A1 Adenosine Receptor Negatively Modulates Coronary Reactive Hyperemia via Counteracting A2A‐mediated H2O2 Production and Opening of KATP Channel in Isolated Mice Hearts

Abstract

We previously demonstrated (Sanjani et.al. FASEB J 26:863.6, 2012) that A2A but not A2B adenosine receptor (AR) mediates coronary reactive hyperemia (RH). This study aims to investigate the role of A1 and A3 ARs in coronary RH using A1, A3 KO and A1/A3 double KO (DKO) mice. Coronary flow (CF) of isolated hearts was measured using Langendorff system. No change in baseline CF, HR, LVDP, and dP/dt was observed between the KO and wide type (WT) mice. However, A1 KO or A1/A3 DKO, but not A3 KO mice showed a higher CF repayment (9.4 ± 0.24 and 9.1 ± 0.45 vs. 7.1 ± 0.22 ml/g, p<0.05) and longer repayment duration (2.7 ± 0.10 and 2.8 ± 0.20 vs. 1.7 ± 0.1 min, p<0.05) than WT mice. SCH58261 (a selective A2A antagonist, 1 μM) significantly decreased the baseline CF in all groups of mice and attenuated the augmented RH in A1 KO and A1/A3 DKO mice to a similar level as WT. Scavenging H2O2 by catalase (2500 U/ml, Sigma) also eliminated the enhanced coronary RH in A1 KO and A1/A3 DKO mice without additive effect of SCH58261. Moreover, blocking KATP channels by glibenclamide (5 μM) significantly attenuated the baseline CF and abolished the enhanced RH in A1 KO and A1/A3 DKO mice, but to a greater extent than SCH58261 and catalase. Our data suggest that A1 but not A3AR counteracts the A2AAR‐mediated CF increase and deletion of A1AR results in enhanced A2AAR‐mediated H2O2 production, opening of KATP channel, and relaxation of coronary artery during RH. (HL 027339 and 094447)