Role of 70-kDa Ribosomal Protein S6 Kinase, Nitric Oxide Synthase, Glycogen Synthase Kinase-3β, and Mitochondrial Permeability Transition Pore in Desflurane-induced Postconditioning in Isolated Human Right Atria

Abstract

Desflurane during early reperfusion has been shown to postcondition human myocardium. Whether it involves "reperfusion injury salvage kinase" pathway remains incompletely studied. The authors tested the involvement of 70-kDa ribosomal protein S6 kinase, nitric oxide synthase, glycogen synthase kinase (GSK)-3beta, and mitochondrial permeability transition pore in desflurane-induced postconditioning. The authors recorded isometric contraction of human right atrial trabeculae suspended in an oxygenated Tyrode's solution (34 degrees C, stimulation frequency 1 Hz). After a 30-min hypoxic period, desflurane 6% was administered during the first 5 min of reoxygenation. Desflurane was administered alone or with pretreatment of rapamycin, a 70-kDa ribosomal protein S6 kinase inhibitor, NG-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, and atractyloside, the mitochondrial permeability transition pore opener. GSK-3beta inhibitor VII was administered during the first few minutes of reoxygenation alone or in the presence of desflurane 6%, rapamycin, NG-nitro-L-arginine methyl ester, and atractyloside. Developed force at the end of a 60-min reoxygenation period was compared (mean +/- SD). Phosphorylation of GSK-3beta was measured using blotting. Desflurane 6% (84 +/- 4% of baseline) enhanced the recovery of force after 60 min of reoxygenation when compared with the control group (54 +/- 4%, P < 0.0001). Rapamycin (68 +/- 8% of baseline), NG-nitro-L-arginine methyl ester (57 +/- 8%), atractyloside (52 +/- 7%) abolished desflurane-induced postconditioning (P < 0.001). GSK-3beta inhibitor-induced postconditioning (84 +/- 5%, P < 0.0001 vs. control) was not modified by desflurane (78 +/- 6%), rapamycin (81 +/- 6%), and NG-nitro-L-arginine methyl ester (82 +/- 10%), but it was abolished by atractyloside (49 +/- 6%). Desflurane increased the phosphorylation of GSK-3beta (3.30 +/- 0.57-fold increase in desflurane vs. control; P < 0.0001). In vitro, desflurane-induced postconditioning protects human myocardium through the activation of 70-kDa ribosomal protein S6 kinase, nitric oxide synthase, inhibition, and phosphorylation of GSK-3beta, and preventing mitochondrial permeability transition pore opening.