Understanding the role of A2B adenosine receptor using knockout in the regulation of coronary flow

Abstract

Adenosine, released due to increased oxygen demand of the heart, exerts its effects through 4 subtypes of receptors (AR) namely, A1, A2A, A2B and A3. The contribution of ARs in the regulation of coronary flow (CF) needs to be further investigated in order to better understand the heterogeneity of CF regulation. We performed mouse Langendorff experiments using two different approaches: 1) use of A2B selective and non‐selective agonists and 2) use of A2A and A2B knockout (KO) mice. BAY 606583 (selective A2B AR agonist) shows no effect on CF in A2B KO mice, however, it increases the CF significantly (p< 0.05) in A2A KO and WT mice (211.0 ± 34.5 vs. 227.0 ± 79.9, respectively, n=4). Furthermore, administration of 5′‐N‐ethylcarboxamido adenosine (NECA, non‐selective agonist) increased the CF in A2A KO mice by 122.0±19.72% from the baseline. However, NECA‐induced effect on CF in WT and A2B KO is not significantly different. We propose this effect to be due to increased expression of A2A AR as a compensatory mechanism since there is no significant difference between NECA and CGS 21680 (A2A AR selective agonist). In addition, bradykinin‐(endothelium‐dependent)‐induced effect on CF between WT and A2B KO mice is not significant. Our data strongly supports a role for A2B AR in the regulation of CF. Further investigations are needed to define signaling pathways for this AR. Supported by HL027339, HL094447, HL071802, and T‐32 HL090610.