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Effect of chronic and selective endothelin receptor antagonism on microvascular function in Type 2 diabetes

¹Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, and ²School of Allied Health, Medical College of Georgia, and ³Department of Physiology, Medical College of Georgia, Augusta, Georgia

Submitted 18 December 2007 ; accepted in final form 16 April 2008

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-dependent vasodilation. The current study examined the individual and/or the relative roles of the ET receptors governing vascular function in the Goto-Kakizaki rat, a mildly hyperglycemic, normotensive, and nonobese model of Type 2 diabetes. Diabetic and control rats received an antagonist to either the ET type A (ET_A; atrasentan; 5 mg·kg^–1·day^–1) or type B (ET_B; A-192621; 15 or 30 mg·kg^–1·day^–1) receptors for 4 wk. 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, whereas 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 the dose-response curve to ACh was shifted to the right, indicating a decreased relaxation at 15 mg/kg A-192621. These results suggest that ET_A receptor blockade attenuates vascular dysfunction and that ET_B receptor antagonism exhibits differential effects depending on the dose of the antagonists and the disease state.

microvessel; vascular dysfunction; Goto-Kakizaki rats

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				K. Sachidanandam, J. R. Hutchinson, M. M. Elgebaly, E. M. Mezzetti, M.-H. Wang, and A. Ergul Differential Effects of Diet-Induced Dyslipidemia and Hyperglycemia on Mesenteric Resistance Artery Structure and Function in Type 2 Diabetes J. Pharmacol. Exp. Ther., January 1, 2009; 328(1): 123 - 130. [Abstract] [Full Text] [PDF]