Document Detail


A pyrroline derivative of mexiletine offers marked protection against ischemia/reperfusion-induced myocardial contractile dysfunction.
MedLine Citation:
PMID:  11046089     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The efficacy and mechanism of protection of a new 2,2,5, 5-tetramethylpyrroline derivative of mexiletine, MEX-NH, against ischemia/reperfusion-induced cardiac dysfunction are reported. The MEX-NH and its nitroxide metabolite are membrane-permeable antioxidants. Studies were performed in an isolated rat heart model to measure the efficacy of MEX-NH in preventing postischemic injury. Serial measurements of contractile function and coronary flow were performed on hearts subjected to 30 min of global 37 degrees C ischemia followed by 45 min of reperfusion. Hearts were either untreated or treated with 25 microM MEX-NH or MEX for 1 min before ischemia. The hearts treated with MEX-NH showed marked recovery of left ventricular developed pressure (96.3 +/- 2.7% of preischemic value) compared with untreated (13.7 +/- 1.0%) or MEX-treated (19.9 +/- 2.7%) hearts. The cardiac sarcolemmal Na(+),K(+)-ATPase activity showed that the enzyme activity was fully restored in hearts treated with MEX-NH compared with 65 +/- 5.3% inhibition in the untreated hearts. Competitive inhibition of [(3)H]ouabain binding revealed that the MEX-NH binds at the K(+)-binding site of the enzyme. The present study establishes that the compound MEX-NH provides marked protection against ischemia/reperfusion-induced contractile dysfunction in isolated hearts. A combination of reversible inhibition of Na(+)/K(+)-ATPase activity during ischemia and site-targeted antioxidative effect upon reperfusion seems to contribute to this cardioprotection.
Authors:
H Li; K Y Xu; L Zhou; T Kalai; J L Zweier; K Hideg; P Kuppusamy
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  295     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2000 Nov 
Date Detail:
Created Date:  2000-11-02     Completed Date:  2000-11-21     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  563-71     Citation Subset:  IM    
Affiliation:
Division of Cardiology, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21224, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Arrhythmia Agents / pharmacology
Antioxidants / pharmacology
Binding, Competitive
Coronary Circulation / drug effects
Dose-Response Relationship, Drug
Female
Hydroxyl Radical / metabolism
Mexiletine / analogs & derivatives,  metabolism,  pharmacology*
Myocardial Contraction / drug effects
Myocardial Ischemia / enzymology
Myocardial Reperfusion Injury / prevention & control*
Myocardium / enzymology,  metabolism
Ouabain / metabolism
Oxidation-Reduction
Pyrroles / metabolism,  pharmacology*
Rats
Rats, Sprague-Dawley
Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors,  metabolism
Ventricular Dysfunction, Left / etiology,  prevention & control*
Ventricular Pressure / drug effects
Grant Support
ID/Acronym/Agency:
CA-78886/CA/NCI NIH HHS; HL-38324/HL/NHLBI NIH HHS; HL52175/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Arrhythmia Agents; 0/Antioxidants; 0/HO 2434; 0/Pyrroles; 31828-71-4/Mexiletine; 3352-57-6/Hydroxyl Radical; 630-60-4/Ouabain; EC 3.6.3.9/Sodium-Potassium-Exchanging ATPase

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


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