A novel sodium-hydrogen exchanger isoform-1 inhibitor, zoniporide, reducesischemic myocardial injury in vitro and in vivo

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 elicite d with 30 min of regional ischemia and 120 min of reperfusion. Zoniporide e licited a concentration-dependent reduction in infarct size (EC50 of 0.25 n M) 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 s ize 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-media ted platelet swelling (maximum inhibition 93%). Furthermore, zoniporide did not cause any in vivo hemodynamic (mean arterial pressure, heart rate, rat e pressure product) changes. Zoniporide represents a novel class of potent NHE-1 inhibitors with potential utility for providing clinical cardioprotec tion.