RT Journal Article
SR Electronic
T1 A Pyrroline Derivative of Mexiletine Offers Marked Protection against Ischemia/Reperfusion-Induced Myocardial Contractile Dysfunction
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 563
OP 571
VO 295
IS 2
A1 Li, Haiquan
A1 Xu, Kai Y.
A1 Zhou, Lan
A1 Kalai, Tamas
A1 Zweier, Jay L.
A1 Hideg, Kalman
A1 Kuppusamy, Periannan
YR 2000
UL http://jpet.aspetjournals.org/content/295/2/563.abstract
AB 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°C ischemia followed by 45 min of reperfusion. Hearts were either untreated or treated with 25 μM 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 [3H]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. The American Society for Pharmacology and Experimental Therapeutics