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CARDIOVASCULAR

Cardioprotective Effect of Morphine and a Blocker of Glycogen Synthase Kinase 3β, SB216763 [3-(2,4-Dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione], via Inhibition of the Mitochondrial Permeability Transition Pore

INSERM, Unité 841, Créteil, France; Université Paris 12, Facultéde Médecine, France (F.N.O., C.P.-M., R.A., R.Z., J.L.D.-R., A.B., D.M.); and Fédération de Cardiologie, Hôpital Henri Mondor, France (J.L.D.-R., A.B.)

Morphine has been shown to protect the myocardium against ischemia-reperfusion injury through inhibition of glycogen synthase kinase-3β (GSK-3β). Given that GSK-3β is known to modulate the mitochondrial permeability transition pore (mPTP), we investigated the role of mPTP in the cardioprotective effect of morphine and the GSK-3β inhibitor SB216763 [SB; 3-(2,4-dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione] during ischemia-reperfusion. Both morphine (0.3 mg/kg) and SB (0.6 mg/kg) reduced infarct size in a model of regional myocardial ischemia-reperfusion in rats (13 ± 1 and 14 ± 3% of the area at risk versus 33 ± 4% in controls; p < 0.05). Morphine and SB protected the ischemic myocardium against Ca²⁺-induced mPTP opening as demonstrated by the increased capacity of mitochondria to retain Ca²⁺ when they were isolated from the ischemic zone 10 min after the onset of reperfusion (59 ± 8 and 66 ± 3 versus 29.5 ± 6 nmol Ca²⁺/mg · protein, respectively; p < 0.05). This was associated with a restoration of mitochondrial oxidative phosphorylation parameters. In isolated adult rat cardiomyocytes subjected to anoxia-reoxygenation, morphine (2 µM), SB (3 µM), and the direct mPTP inhibitor cyclosporine A (3 µM) delayed mPTP opening as assessed by the calcein loading Co²⁺-quenching technique. This was accompanied by an increase in cell survival as measured by nuclear staining with propidium iodide. These in vitro effects of morphine on inhibition of mPTP opening during anoxia-reoxygenation were suppressed by the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor wortmannin (0.1 µM). These data indicate that the infarct-limiting effect of morphine and SB is linked by a cause-effect relationship, which leads to an increased mitochondrial resistance and inhibition of mPTP opening through the PI3-kinase pathway and subsequent inactivation of GSK-3β.

Address correspondence to: Dr. Alain Berdeaux, INSERM U 841, équipe 3, Faculté de Médecine de Créteil, 8 rue du Général Sarrail, F-94010 Créteil, France. E-mail: alain.berdeaux{at}inserm.fr

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