A novel sodium-hydrogen exchanger isoform-1 inhibitor, zoniporide, reduces ischemic 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 elicited with 30 min of regional ischemia and 120 min of reperfusion. Zoniporide elicited a concentration-dependent reduction in infarct size (EC(50) 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 (EC(50) 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 (ED(50) 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.
Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Pfizer Inc., 3125 Eastern Point Road, Groton, CT 06340, USA.
D R
DR
Knight
A H
AH
Smith
D M
DM
Flynn
J T
JT
MacAndrew
S S
SS
Ellery
J X
JX
Kong
R B
RB
Marala
R T
RT
Wester
A
A
Guzman-Perez
R J
RJ
Hill
W P
WP
Magee
W R
WR
Tracey
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000188:drug therapy*; D020011:Protective Agents / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011817:Rabbits; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000502:physiology
D006146:Guanidines; D020011:Protective Agents; D011720:Pyrazoles; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; C424422:zoniporide