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Am J Physiol Heart Circ Physiol 293: H2281-H2288, 2007. First published July 27, 2007; doi:10.1152/ajpheart.00566.2007
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Altered role of smooth muscle endothelin receptors in coronary endothelin-1 and {alpha}1-adrenoceptor-mediated vasoconstriction in Type 2 diabetes

S. B. Bender and R. E. Klabunde

Department of Biomedical Sciences, Ohio University College of Osteopathic Medicine, Athens, Ohio

Submitted 15 May 2007 ; accepted in final form 23 July 2007

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 {alpha}1-adrenoceptors ({alpha}1-AR). ETA and ETB receptor expression and plasma ET-1 levels are elevated in T2D; however, whether this influences coronary {alpha}1-AR function has not been examined. Therefore, we examined the effect of ETA and ETB receptor inhibition on coronary vasoconstriction to ET-1 and {alpha}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 {alpha}1-AR agonist phenylephrine (PE) were examined alone and in the presence of the nitric oxide synthase inhibitor N{omega}-nitro-L-arginine methyl ester (L-NAME) alone or in combination with selective ETA or ETB receptor 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, ETA receptor inhibition attenuated ET-1 vasoconstriction in both groups, whereas ETB inhibition abolished this response only in control hearts. In addition, ETA inhibition enhanced {alpha}1-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 ETB receptors, whereas the interaction with {alpha}1-ARs is mediated solely through the ETA receptor subtype.

isolated heart; C57BL/6J mouse; diet-induced diabetes


Address for reprint requests and other correspondence: R. E. Klabunde, Dept. of Biomedical Sciences, I-304, Ohio Univ. College of Osteopathic Medicine, Athens, OH 45701 (e-mail: klabunde{at}ohio.edu)






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