Overexpression of A₃ adenosine receptors decreases heart rate, preserves energetics, and protects ischemic hearts

To determine whether A₃ adenosine receptor (A₃AR) signaling modulates myocardial function, energetics, and cardioprotection, hearts from wild-type and A₃AR-overexpressor mice were subjected to 20-min ischemia and 40-min reperfusion while ³¹P NMR spectra were acquired. Basal heart rate and left ventricular developed pressure (LVDP) were lower in A₃AR-overexpressor hearts than wild-type hearts. Ischemic ATP depletion was delayed and postischemic recoveries of contractile function, ATP, and phosphocreatine were greater in A₃AR-hearts. To determine the role of depressed heart rate and to confirm A₃AR-specific signaling, hearts were paced at 480 beats/min with or without 60 nmol/l MRS-1220 (A₃AR-specific inhibitor) and then subjected to ischemia-reperfusion. LVDP was similar in paced A₃AR-overexpressor and paced wild-type hearts. Differences in ischemic ATP depletion and postischemic contractile and energetic dysfunction remained in paced A₃AR-overexpressor hearts versus paced wild-type hearts but were abolished by MRS-1220. In summary, A₃AR overexpression decreased basal heart rate and contractility, preserved ischemic ATP, and decreased postischemic dysfunction. Pacing abolished the decreased contractility but not the ATP preservation or cardioprotection. Therefore, A₃AR overexpression results in cardioprotection via a specific A₃AR effect, possibly involving preservation of ATP during ischemia.