Role of 70-kDa ribosomal protein S6 kinase, nitric oxide synthase, glycogen synthase kinase-3 beta, and mitochondrial permeability transition pore in desflurane-induced postconditioning in isolated human right atria.
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)-3beta, 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 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.


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-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).


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-3beta, and preventing mitochondrial permeability transition pore opening.
Lemoine
Sandrine
S
Laboratory of Experimental Anesthesiology and Cellular Physiology EA3212, Institut Fédératif de Recherche ICORE146 Université de Caen Basse Normandie, Caen, France.
Zhu
Lan
L
Beauchef
Gallic
G
Lepage
Olivier
O
Babatasi
Gérard
G
Ivascau
Caline
C
Massetti
Massimo
M
Galera
Philippe
P
Gérard
Jean-Louis
JL
Hanouz
Jean-Luc
JL
D016280:Atrial Function, Right / Q000187:drug effects* / Q000502:physiology*; D000077335:Desflurane; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007530:Isoflurane / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology*; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D019001:Nitric Oxide Synthase / Q000502:physiology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000502:physiology*; D013997:Time Factors
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D000077335:Desflurane; D007530:Isoflurane; D019001:Nitric Oxide Synthase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038362:Glycogen Synthase Kinase 3