title: A1 adenosine receptor negatively modulates coronary reactive hyperemia via counteracting A2A-mediated H2O2 production and KATP opening in isolated mouse hearts.
abstract: We previously demonstrated that A2A, but not A2B, adenosine receptors (ARs) mediate coronary reactive hyperemia (RH), possibly by producing H2O2 and, subsequently, opening ATP-dependent K(+) (KATP) channels in coronary smooth muscle cells. In this study, A1 AR knockout (KO), A3 AR KO, and A1 and A3 AR double-KO (A1/A3 DKO) mice were used to investigate the roles and mechanisms of A1 and A3 ARs in modulation of coronary RH. Coronary flow of isolated hearts was measured using the Langendorff system. A1 KO and A1/A3 DKO, but not A3 KO, mice showed a higher flow debt repayment [~30% more than wild-type (WT) mice, P < 0.05] following a 15-s occlusion. SCH-58261 (a selective A2A AR antagonist, 1 μM) eliminated the augmented RH, suggesting the involvement of enhanced A2A AR-mediated signaling in A1 KO mice. In isolated coronary arteries, immunohistochemistry showed an upregulation of A2A AR (1.6 ± 0.2 times that of WT mice, P < 0.05) and a higher magnitude of adenosine-induced H2O2 production in A1 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 KATP channel blocker, 5 μM), but not N(G)-nitro-l-arginine methyl ester, also abolished the enhanced RH in A1 KO mice. Our data suggest that A1, but not A3, AR counteracts the A2A AR-mediated CF increase and that deletion of A1 AR results in upregulation of A2A AR and/or removal of the negative modulatory effect of A1 AR, thus leading to an enhanced A2A AR-mediated H2O2 production, KATP channel opening, and coronary vasodilation during RH. This is the first report implying that A1 AR has a role in coronary RH.
authors.affiliation: Department of Physiology and Pharmacology, West Virginia University, Morgantown, West Virginia;
authors.forename: Xueping
authors.initials: X
authors.lastname: Zhou
authors.forename: Bunyen
authors.initials: B
authors.lastname: Teng
authors.forename: Stephen
authors.initials: S
authors.lastname: Tilley
authors.forename: S Jamal
authors.initials: SJ
authors.lastname: Mustafa
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006940:Hyperemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010477:Perfusion; D026902:Potassium Channel Blockers / Q000494:pharmacology; D043682:Receptor, Adenosine A1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000187:drug effects / Q000378:metabolism*; D043684:Receptor, Adenosine A3 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000975:Antioxidants; D054086:KATP Channels; D026902:Potassium Channel Blockers; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D006861:Hydrogen Peroxide
keywords: A1 adenosine receptor knockout; A3 adenosine receptor knockout; ATP-dependent K+ channels; coronary reactive hyperemia; hydrogen peroxide
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