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

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 (ET...) and type B (ET...) receptors that have been implicated in cross talk with α...-adrenoceptors (α...-AR). ET... and ET... receptor expression and plasma ET-1 levels are elevated in T2D; however, whether this influences coronary α...-AR function has not been examined. Therefore, we examined the effect of ET... and ET... receptor inhibition on coronary vasoconstriction to ET-1 and α...-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 α...-AR agonist phenylephrine (PE) were examined alone and in the presence of the nitric oxide synthase inhibitor N...-nitro-L-arginine methyl ester (L-NAME) alone or in combination with selective ET... or ET... receptor inhibitors BQ-123 and BQ-788, respectively. Vasoconstriction to ET-1 was enhanced, whereas ET..., but not ET..., receptor blockade reduced basal coronary tone in T2D hearts. In the presence of L-NAME, ET... receptor inhibition attenuated ET-1 vasoconstriction in both groups, whereas ET... inhibition abolished this response only in control hearts. In addition, ET... inhibition enhanced α...-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 ET... receptors, whereas the interaction with α...-ARs is mediated solely through the ET... receptor subtype. (ProQuest: ... denotes formulae/symbols omitted.)