Alpha-adrenergic supersensitivity and decreased number of alpha-adrenoceptors in heart from acute diabetic rats.
The inotropic effect of methoxamine, as well as the alpha-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 alpha-agonist was enhanced. This phenomenon was accompanied by an increase in receptor affinity, while the number of alpha-adrenoceptor sites decreased. Inhibitors of alpha 1-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 alpha-agonist in normal ventricles and increased the affinity with a decreased number of alpha-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 alpha-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 alpha-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 alpha-agonist could be due to high activity of phospholipase C (with an increase in DAG production) which induces alteration in the membrane alpha-adrenergic receptors.
Wald
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Centrol de Estudios Farmacológicos y de Principios Naturales, Consejo Nacional de Investigaciones Cientificas y Técnicas de la República Argentina, Buenos Aires.
Borda
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ES
Sterin-Borda
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L
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008297:Male; D008729:Methoxamine / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D011224:Prazosin / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*
D011942:Receptors, Adrenergic, alpha; D008729:Methoxamine; D011224:Prazosin