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°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.