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Am J Physiol Heart Circ Physiol (November 21, 2002). doi:10.1152/ajpheart.00784.2002
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Articles in PresS, published online ahead of print November 21, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00784.2002
Submitted on September 5, 2002
Accepted on November 14, 2002

DIFFERING CARDIOPROTECTIVE EFFICACY OF THE Na+-Ca2+ EXCHANGER INHIBITORS, SEA0400 AND KB-R7943

William P. Magee1, Gayatri Deshmukh1, Michael P. DeNinno1, Jill C. Sutt1, Justin G. Chapman1, and W. Ross Tracey1*

1 Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Pfizer Inc., Groton, CT, USA

* To whom correspondence should be addressed. E-mail: w_ross_tracey{at}groton.pfizer.com.

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) 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. 1 µM SEA0400 improved post-ischemic 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, KB-R7943's ability 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 recovery of function. NCX inhibition represents an attractive approach for achieving clinical cardioprotection.




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