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