The mammalian myocardium expresses four adenosine receptor (AR) subtypes: A(1)AR, A(2a)AR, A(2b)AR, and A(3)AR. The A(1)AR 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 A(2a)AR and A(2b)AR on cardiac contractility. Experiments were conducted in paced, constant pressure-perfused isolated hearts from wild-type (WT), A(2a)AR knockout (KO), and A(2b)AR KO mice. The A(2a)AR 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 A(2a)AR KO hearts. However, A(2a)AR gene ablation resulted in a potentiation of the antiadrenergic effects mediated by the A(1)AR agonist 2-chloro-N-cyclopentyladenosine. The nonselective AR agonist 5'-N-ethylcarboxamido adenosine and the selective A(2b)AR agonist BAY 60-6583 induced coronary flow-independent increases in contractility, but BAY 60-6583 did not alter Iso-induced contractile responses. The A(1)AR antiadrenergic effect was not potentiated in A(2b)AR 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 A(2a)AR does not increase cardiac contractility directly but indirectly alters contractility by modulating the A(1)AR antiadrenergic effect, whereas A(2b)AR exerts direct contractile effects but does not alter β-adrenergic or A(1)AR antiadrenergic effects. These results indicate that multiple ARs differentially modulate cardiac function.

These results suggest that exercise-induced up-regulation of tumor necrosis factor-alpha before stroke and extracellular signal-regulated kinase 1/2 phosphorylation play a role in decreasing brain inflammation by regulating matrix metalloproteinase-9 activity.

Mammalian myocardium expresses four adenosine receptor (AR) subtypes (A1, A2a, A2b, & A3). A1AR inhibits the β‐adrenergic receptor‐mediated positive inotropy, but the role of A2aAR in altering cardiac contractility is controversial. The objective of this study was to determine the effects of A2aAR on A1AR‐anti‐adrenergic response. Experiments were conducted in wild type (WT) and A2a‐knock‐out (KO) isolated perfused mouse hearts by measuring left ventricular systolic pressure (LVSP), +dP/dt, & −dP/dt. A2aAR agonist CGS‐21680 alone did not alter contractility or the isoproterenol (ISO)‐induced contractile response. Effects of 200nM CCPA pre‐treatment on 2 nM ISO are shown below (n≥4, data expressed as % increase from baseline, *p<0.05 CCPA+ISO vs ISO, #p<0.05 KO‐CCPA+ISO vs WT‐CCPA+ISO): LVSP +dP/dt −dP/dt WT‐ISO 76±4 109±7 133±7 WT‐CCPA+ISO 35±4* 48±4* 56±5* KO‐ISO 86±8 129±10 154±9 KO‐CCPA+ISO 16±3*# 19±4*# 31±5*# Reversing the sequence of agonist infusion (i.e. ISO, then CCPA) significantly reduced the A1AR anti‐adrenergic response. These results indicate that anti‐adrenergic effects of A1AR are potentiated in the absence of A2aAR, and that A1AR pre‐activation is necessary to elicit the full anti‐adrenergic response. Since A2aAR only alters contractility indirectly, these data suggest that receptor cross‐talk/direct receptor interactions may account for the observed contractile response.

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