α-Adrenergic supersensitivity and decreased number of α-adrenoceptors in heart from acute diabetic rats

Publisher Website
Google Scholar
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 Kd and Bmax 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.