Protein Kinase C Translocation and Src Protein Tyrosine Kinase Activation Mediate Isoflurane-induced Preconditioning In Vivo 

2004 ◽  
Vol 100 (3) ◽  
pp. 532-539 ◽  
Author(s):  
Lynda M. Ludwig ◽  
Dorothee Weihrauch ◽  
Judy R. Kersten ◽  
Paul S. Pagel ◽  
David C. Warltier
Keyword(s):  
Reactive Oxygen Species ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Infarct Size ◽  
Adenosine Triphosphate ◽  
Protein Tyrosine Kinase ◽  
Oxygen Species ◽  
Kinase C

Background The authors tested the hypotheses that protein kinase C (PKC)-specific isoform translocation and Src protein tyrosine kinase (PTK) activation play important roles in isoflurane-induced preconditioning in vivo. Methods Rats (n = 125) instrumented for measurement of hemodynamics underwent 30 min of coronary artery occlusion followed by 2 h of reperfusion and received 0.9% saline (control); PKC inhibitors chelerythrine (5 mg/kg), rottlerin (0.3 mg/kg), or PKC-epsilonV1-2 peptide (1 mg/kg); PTK inhibitors lavendustin A (1 mg/kg) or 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1; 1 mg/kg); mitochondrial adenosine triphosphate-sensitive potassium channel antagonist 5-hydroxydecanote (10 mg/kg); or reactive oxygen species scavenger N-acetylcysteine (150 mg/kg) in the absence and presence of a 30-min exposure to isoflurane (1.0 minimum alveolar concentration) in separate groups. Isoflurane was discontinued 15 min before coronary occlusion (memory period). Infarct size was determined using triphenyltetrazolium staining. Immunohistochemistry and confocal microscopic imaging were performed to examine PKC translocation in separate groups of rats. Results Isoflurane significantly (P < 0.05) reduced infarct size (40 +/- 3% [n = 13]) as compared with control experiments (58 +/- 2% [n = 12]). Chelerythrine, rottlerin, PKC-epsilonV1-2 peptide, lavendustin A, PP1, 5-hydroxydecanote, and N-acetylcysteine abolished the anti-ischemic actions of isoflurane (58 +/- 2% [n = 8], 50 +/- 3% [n = 9], 53 +/- 2% [n = 9], 59 +/- 3% [n = 6], 57 +/- 3% [n = 7], 60 +/- 3% [n = 7], and 53 +/- 3% [n = 6], respectively). Isoflurane stimulated translocation of the delta and epsilon isoforms of PKC to sarcolemmal and mitochondrial membranes, respectively. Conclusions Protein kinase C-delta, PKC-epsilon, and Src PTK mediate isoflurane-induced preconditioning in the intact rat heart. Opening of mitochondrial adenosine triphosphate-sensitive potassium channels and generation of reactive oxygen species are upstream events of PKC activation in this signal transduction process.

Reactive Oxygen Species Precede Protein Kinase C-δ Activation Independent of Adenosine Triphosphate–sensitive Mitochondrial Channel Opening in Sevoflurane-induced Cardioprotection

2004 ◽  
Vol 100 (3) ◽  
pp. 506-514 ◽  
Author(s):  
R. Arthur Bouwman ◽  
René J. P. Musters ◽  
Brechje J. van Beek-Harmsen ◽  
Jaap J. de Lange ◽  
Christa Boer
Keyword(s):  
Reactive Oxygen Species ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Adenosine Triphosphate ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Pkc Delta ◽  
Kinase C ◽  
Pkc Epsilon ◽  
Channel Opening

Background In the current study, the authors investigated the distinct role and relative order of protein kinase C (PKC)-delta, adenosine triphosphate-sensitive mitochondrial K+ (mito K+(ATP)) channels, and reactive oxygen species (ROS) in the signal transduction of sevoflurane-induced cardioprotection and specifically addressed their mechanistic link. Methods Isolated rat trabeculae were preconditioned with 3.8% sevoflurane and subsequently subjected to an ischemic protocol by superfusion of trabeculae with hypoxic, glucose-free buffer (40 min) followed by 60 min of reperfusion. In addition, the acute affect of sevoflurane on PKC-delta and PKC-epsilon translocation and nitrotyrosine formation was established with use of immunofluorescent analysis. The inhibitors chelerythrine (6 microM), rottlerin (1 microM), 5-hydroxydecanoic acid sodium (100 microM), and n-(2-mercaptopropionyl)-glycine (300 microM) were used to study the particular role of PKC, PKC-delta, mito K+(ATP), and ROS in sevoflurane-related intracellular signaling. Results Preconditioning of trabeculae with sevoflurane preserved contractile function after ischemia. This contractile preservation was dependent on PKC-delta activation, mito K+(ATP) channel opening, and ROS production. In addition, on acute stimulation by sevoflurane, PKC-delta but not PKC-epsilon translocated to the sarcolemmal membrane. This translocation was inhibited by PKC inhibitors and ROS scavenging but not by inhibition of mito K+(ATP) channels. Furthermore, sevoflurane directly induced nitrosylation of sarcolemmal proteins, suggesting the formation of peroxynitrite. Conclusions In sevoflurane-induced cardioprotection, ROS release but not mito K+(ATP) channel opening precedes PKC-delta activation. Sevoflurane induces sarcolemmal nitrotyrosine formation, which might be involved in the recruitment of PKC-delta to the cell membrane.

Mitochondrial Adenosine Triphosphate–regulated Potassium Channel Opening Acts as a Trigger for Isoflurane-induced Preconditioning by Generating Reactive Oxygen Species

2003 ◽  
Vol 98 (4) ◽  
pp. 935-943 ◽  
Author(s):  
Katsuya Tanaka ◽  
Dorothee Weihrauch ◽  
Lynda M. Ludwig ◽  
Judy R. Kersten ◽  
Paul S. Pagel ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Infarct Size ◽  
Adenosine Triphosphate ◽  
Superoxide Anion ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Superoxide Anion Production ◽  
Channel Opening ◽  
Anion Production

Background Whether the opening of mitochondrial adenosine triphosphate-regulated potassium (K(ATP)) channels is a trigger or an end effector of anesthetic-induced preconditioning is unknown. We tested the hypothesis that the opening of mitochondrial K(ATP) channels triggers isoflurane-induced preconditioning by generating reactive oxygen species (ROS) in vivo. Methods Pentobarbital-anesthetized rabbits were subjected to a 30-min coronary artery occlusion followed by 3 h reperfusion. Rabbits were randomly assigned to receive a vehicle (0.9% saline) or the selective mitochondrial K(ATP) channel blocker 5-hydroxydecanoate (5-HD) alone 10 min before or immediately after a 30-min exposure to 1.0 minimum alveolar concentration (MAC) isoflurane. In another series of experiments, the fluorescent probe dihydroethidium was used to assess superoxide anion production during administration of 5-HD or the ROS scavengers N-acetylcysteine or N-2-mercaptopropionyl glycine (2-MPG) in the presence or absence of 1.0 MAC isoflurane. Myocardial infarct size and superoxide anion production were measured using triphenyltetrazolium staining and confocal fluorescence microscopy, respectively. Results Isoflurane (P < 0.05) decreased infarct size to 19 +/- 3% (mean +/- SEM) of the left ventricular area at risk as compared to the control (38 +/- 4%). 5-HD administered before but not after isoflurane abolished this beneficial effect (37 +/- 4% as compared to 24 +/- 3%). 5-HD alone had no effect on infarct size (42 +/- 3%). Isoflurane increased fluorescence intensity. Pretreatment with N-acetylcysteine, 2-MPG, or 5-HD before isoflurane abolished increases in fluorescence, but administration of 5-HD after isoflurane only partially attenuated increases in fluorescence produced by the volatile anesthetic agent. Conclusions The results indicate that mitochondrial K(ATP) channel opening acts as a trigger for isoflurane-induced preconditioning by generating ROS in vivo.

The role of nitric oxide, reactive oxygen species, and protein kinase C in oxytocin-induced cardioprotection in ischemic rat heart

Peptides ◽  
2012 ◽  
Vol 37 (2) ◽  
pp. 314-319 ◽  
Author(s):  
Mahdieh Faghihi ◽  
Ali Mohammad Alizadeh ◽  
Vahid Khori ◽  
Mostafa Latifpour ◽  
Saeed Khodayari
Keyword(s):  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Rat Heart ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Kinase C
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