Role of thromboxanes in alterations of the diabetic β-adrenergic system

Abstract

The inotropic effects of isoproterenol (ISO), as well as the β-adrenoceptors population, were measured in cardiac tissues from normal and short-term (3 days) diabetic rats. ISO increased the tension of both normal and diabetic ventricles, but the efficacy ( E max) of the concentration-response curve was greater on ventricles from diabetic rats than in those from the normal control. This phenomenon was accompanied by a decrease in the number of β-adrenoceptor sites ( B max) during diabetes. Insulin-treated diabetic hearts partially reversed the phenomenon. Propanolol blocked, in a competitive manner, the positive inotropic action of ISO in both types of ventricles. Inhibition of the synthesis and receptors of thromboxane (TX) reduced the hyperreactivity to ISO and increased the number of β-adrenoceptors during diabetes, producing B max values almost similar to those of the normal heart. Additionally, the diabetic heart generated and released a greater amount of TXB 2 than the normal heart, even in the presence or absence of ISO. The stimulatory effect of ISO upon TXB 2 release was altered by the specific β-adrenergic blockade and by verapamil. In addition, the drugs able to induce a sustained increase of endogenous cAMP also inhibited the release of TXB 2 by diabetic ventricles. Exogenous TXB 2 exerted the same type of hyperreactivity in diabetic ventricles. This phenomenon was accompanied by an inhibition of Na + + K +-ATPase activity. These results suggest that β-adrenergic inotropic stimulation is secondary to receptor-mediated hydrolysis of arachidonic acid with subsequent release of thromboxanes, which, in turn, may be responsible for both the superreactivity and the decrease in the number of β-adrenoceptors during diabetes. The abnormal reactivity to β-agonists also could be associated with alterations of the diabetic cardiac Na + + K +-ATPase activity induced by TXB 2 whose production is increased during diabetes.