A2A adenosine receptor‐mediated increase in coronary flow is dependent on NADPH oxidase‐derived reactive oxygen species (1071.1)

Adenosine induces an increase in coronary flow (CF) mainly through the activation of both A2A and A2B adenosine receptors (ARs); however, the mechanisms responsible for the regulation of CF are not fully understood. Earlier data from our laboratory showed an interaction between adenosine, NADPH oxidase (NOX) and reactive oxygen species (ROS). We hypothesize that adenosine-mediated increase in CF is dependent upon NOX activation through A2A but not A2B AR. Concentration response curves to adenosine and the A2A AR selective agonist (CGS-21680) were performed in isolated perfused hearts from WT, A2A and A2B AR knockouts (A2AKO and A2BKO). Adenosine-induced dose-dependent increase in CF was significantly decreased (p<0.05) with pre-treatment with gp91 ds-tat (a NOX inhibitor; gp91) or EUK134 (a catalase/superoxide dismutase mimic ; EUK) in both WT (WT: 229.7% ± 6.5 vs. WT+gp91: 178% ± 5.9 and WT: 228.4% ± 7.2 vs. WT+EUK: 178.8% ± 5.5) and A2BKO ( A2BKO: 241.3% ± 9.1 vs. A2BKO+gp91: 191% ± 8.7 and A2BKO: 254% ± 9.3 vs. A2BKO+EUK: 194.4% ± 7.9), but not in A2AKO isolated hearts (P>0.05) (A2AKO: 271.5% ± 17.4 vs. A2AKO+gp91: 240.8% ± 13.6 and A2AKO: 271.2% ± 18.4 vs. A2AKO+EUK: 257.6% ± 15.6). Also, CGS-21680 caused a concentration-dependent increase in CF in both WT and A2BKO, but not in A2AKO, which was significantly reduced (P<0.05) using gp91 (WT: 226% ± 8.4 vs. WT+gp91: 191.6% ± 6.6 and A2BKO: 182.6% ± 4.4 vs. A2BKO+gp91: 159.7% ± 4.3). Our data suggest that adenosine-induced increase in CF through the activation of A2AKO AR is dependent upon NOX activation and ROS generation.