Altered inotropic reactivity in diabetic rabbit right ventricular myocardium

Alloxan monohydrate was used to induce diabetes in rabbits, which were maintained for a 3-month period with or without daily insulin replacement along with age-matched controls. Isolated right ventricular myocardial strips were used to generate dose-response curves to isoproterenol, forskolin, and Bay K 8644. Basal developed force was significantly elevated in diabetic ventricular strips. While isoproterenol acted as a full inotropic agonist, diabetic preparations revealed a consistent but insignificant decrease in the maximum developed force. While both sensitivity to isoproterenol and beta-adrenoceptor density were decreased in preparations from diabetic rabbits, there was no associated increase in circulating plasma catecholamines. In contrast, forskolin and Bay K 8644 were partial agonists in control preparations but full inotropic agonists in diabetic preparations, demonstrating significant increases in maximum developed force. This hyperresponsiveness was not associated with altered calcium channel density. Finally, insulin replacement reduced or prevented all diabetic-related changes. These data indicate that the hyperresponsiveness to forskolin and Bay K 8644 represents an altered utilization of intracellular calcium in the diabetic rabbit, converting them into full agonists similar to isoproterenol. The decrease in sensitivity to isoproterenol correlated with a decrease in beta-adrenoceptor density but not elevated circulating catecholamines as previously observed in diabetic rats.