Absence of adenosine-mediated aortic relaxation in A(2A) adenosine receptor knockout mice.
Adenosine mediates vascular responses through four receptor subtypes: A(1), A(2A), A(2B), and A(3). The role of A(2A) receptors in aortic vascular tone was investigated using A(2A) adenosine receptor (AR) knockout (A(2A)KO) and corresponding wild-type (A(2A)WT) mice. Isolated aortic rings from A(2A)WT and A(2A)KO mice were precontracted with phenylephrine (10(-7) M), and concentration responses for adenosine analogs and selective agonists/antagonists were obtained. Nonselective adenosine analog (NECA; EC(50) = 6.78 microM) and CGS-21680 (A(2A)AR selective agonist; EC(50) = 0.013 microM) produced concentration-dependent relaxation (maximum of 25% and 28% relaxation at 10(-5) M NECA and CGS-21680, respectively) in A(2A)WT aorta. In A(2A)KO aorta, NECA (EC(50) = 0.075 microM) induced concentration-dependent contraction (maximum contraction of 47% at 10(-6) M; P < 0.05 compared with A(2A)WT), whereas CGS-21680 produced no response. SCH-58261 (10(-6) M; A(2A)AR selective antagonist) abolished both NECA- and CGS-21680-mediated vasorelaxation in A(2A)WT (P < 0.05), whereas no change was observed in A(2A)KO. When DPCPX (10(-5) M; A(1) selective antagonist) was used in NECA concentration response, greater vasorelaxation was observed in A(2A)WT (50% vs. 25% in controls at 10(-5) M; P < 0.05), whereas lower contraction was seen in A(2A)KO 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(2A)AR KO mice had significantly lower aortic relaxation and endothelial function, suggesting that the A(2A)AR plays an important role in vasorelaxation, probably through an endothelium-dependent mechanism.
Ponnoth
Dovenia S
DS
Department of Physiology and Pharmacology, Center for Interdisciplinary Research in Cardiovascular Sciences, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, West Virginia, USA.
Sanjani
Maryam Sharifi
MS
Ledent
Catherine
C
Roush
Kevin
K
Krahn
Thomas
T
Mustafa
S Jamal
SJ
D000109:Acetylcholine / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005415:Flavins / Q000494:pharmacology; D005786:Gene Expression Regulation; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010627:Phenethylamines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics; D043704:Receptor, Adenosine A2B / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D000631:Aminopyridines; C518875:BAY 60-6583; D005415:Flavins; D010627:Phenethylamines; D011743:Pyrimidines; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D014230:Triazoles; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); C008173:isoalloxazine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; D000109:Acetylcholine