased number of α-adrenoceptor sites in normal ventricles, producing values of K(d) of B(max) similar to those of the acute diabetic heart. Inhibitors of protein kinase C partially reduced the supersensitivity to α-agonists in diabetic ventricles and prevented the stimulatory action of DAG upon the positive inotropic effect of methoxamine in normal ventricles. These results suggest that α-adrenergic inotropic stimulation is secondary to receptor-mediated hydrolysis of phosphoinositides, generating some oxidative metabolites (DAG) which, in turn, may be responsible for the inotropic effect. In the acute diabetic state, the supersensitivity to α-agonist could be due to high activity of phospholipase C (with an increase in DAG production) which induces alteration in the membrane α-adrenergic receptors.