TY - JOUR T1 - A Novel Sodium-Hydrogen Exchanger Isoform-1 Inhibitor, Zoniporide, Reduces Ischemic Myocardial Injury in Vitro and in Vivo JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 254 LP - 259 VL - 297 IS - 1 AU - Delvin R. Knight AU - Andrew H. Smith AU - David M. Flynn AU - Joseph T. MacAndrew AU - Suzanne S. Ellery AU - Jimmy X. Kong AU - Ravi B. Marala AU - Ronald T. Wester AU - Angel Guzman-Perez AU - Roger J. Hill AU - William P. Magee AU - W. Ross Tracey Y1 - 2001/04/01 UR - http://jpet.aspetjournals.org/content/297/1/254.abstract N2 - The cardioprotective efficacy of zoniporide (CP-597,396), a novel, potent, and selective inhibitor of the sodium-hydrogen exchanger isoform 1 (NHE-1), was evaluated both in vitro and in vivo using rabbit models of myocardial ischemia-reperfusion injury. In these models, myocardial injury was elicited with 30 min of regional ischemia and 120 min of reperfusion. Zoniporide elicited a concentration-dependent reduction in infarct size (EC50 of 0.25 nM) in the isolated heart (Langendorff) and reduced infarct size by 83% (50 nM). This compound was 2.5- to 20-fold more potent than either eniporide or cariporide (EC50 of 0.69 and 5.11 nM, respectively), and reduced infarct size to a greater extent than eniporide (58% reduction in infarct size). In open-chest, anesthetized rabbits, zoniporide also elicited a dose-dependent reduction in infarct size (ED50of 0.45 mg/kg/h) and inhibited NHE-1-mediated platelet swelling (maximum inhibition 93%). Furthermore, zoniporide did not cause any in vivo hemodynamic (mean arterial pressure, heart rate, rate pressure product) changes. Zoniporide represents a novel class of potent NHE-1 inhibitors with potential utility for providing clinical cardioprotection. The American Society for Pharmacology and Experimental Therapeutics ER -