Diabetes and streptozotocin-induced alterations in the rat myocardial [beta]-adrenoceptor system
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Diabetogenic agent streptozotocin (STZ) was used to induce diabetes in male Sprague-Dawley rats. A single i.v. administration of the drug resulted in marked hyperglycemia, glycosuria, polyuria, polydipsia, and hyperphagia. The diabetic state was found to be associated with alterations in cardiovascular tissue responsiveness and sensitivity. Vascular alterations Thoracic aortic strips isolated from STZ-treated animals were found to be less responsive to calcium, relative to control animals. However sensitivity to the a-agonists, norepinephrine and methoxamine, was unchanged. In contrast to aorta, tail arteries were similar in responsiveness to calcium and supersensitive to the contractile effects of the a-agonists. The supersensitivity was found to be associated with decreased tissue norepinephrine content. This indication of neuropathy suggested that both pre- and post-junctional alterations influence sensitivity of the tail artery to a-agonists in STZ-diabetic animals. Myocardial alterations Basal rate of spontaneously beating atria and maximum chronotropic responses to isoproterenol were lowered after STZ treatment. Sensitivity to the B-agonist however, was not affected. Right ventricular tissue isolated from STZ-treated animals was found to be subsensitive to the inotropic effects of isoproterenol. The subsensitivity phenomenon was found to be accompanied by decreased myocardial B-adrenoceptor density, increased basal developed force, and supersensitivity to calcium. Detailed characterization of the subsensitivity phenomenon revealed that it was independent of (a) age of the animal, (b) duration of diabetes up to six months, (c) direct cardiotoxic effects of STZ, (d) resting tension, (e) frequency of stimulation, (f) changes in heart norepinephrine content, (g) BDF, and (h) supersensitivity to calcium. Inotropic responses obtained with methoxamine, an adenylate cyclase (AC)-independent agonist; glucagon, a receptor- and AC dependent agonist; and forskolin, a direct activator of AC; provided indirect evidence for a "defect" in the ability of isoproterenol to activate AC, via B-adrenoceptor stimulation, in hearts obtained from STZ-treated animals. This defect was linked to (1) decreased B-adrenoceptor density and (2) decrease in the high affinity state population of the B-adrenoceptor. Since the high affinity state of the receptor is a necessary intermediate for AC activation and myocardial contraction, it might be proposed that the decreased population of receptors in this state after STZ treatment contributes to the development of inotropic subsensitivity to isoproterenol. It is further proposed that the down-regulation of receptor population is related to an increase in circulating epinephrine levels, which were evident in diabetic animals. It might also be proposed that myocardial inotropic subsensitivity to B-stimulation is an important factor contributing to heart failure seen among diabetic patients.