Abstract
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.
Footnotes
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Send reprint requests to: W. Ross Tracey, Ph.D., Pfizer Global Research and Development, MS8220-3125 Eastern Point Rd., Groton, CT 06340. E-mail:w_ross_tracey{at}groton.pfizer.com
- Abbreviations:
- NHE
- sodium-hydrogen exchanger
- HR
- heart rate
- LVDP
- left ventricular developed pressure
- CF
- total coronary flow
- MAP
- mean arterial pressure
- RPP
- rate pressure product
- LV
- left ventricle
- % IA/AAR
- infarct area expressed as a percentage of area-at-risk
- % AAR/LV
- area-at-risk expressed as a percentage of left ventricular area
- PRP
- platelet-rich plasma
- Received October 23, 2000.
- Accepted January 8, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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