Role of thromboxanes in alterations of the diabetic beta-adrenergic system.
The inotropic effects of isoproterenol (ISO), as well as the beta-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 (Emax) 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 beta-adrenoceptor sites (Bmax) 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 beta-adrenoceptors during diabetes, producing Bmax values almost similar to those of the normal heart. Additionally, the diabetic heart generated and released a greater amount of TXB2 than the normal heart, even in the presence or absence of ISO. The stimulatory effect of ISO upon TXB2 release was altered by the specific beta-adrenergic blockade and by verapamil. In addition, the drugs able to induce a sustained increase of endogenous cAMP also inhibited the release of TXB2 by diabetic ventricles. Exogenous TXB2 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 beta-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 beta-adrenoceptors during diabetes. The abnormal reactivity to beta-agonists also could be associated with alterations of the diabetic cardiac Na+ + K+-ATPase activity induced by TXB2 whose production is increased during diabetes.
Wald
M
M
Centro de Estudios Farmacológicos y de Principios Naturales (CEFAPRIN), Buenos Aires, Argentina.
Pascual
J
J
Sterin-Borda
L
L
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004082:Dihydroalprenolol / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000032:analysis / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000032:analysis; D013929:Thromboxane B2 / Q000032:analysis / Q000502:physiology*
D001713:Biphenyl Compounds; D011943:Receptors, Adrenergic, beta; D013929:Thromboxane B2; D004082:Dihydroalprenolol; C046926:AH 23848; D000254:Sodium-Potassium-Exchanging ATPase; D007545:Isoproterenol