Interactions between A^sub 2A^ adenosine receptors, hydrogen peroxide, and K^sub ATP^ channels in coronary reactive hyperemia

Myocardial metabolites such as adenosine mediate reactive hyperemia, in part, by activating ATP-dependent K+ (K...) channels in coronary smooth muscle. In this study, we investigated the role of adenosine A... and A... receptors and their signaling mechanisms in reactive hyperemia. We hypothesized that coronary reactive hyperemia involves A... receptors, hydrogen peroxide (H...O...), and K... channels. We used A... and A... knockout (KO) and A... 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... KO and A.../... DKO mice (98 ± 9 and 105 ± 6%; P < 0.05), but not A2B KO mice (123 ± 13%). Patch-clamp experiments demonstrated that adenosine activated glibenclamide-sensitive K... current in smooth muscle cells from WT and A... KO mice (90 ± 23% of WT) but not A... KO or A.../A... DKO mice (30 ± 4 and 35 ± 8% of WT; P < 0.05). Additionally, H...O... activated K... current in smooth muscle cells (358 ± 99%; P < 0.05). Catalase, an enzyme that breaks down H...O..., 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... KO mice (98 ± 7%). Our findings suggest that adenosine A... receptors are coupled to smooth muscle K... channels in reactive hyperemia via the production of H...O... as a signaling intermediate. (ProQuest: ... denotes formulae/symbols omitted.)