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CARDIOVASCULAR

The A₃ Adenosine Receptor Agonist CP-532,903 [N⁶-(2,5-Dichlorobenzyl)-3'-aminoadenosine-5'-N-methylcarboxamide] Protects against Myocardial Ischemia/Reperfusion Injury via the Sarcolemmal ATP-Sensitive Potassium Channel

Departments of Pharmacology and Toxicology (T.C.W., Z.-D.G., G.J.G., W.-M.K., M.W.B., J.A.A.) and Anesthesiology (A.T., Y.M., M.W.B., W.-M.K.), Medical College of Wisconsin, Milwaukee, Wisconsin; and Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, Connecticut (W.R.T.)

We examined the cardioprotective profile of the new A₃ adenosine receptor (AR) agonist CP-532,903 [N⁶-(2,5-dichlorobenzyl)-3'-aminoadenosine-5'-N-methylcarboxamide] in an in vivo mouse model of infarction and an isolated heart model of global ischemia/reperfusion injury. In radioligand binding and cAMP accumulation assays using human embryonic kidney 293 cells expressing recombinant mouse ARs, CP-532,903 was found to bind with high affinity to mouse A₃ARs (K_i = 9.0 ± 2.5 nM) and with high selectivity versus mouse A₁AR (100-fold) and A_2AARs (1000-fold). In in vivo ischemia/reperfusion experiments, pretreating mice with 30 or 100 µg/kg CP-532,903 reduced infarct size from 59.2 ± 2.1% of the risk region in vehicle-treated mice to 42.5 ± 2.3 and 39.0 ± 2.9%, respectively. Likewise, treating isolated mouse hearts with CP-532,903 (10, 30, or 100 nM) concentration dependently improved recovery of contractile function after 20 min of global ischemia and 45 min of reperfusion, including developed pressure and maximal rate of contraction/relaxation. In both models of ischemia/reperfusion injury, CP-532,903 provided no benefit in studies using mice with genetic disruption of the A₃AR gene, A₃ knockout (KO) mice. In isolated heart studies, protection provided by CP-532,903 and ischemic preconditioning induced by three brief ischemia/reperfusion cycles were lost in Kir6.2 KO mice lacking expression of the pore-forming subunit of the sarcolemmal ATP-sensitive potassium (K_ATP) channel. Whole-cell patch-clamp recordings provided evidence that the A₃AR is functionally coupled to the sarcolemmal K_ATP channel in murine cardiomyocytes. We conclude that CP-532,903 is a highly selective agonist of the mouse A₃AR that protects against ischemia/reperfusion injury by activating sarcolemmal K_ATP channels.

Address correspondence to: Dr. John A. Auchampach, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail: jauchamp{at}mcw.edu

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