Interactions between A2A adenosine receptor, hydrogen peroxide, and KATP channel in coronary reactive hyperemia

Abstract

Myocardial metabolites such as adenosine mediate reactive hyperemia (RH) partially through glibenclamide‐sensitive KATP channels in coronary vascular smooth muscle (VSM). We tested the hypothesis that A2A receptors link to KATP channel activation via hydrogen peroxide (H2O2). Using A2A knockout (KO), A2BKO, and A2A/2B double KO mice, we performed RH experiments in Langendorff‐perfused hearts and whole‐cell patch clamp experiments on isolated VSM cells. Flow repayment (ml/g) following a 15 sec occlusion in WT hearts was 6.3 ± 0.4 and reduced in A2AKO (4.5 ± 0.2), but not A2BKO (6.1 ± 0.3), mice. Catalase (1250 U/ml), which breaks down H2O2, significantly reduced flow repayment (ml/g) in WT (4.4 ± 0.4) but not A2AKO (4.1 ± 0.4) hearts. Patch clamp experiments demonstrated that adenosine (10 μM) activated a glibenclamide (10 μM)‐sensitive conductance (nS/pF) in VSM cells from WT (0.05 ± 0.01) but not A2A/A2BKO (0.02 ± 0.01) mice. Additionally, in WT VSM cells, H2O2 (1 mM) activated a glibenclamide‐sensitive conductance (0.07 ± 0.02 nS/pF). Our data indicate that A2A receptors are coupled to KATP channels, in part, via the production of H2O2 as a signaling intermediate. HL027339, HL094447, HL071802, T32 HL090610.