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INNOVATIVE METHODOLOGY

Evidence for the involvement of nitric oxide in A_2B receptor-mediated vasorelaxation of mouse aorta

¹Department of Physiology and Pharmacology, Center for Interdisciplinary Research in Cardiovascular Sciences, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, West Virginia, ²David Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio

Submitted 6 June 2006 ; accepted in final form 10 August 2006

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: 5'-N-ethylcarboxamidoadenosine (NECA) > 2-chloroadenosine > adenosine >> CGS-21680, which is consistent with the profile of A_2B-adenosine receptor (A_2BAR). In endothelium-intact tissues, acetylcholine produced relaxation ranging from 65 to 80% in phenylephrine (PE, 10^–7 M)-precontracted mouse aorta, whereas no relaxation was observed in endothelium-denuded tissues. The A_2BAR 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 A_2BAR in this tissue. This conclusion was further supported by the following findings: 1) in the endothelium-intact mouse aorta, the EC₅₀ values 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; 2) NECA-induced relaxation was significantly blocked by N^G-nitro-L-arginine methyl ester (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; 3) 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 with control (PE + NECA); and 4) endothelial nitric oxide synthase gene expression was found to be 67% (P < 0.05) less in endothelium-denuded as opposed to endothelium-intact mouse aorta. Thus these data demonstrate that adenosine-mediated vasorelaxation is partially dependent on A_2BAR in mouse aorta.

adenosine; endothelium

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