期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 305, 期 11, 页码 H1668-H1679出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00495.2013
关键词
coronary reactive hyperemia; A(1) adenosine receptor knockout; A(3) adenosine receptor knockout; hydrogen peroxide; ATP-dependent K+ channels
资金
- National Heart, Lung, and Blood Institute [HL-027339, HL-09444, HL-071802]
We previously demonstrated that A(2A), but not A(2B), adenosine receptors (ARs) mediate coronary reactive hyperemia (RH), possibly by producing H2O2 and, subsequently, opening ATP-dependent K+ (K-ATP) channels in coronary smooth muscle cells. In this study, A(1) AR knockout (KO), A(3) AR KO, and A(1) and A(3) AR double-KO (A(1)/A(3) DKO) mice were used to investigate the roles and mechanisms of A(1) and A(3) ARs in modulation of coronary RH. Coronary flow of isolated hearts was measured using the Langendorff system. A(1) KO and A(1)/A(3) DKO, but not A(3) KO, mice showed a higher flow debt repayment [similar to 30% more than wild-type (WT) mice, P < 0.05] following a 15-s occlusion. SCH-58261 (a selective A(2A) AR antagonist, 1 mu M) eliminated the augmented RH, suggesting the involvement of enhanced A(2A) AR-mediated signaling in A(1) KO mice. In isolated coronary arteries, immunohistochemistry showed an upregulation of A(2A) AR (1.6 +/- 0.2 times that of WT mice, P < 0.05) and a higher magnitude of adenosine-induced H2O2 production in A(1) KO mice (1.8 +/- 0.3 times that of WT mice, P < 0.05), which was blocked by SCH-58261. Catalase (2,500 U/ml) and glibenclamide (a K-ATP channel blocker, 5 mu M), but not N-G-nitro-L-arginine methyl ester, also abolished the enhanced RH in A(1) KO mice. Our data suggest that A(1), but not A(3), AR counteracts the A(2A) AR-mediated CF increase and that deletion of A(1) AR results in upregulation of A(2A) AR and/or removal of the negative modulatory effect of A(1) AR, thus leading to an enhanced A(2A) AR-mediated H2O2 production, K-ATP channel opening, and coronary vasodilation during RH. This is the first report implying that A(1) AR has a role in coronary RH.
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