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1 Department of Physiology & Pharmacology and Center for Interdisciplinary Research in Cardiovascular Sciences (CIRCS), West Virginia University, Morgantown, West Virginia, United States
2 Heart and Lung Research Institute, Ohio State University, Columbus, Ohio, United States
* To whom correspondence should be addressed. E-mail: smustafa{at}hsc.wvu.edu.
We have investigated the role of adenosine and its analogs on vasorelaxation of mouse aorta in intact endothelium with rank order of potency as follows: NECA>CAD>adenosine>> CGS-21680 which is consistent with the profile of A2B adenosine receptor (A2BAR). In endothelium-intact tissues, acetylcholine produced relaxation ranging from 65-80% in phenylephrine (PE, 10-7 M) pre-contracted mouse aorta, whereas it produced no relaxation in endothelium-denuded tissues. The A2BAR antagonist, alloxazine (10-5 M) shifted concentration response curve for NECA (EC50 = 0.005 x 10-5 M) to the right with an EC50 of 2.8 x 10-5 M demonstrating that this relaxation is partially dependent on functional endothelium mediated predominantly via A2BAR. This conclusion was further supported by the following findings: (a) in the intact endothelium mouse aorta, the EC50s for NECA and adenosine were found to be 0.05 and 1.99 x 10-4 M, respectively; however, in denuded endothelium, these values were 0.098 and 3.55 x 10-4 M, respectively; (b) NECA-induced relaxation was significantly blocked by L-NAME (10-4 M) in endothelium-intact tissues which was reversed by pretreatment with L-arginine (10-4 M); whereas no significant inhibition was found in endothelium-denuded tissues; (c) total nitrites and nitrates (NOx) in intact endothelium with L-NAME (10-4 M) alone and in combination with L-arginine were 59% (p<0.05) and 96%, respectively in comparison to control (PE+NECA), and (d) eNOS gene expression was found to be 67% (p<0.05) less in endothelium denuded when compared to intact mouse aorta. Thus, these data demonstrate that activation of A2BAR plays an important role in endothelium-mediated relaxation of mouse aorta through nitric oxide released by eNOS.
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