Differential effects of adenosine A2a and A2b receptors on cardiac contractility

Abstract

The mammalian myocardium expresses four adenosine receptor (AR) subtypes: A1AR, A2aAR, A2bAR, and A3AR. The A1AR is well known for its profound antiadrenergic effects, but the roles of other AR subtypes in modulating contractility remain inconclusive. Thus, the objective of this study was to determine the direct and indirect effects of A2aAR and A2bAR on cardiac contractility. Experiments were conducted in paced, constant pressure-perfused isolated hearts from wild-type (WT), A2aAR knockout (KO), and A2bAR KO mice. The A2aAR agonist CGS-21680 did not alter basal contractility or β-adrenergic receptor agonist isoproterenol (Iso)-mediated positive inotropic responses, and Iso-induced effects were unaltered in A2aAR KO hearts. However, A2aAR gene ablation resulted in a potentiation of the antiadrenergic effects mediated by the A1AR agonist 2-chloro- N-cyclopentyladenosine. The nonselective AR agonist 5′- N-ethylcarboxamido adenosine and the selective A2bAR agonist BAY 60-6583 induced coronary flow-independent increases in contractility, but BAY 60-6583 did not alter Iso-induced contractile responses. The A1AR antiadrenergic effect was not potentiated in A2bAR KO hearts. The expression of all four AR subtypes in the heart and ventricular myocytes was confirmed using real-time quantitative PCR. Taken together, these results indicate that A2aAR does not increase cardiac contractility directly but indirectly alters contractility by modulating the A1AR antiadrenergic effect, whereas A2bAR exerts direct contractile effects but does not alter β-adrenergic or A1AR antiadrenergic effects. These results indicate that multiple ARs differentially modulate cardiac function.