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.