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Vol. 297, Issue 1, 254-259, April 2001

A Novel Sodium-Hydrogen Exchanger Isoform-1 Inhibitor, Zoniporide, Reduces Ischemic Myocardial Injury in Vitro and in Vivo

Delvin R. Knight, Andrew H. Smith, David M. Flynn, Joseph T. MacAndrew, Suzanne S. Ellery, Jimmy X. Kong, Ravi B. Marala, Ronald T. Wester, Angel Guzman-Perez, Roger J. Hill, William P. Magee and W. Ross Tracey

Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut

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 (ED50 of 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.

0022-3565/01/2971-0254$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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