Abstract 511: Altered Role of Endothelin Type B Receptors in Coronary Vasoconstriction to Endothelin-1 in Obese Type 2 Diabetic Mice
Obesity and type 2 diabetes cause endothelial dysfunction characterized by alterations in local vascular regulatory systems such as the endothelin system. The role of endothelin type B (ETB) receptors in normal and diabetic coronary vascular regulation remains unclear. Recently, diabetes-induced elevations of ETB receptor mRNA were elucidated; however, the functional significance of this change is unknown. ETB receptor activation may lead to vasodilation or vasoconstriction depending on the relative contributions of endothelial and vascular smooth muscle ETB receptors, respectively. We examined the hypothesis that diabetes augments the role of ETB receptors in basal coronary tone and coronary vasoconstriction to endothelin-1 (ET-1). Isolated, buffer-perfused hearts from lean and high-fat diet-induced obese type 2 diabetic mice were utilized (6 –12 mice/group). The diabetic mice exhibited obesity, hyperglycemia, hyperinsulinemia and dyslipidemia. Selective ETB receptor inhibition with BQ-788 (10-6 M) reduced coronary vascular resistance (CVR) by 30% in diabetic hearts compared to no change in lean hearts. Dose-response studies with the selective ETB receptor agonist IRL-1620 (10-11 - 10-9 M) induced pronounced vasoconstriction (40% CVR increase) in diabetic hearts compared to no change at any dose in lean hearts. Coronary vasoconstriction to ET-1 (10-10 M), in the presence of BQ-788 and nitric oxide synthase inhibition with L-NAME (10-5 M), was abolished in lean hearts and unaffected in diabetic hearts. Nitric oxide production, basal and endothelial ETB receptor-mediated, was inhibited to remove its negative influence on ET-1-mediated responses. In conclusion, these data indicate that the role of ETB receptors in normal mouse coronary regulation is minimal possibly due to a balance of endothelial and smooth muscle ETB receptor-mediated responses; however, the role of vascular smooth muscle ETB receptors is enhanced in diabetes. These data also suggest that basal ETB receptor activation is necessary for ET-1-mediated coronary vasoconstriction and that this permissive role of ETB receptors may be uncoupled by diabetes. Therefore, the altered role of ETB receptors in diabetes may contribute to defects in coronary blood flow regulation.