The novel adenosine A3 receptor-selective agonist CP-532,903 reduced infarct size by up to 77% in isolated rabbit hearts and 50% in vivo (P<0.05 vs. control).
Does CP-532,903 reduce infarct size in rabbit models of ischemia-reperfusion injury?
The novel adenosine A3 receptor-selective agonist CP-532,903 significantly reduces infarct size in rabbit models of ischemia-reperfusion injury, highlighting its potential for clinical cardioprotection.
Effect estimate: 77% maximum reduction (isolated hearts), 50% reduction (in vivo)
p-value: p=<0.05
We recently reported the identification of a novel human adenosine A3 receptor-selective agonist, (2S,3S,4R,5R)-3-amino-5-6-[5-chloro-2-(3-methylisoxazol-5-ylmethoxy)benzylaminopurin-9-yl]-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide (CP-608,039), with 1,260-fold selectivity for the human A3 versus human A1 receptor (DeNinno et al., J Med Chem 46: 353-355, 2003). However, because the modest (20-fold) rabbit A3 receptor selectivity of CP-608,039 precludes demonstration of A3-mediated cardioprotection in rabbit models, we identified another member of this class, (2S,3S,4R,5R)-3-amino-5-6-(2,5-dichlorobenzylamino)purin-9-yl-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide (CP-532,903), which both retained human A3 receptor selectivity (210-fold; human A3/human A1 Ki: 23/4,800 nM) and had improved rabbit A3 receptor selectivity (90-fold; rabbit A3/rabbit A1 Ki: 23/2,000 nM). Infarct size was measured in Langendorff hearts or in vivo after 30 min of regional ischemia and 120 min of reperfusion. Five-minute perfusion with CP-532,903 before ischemia-reperfusion elicited a concentration-dependent reduction in infarct size in isolated hearts (EC50: 0.97 nM; maximum reduction in infarct size: 77%, P or = 0.05) from the cardioprotection provided by the same concentration of drug given before ischemia. The selective rabbit A1 receptor antagonist BWA1433 did not affect CP-532,903-dependent cardioprotection. In vivo, CP-532,903 (1 mg/kg) reduced infarct size by 50% in the absence of significant hemodynamic effects (mean arterial pressure, heart rate, rate-pressure product). CP-532,903 and CP-608,039 represent a novel class of human A3 receptor-selective agonists that may prove suitable for investigation of the clinical cardioprotective efficacy of A3 receptor activation.
Tracey et al. (Mon,) conducted a other in Ischemic myocardial injury. CP-532,903 vs. Control was evaluated on Infarct size (77% maximum reduction (isolated hearts), 50% reduction (in vivo), p=<0.05). The novel adenosine A3 receptor-selective agonist CP-532,903 reduced infarct size by up to 77% in isolated rabbit hearts and 50% in vivo (P<0.05 vs. control).