Altered role of smooth muscle endothelin receptors in coronary endothelin-1 and α1-adrenoceptor-mediated vasoconstriction in Type 2 diabetes

Abstract

Regulation of vascular tone and blood flow involves interactions between numerous local and systemic vascular control signals, many of which are altered by Type 2 diabetes (T2D). Vascular responses to endothelin-1 (ET-1) are mediated by endothelin type A (ETA) and type B (ETB) receptors that have been implicated in cross talk with α1-adrenoceptors (α1-AR). ETAand ETBreceptor expression and plasma ET-1 levels are elevated in T2D; however, whether this influences coronary α1-AR function has not been examined. Therefore, we examined the effect of ETAand ETBreceptor inhibition on coronary vasoconstriction to ET-1 and α1-AR activation in a mouse model of T2D. Coronary vascular responses were examined in isolated mouse hearts from control and diet-induced T2D C57BL/6J mice. Responses to ET-1 and the selective α1-AR agonist phenylephrine (PE) were examined alone and in the presence of the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) alone or in combination with selective ETAor ETBreceptor inhibitors BQ-123 and BQ-788, respectively. Vasoconstriction to ET-1 was enhanced, whereas ETB, but not ETA, receptor blockade reduced basal coronary tone in T2D hearts. In the presence of l-NAME, ETAreceptor inhibition attenuated ET-1 vasoconstriction in both groups, whereas ETBinhibition abolished this response only in control hearts. In addition, ETAinhibition enhanced α1-AR-mediated vasoconstriction in T2D, but not control, hearts following l-NAME treatment. Therefore, in this model, enhanced coronary ET-1 responsiveness is mediated primarily through smooth muscle ETBreceptors, whereas the interaction with α1-ARs is mediated solely through the ETAreceptor subtype.