Vascular dysfunction, which presents either as an increased response to vasoconstrictors or an impaired relaxation to dilator agents results in worsened cardiovascular outcomes in diabetes. We have established that the mesenteric circulation in Type 2 diabetes is hyperreactive to the potent vasoconstrictor endothelin-1 (ET-1) and displays increased nitric-oxide (NO)-dependant vasodilation. The current study examined the individual and/or the relative roles of the ET receptors governing vascular function in the Goto-Kakizaki (GK) rat, a mildly hyperglycemic, normotensive and non-obese model of Type 2 diabetes. Diabetic and control rats received an antagonist to either the ET_A (Atrasentan, 5 mg/kg/day) or the ET_B (A-192621, 15 or 30 mg/kg/day) receptors for four weeks. Third-order mesenteric arteries were isolated and vascular function was assessed with a wire-myograph. Maximum response to ET-1 was increased in diabetes, and attenuated by ET_A antagonism. ET_B blockade with 15 mg/kg A-192621 augmented vasoconstriction in controls while it had no further effect on ET-1 hyperreactivity in diabetes. The higher dose of A-192621 showed an ET_A-like effect and decreased vasoconstriction in diabetes. Maximum relaxation to acetylcholine (ACh) was similar across groups and treatments. ET_B antagonism at either dose had no effect on vasorelaxation in control rats, whereas in diabetes dose-response curve to Ach was shifted to right indicating decreased relaxation at 15 mg/kg A-192621. These results suggest that ET_A receptor blockade attenuates vascular dysfunction and ET_B receptor antagonism exhibit differential effects depending on dose of antagonists and disease state.