A pyrroline derivative of mexiletine offers marked protection against ischemia/reperfusion-induced myocardial contractile dysfunction.
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.
Li
H
H
Division of Cardiology, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21224, USA.
Xu
K Y
KY
Zhou
L
L
Kalai
T
T
Zweier
J L
JL
Hideg
K
K
Kuppusamy
P
P
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001667:Binding, Competitive; D003326:Coronary Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D017665:Hydroxyl Radical / Q000378:metabolism; D008801:Mexiletine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000201:enzymology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D010042:Ouabain / Q000378:metabolism; D010084:Oxidation-Reduction; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000517:prevention & control*; D017725:Ventricular Pressure / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D000975:Antioxidants; C415839:HO 2434; D011758:Pyrroles; D008801:Mexiletine; D017665:Hydroxyl Radical; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase