title: Interactions between A(2A) adenosine receptors, hydrogen peroxide, and KATP channels in coronary reactive hyperemia.
abstract: Myocardial metabolites such as adenosine mediate reactive hyperemia, in part, by activating ATP-dependent K(+) (K(ATP)) channels in coronary smooth muscle. In this study, we investigated the role of adenosine A(2A) and A(2B) receptors and their signaling mechanisms in reactive hyperemia. We hypothesized that coronary reactive hyperemia involves A(2A) receptors, hydrogen peroxide (H(2)O(2)), and KATP channels. We used A(2A) and A(2B) knockout (KO) and A(2A/2B) double KO (DKO) mouse hearts for Langendorff experiments. Flow debt for a 15-s occlusion was repaid 128 ± 8% in hearts from wild-type (WT) mice; this was reduced in hearts from A(2A) KO and A(2A)/(2B) DKO mice (98 ± 9 and 105 ± 6%; P < 0.05), but not A(2B) KO mice (123 ± 13%). Patch-clamp experiments demonstrated that adenosine activated glibenclamide-sensitive KATP current in smooth muscle cells from WT and A(2B) KO mice (90 ± 23% of WT) but not A(2A) KO or A(2A)/A(2B) DKO mice (30 ± 4 and 35 ± 8% of WT; P < 0.05). Additionally, H(2)O(2) activated KATP current in smooth muscle cells (358 ± 99%; P < 0.05). Catalase, an enzyme that breaks down H(2)O(2), attenuated adenosine-induced coronary vasodilation, reducing the percent increase in flow from 284 ± 53 to 89 ± 13% (P < 0.05). Catalase reduced the repayment of flow debt in hearts from WT mice (84 ± 9%; P < 0.05) but had no effect on the already diminished repayment in hearts from A(2A) KO mice (98 ± 7%). Our findings suggest that adenosine A(2A) receptors are coupled to smooth muscle KATP channels in reactive hyperemia via the production of H(2)O(2) as a signaling intermediate.
authors.affiliation: Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Sharifi-Sanjani
authors.forename: Xueping
authors.initials: X
authors.lastname: Zhou
authors.forename: Shinichi
authors.initials: S
authors.lastname: Asano
authors.forename: Stephen
authors.initials: S
authors.lastname: Tilley
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.forename: Bunyen
authors.initials: B
authors.lastname: Teng
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Dick
authors.forename: S Jamal
authors.initials: SJ
authors.lastname: Mustafa
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D002374:Catalase / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000502:physiology*; D005905:Glyburide / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006940:Hyperemia / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D054086:KATP Channels / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D018408:Patch-Clamp Techniques; D043705:Receptor, Adenosine A2A / Q000187:drug effects / Q000502:physiology*; D043704:Receptor, Adenosine A2B / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D054086:KATP Channels; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D014665:Vasodilator Agents; D006861:Hydrogen Peroxide; D002374:Catalase; D009247:NADH, NADPH Oxidoreductases; D000241:Adenosine; D005905:Glyburide
keywords: adenosine receptors; coronary circulation; ischemic vasodilatation; reactive oxygen species