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This Article Full Text Full Text (PDF) All Versions of this Article: 297/5/H1655    most recent 00192.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Ponnoth, D. S. Articles by Mustafa, S. J. PubMed PubMed Citation Articles by Ponnoth, D. S. Articles by Mustafa, S. J.

Absence of adenosine-mediated aortic relaxation in A_2A adenosine receptor knockout mice

¹Department of Physiology and Pharmacology, Center for Interdisciplinary Research in Cardiovascular Sciences, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, West Virginia; ²Université Libre de Bruxelles, Brussels, Belgium; and ³Bayer Health Care AG, Wuppertal, Germany

Submitted February 26, 2009 ; accepted in final form September 8, 2009

Adenosine mediates vascular responses through four receptor subtypes: A₁, A_2A, A_2B, and A₃. The role of A_2A receptors in aortic vascular tone was investigated using A_2A adenosine receptor (AR) knockout (A_2AKO) and corresponding wild-type (A_2AWT) mice. Isolated aortic rings from A_2AWT and A_2AKO mice were precontracted with phenylephrine (10^–7 M), and concentration responses for adenosine analogs and selective agonists/antagonists were obtained. Nonselective adenosine analog (NECA; EC₅₀ = 6.78 µM) and CGS-21680 (A_2AAR selective agonist; EC₅₀ = 0.013 µM) produced concentration-dependent relaxation (maximum of 25% and 28% relaxation at 10^–5 M NECA and CGS-21680, respectively) in A_2AWT aorta. In A_2AKO aorta, NECA (EC₅₀ = 0.075 µM) induced concentration-dependent contraction (maximum contraction of 47% at 10^–6 M; P < 0.05 compared with A_2AWT), whereas CGS-21680 produced no response. SCH-58261 (10^–6 M; A_2AAR selective antagonist) abolished both NECA- and CGS-21680-mediated vasorelaxation in A_2AWT (P < 0.05), whereas no change was observed in A_2AKO. When DPCPX (10^–5 M; A₁ selective antagonist) was used in NECA concentration response, greater vasorelaxation was observed in A_2AWT (50% vs. 25% in controls at 10^–5 M; P < 0.05), whereas lower contraction was seen in A_2AKO tissues (5% vs. 47% in controls at 10^–6 M; P < 0.05). Aortic endothelial function, determined by response to acetylcholine, was significantly higher in WT compared with KO (66% vs. 51%; P < 0.05). BAY 60–6583 (A_2B selective agonist) produced similar relaxation in both KO and WT tissues. In conclusion, A_2AAR KO mice had significantly lower aortic relaxation and endothelial function, suggesting that the A_2AAR plays an important role in vasorelaxation, probably through an endothelium-dependent mechanism.

endothelium; mouse aorta; vasorelaxation; adenosine agonists; antagonists