Interactions between A2A adenosine receptors, hydrogen peroxide, and KATP channels in coronary reactive hyperemia

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 (H2O2), and K-ATP 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, H2O2 activated K-ATP current in smooth muscle cells (358 +/- 99%; P < 0.05). Catalase, an enzyme that breaks down H2O2, 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 K-ATP channels in reactive hyperemia via the production of H2O2 as a signaling intermediate.