title: Differing cardioprotective efficacy of the Na+/Ca2+ exchanger inhibitors SEA0400 and KB-R7943.
abstract: KB-R7943 and SEA0400 are Na(+)/Ca(2+) 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 EC(50): 5.7 nM). SEA0400 was more efficacious than KB-R7943 (reduction in infarct size at 1 microM: SEA0400, 75%; KB-R7943, 40%). Treatment with either inhibitor yielded similar reductions in infarct size whether administered before or after regional ischemia. SEA0400 (1 microM) improved postischemic recovery of function (+/-dP/dt), whereas KB-R7943 impaired cardiac function at >/=1 microM. At 5-20 microM, 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.
authors.affiliation: Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Pfizer Incorporated, Groton, Connecticut 06340, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Magee
authors.forename: Gayatri
authors.initials: G
authors.lastname: Deshmukh
authors.forename: Michael P
authors.initials: MP
authors.lastname: Deninno
authors.forename: Jill C
authors.initials: JC
authors.lastname: Sutt
authors.forename: Justin G
authors.initials: JG
authors.lastname: Chapman
authors.forename: W Ross
authors.initials: WR
authors.lastname: Tracey
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006321:Heart / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000503:physiopathology; D015425:Myocardial Reperfusion; D010647:Phenyl Ethers / Q000494:pharmacology*; D011817:Rabbits; D020127:Recovery of Function / Q000187:drug effects; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D000814:Aniline Compounds; D002316:Cardiotonic Agents; D010647:Phenyl Ethers; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger; D013890:Thiourea