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Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Pfizer Incorporated, Groton, Connecticut 06340
KB-R7943 and SEA0400 are
Na+/Ca2+ 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
EC50: 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/dt), 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/dt. 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/dt. NCX inhibition
represents an attractive approach for achieving clinical cardioprotection.
ischemia; reperfusion; heart; infarct; rabbit
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