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

Background: 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)-3β, and mitochondrial permeability transition pore in desflurane-induced postconditioning. Methods: The authors recorded isometric contraction of human right atrial trabeculae suspended in an oxygenated Tyrode's solution (34°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-3β 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-3β was measured using blotting. Results: 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-3β 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-3β (3.30 ± 0.57-fold increase in desflurane vs. control; P < 0.0001). Conclusions: 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-3β, and preventing mitochondrial permeability transition pore opening. Copyright © 2010, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins.