Differing cardioprotective efficacy of the Na+/Ca2+ exchanger inhibitors SEA0400 and KB-R7943

Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Pfizer Incorporated, Groton, Connecticut 06340 KB-R7943 and SEA0400 are Na + /Ca 2+ exchanger (NCX) inhibitors with differing potency and selectivity. The cardioprotective efficacy of these NCX inhibitors was examined in isolated rabbit hearts (Langendorff perfused) subjected to regional ischemia (coronary artery ligation) and reperfusion. KB-R7943 and SEA0400 elicited concentration-dependent reductions in infarct size (SEA0400 EC 50 : 5.7 nM). SEA0400 was more efficacious than KB-R7943 (reduction in infarct size at 1 µM: SEA0400, 75%; KB-R7943, 40%). Treatment with either inhibitor yielded similar reductions in infarct size whether administered before or after regional ischemia. SEA0400 (1 µM) improved postischemic recovery of function (±dP/d t ), whereas KB-R7943 impaired cardiac function at 1 µM. At 5-20 µM, KBR-7943 elicited rapid and profound depressions of heart rate, left ventricular developed pressure, and ±dP/d t . Thus the ability of KB-R7943 to provide cardioprotection is modest and limited by negative effects on cardiac function, whereas the more selective NCX inhibitor SEA0400 elicits marked reductions in myocardial ischemic injury and improved ±dP/d t . NCX inhibition represents an attractive approach for achieving clinical cardioprotection. ischemia; reperfusion; heart; infarct; rabbit