Adenosine A_2A and A_2B receptors are both required for adenosine A₁ receptor-mediated cardioprotection

<jats:p> All four adenosine receptor subtypes have been shown to play a role in cardioprotection, and there is evidence that all four subtypes may be expressed in cardiomyocytes. There is also increasing evidence that optimal adenosine cardioprotection requires the activation of more than one receptor subtype. The purpose of this study was to determine whether adenosine A<jats:sub>2A</jats:sub> and/or A<jats:sub>2B</jats:sub> receptors modulate adenosine A<jats:sub>1</jats:sub> receptor-mediated cardioprotection. Isolated perfused hearts of wild-type (WT), A<jats:sub>2A</jats:sub> knockout (KO), and A<jats:sub>2B</jats:sub>KO mice, perfused at constant pressure and constant heart rate, underwent 30 min of global ischemia and 60 min of reperfusion. The adenosine A<jats:sub>1</jats:sub> receptor agonist N<jats:sup>6</jats:sup>-cyclohexyladenosine (CHA; 200 nM) was administrated 10 min before ischemia and for the first 10 min of reperfusion. Treatment with CHA significantly improved postischemic left ventricular developed pressure (74 ± 4% vs. 44 ± 4% of preischemic left ventricular developed pressure at 60 min of reperfusion) and reduced infarct size (30 ± 2% with CHA vs. 52 ± 5% in control) in WT hearts, effects that were blocked by the A<jats:sub>1</jats:sub> antagonist 8-cyclopentyl-1,3-dipropylxanthine (100 nM). Treatments with the A<jats:sub>2A</jats:sub> receptor agonist CGS-21680 (200 nM) and the A<jats:sub>2B</jats:sub> agonist BAY 60-6583 (200 nM) did not exert any beneficial effects. Deletion of adenosine A<jats:sub>2A</jats:sub> or A<jats:sub>2B</jats:sub> receptor subtypes did not alter ischemia-reperfusion injury, but CHA failed to exert a cardioprotective effect in hearts of mice from either KO group. These findings indicate that both adenosine A<jats:sub>2A</jats:sub> and A<jats:sub>2B</jats:sub> receptors are required for adenosine A<jats:sub>1</jats:sub> receptor-mediated cardioprotection, implicating a role for interactions among receptor subtypes. </jats:p>