Vol. 295, Issue 2, 563-571, November 2000

A Pyrroline Derivative of Mexiletine Offers Marked Protection against Ischemia/Reperfusion-Induced Myocardial Contractile Dysfunction¹

Haiquan Li, Kai Y. Xu, Lan Zhou, Tamas Kalai, Jay L. Zweier, Kalman Hideg and Periannan Kuppusamy

Division of Cardiology, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland (H.L., K.Y.X., L.Z., J.L.Z., P.K.); and Institute of Organic and Medicinal Chemistry, University of Pécs, Pécs, Hungary (T.K., K.H.)

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.