Document Detail


Differing cardioprotective efficacy of the Na+/Ca2+ exchanger inhibitors SEA0400 and KB-R7943.
MedLine Citation:
PMID:  12446284     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
William P Magee; Gayatri Deshmukh; Michael P Deninno; Jill C Sutt; Justin G Chapman; W Ross Tracey
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Publication Detail:
Type:  In Vitro; Journal Article     Date:  2002-11-21
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  284     ISSN:  0363-6135     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2003 Mar 
Date Detail:
Created Date:  2003-02-11     Completed Date:  2003-03-11     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H903-10     Citation Subset:  IM    
Affiliation:
Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Pfizer Incorporated, Groton, Connecticut 06340, USA.
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MeSH Terms
Descriptor/Qualifier:
Aniline Compounds / pharmacology*
Animals
Blood Pressure / drug effects
Cardiotonic Agents / pharmacology*
Coronary Circulation / drug effects
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Heart / drug effects*,  physiology,  physiopathology
Heart Rate / drug effects
Male
Myocardial Infarction / pathology,  prevention & control*
Myocardial Ischemia / physiopathology
Myocardial Reperfusion
Phenyl Ethers / pharmacology*
Rabbits
Recovery of Function / drug effects
Sodium-Calcium Exchanger / antagonists & inhibitors
Thiourea / analogs & derivatives*,  pharmacology*
Ventricular Function, Left / drug effects
Chemical
Reg. No./Substance:
0/2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; 0/Aniline Compounds; 0/Cardiotonic Agents; 0/Phenyl Ethers; 0/SEA 0400; 0/Sodium-Calcium Exchanger; 62-56-6/Thiourea

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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