HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

A pyrroline derivative of mexiletine offers marked protection against ischemia/reperfusion-induced myocardial contractile dysfunction.

Abstract
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.
AuthorsH Li, K Y Xu, L Zhou, T Kalai, J L Zweier, K Hideg, P Kuppusamy
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 295 Issue 2 Pg. 563-71 (Nov 2000) ISSN: 0022-3565 [Print] United States
PMID11046089 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Anti-Arrhythmia Agents
  • Antioxidants
  • HO 2434
  • Pyrroles
  • Mexiletine
  • Hydroxyl Radical
  • Ouabain
  • Sodium-Potassium-Exchanging ATPase
Topics
  • 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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: