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_A) and type B (ET_B) receptors which have been implicated in crosstalk with ₁-adrenoceptors (₁-AR). ET_A and ET_B receptor expression and plasma ET-1 levels are elevated in T2D; however, whether this influences coronary ₁-AR function has not been examined. Therefore, we examined the effect of ET_A and ET_B receptor inhibition on coronary vasoconstriction to ET-1 and ₁-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 ₁-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_A or ET_B receptor inhibitors BQ-123 and BQ-788, respectively. Vasoconstriction to ET-1 was enhanced while ET_B, but not ET_A, receptor blockade reduced basal coronary tone in T2D hearts. In the presence of L-NAME, ET_A receptor inhibition attenuated ET-1 vasoconstriction in both groups whereas ET_B inhibition abolished this response only in control hearts. In addition, ET_A inhibition enhanced ₁-AR-mediated vasoconstriction in T2D, but not control, hearts following L-NAME treatment. Therefore, in this model of type 2 diabetes, enhanced coronary ET-1 responsiveness is mediated primarily through smooth muscle ET_B receptors whereas the interaction with ₁-ARs is mediated solely through the ET_A receptor subtype.