Sevoflurane enhances ethanol-induced cardiac preconditioning through modulation of protein kinase C, mitochondrial KATP channels, and nitric oxide synthase, in guinea pig hearts.
BACKGROUND
Volatile anesthetics and regular ethanol consumption induce cardioprotection mimicking ischemic preconditioning. We investigated whether sevoflurane enhances ethanol preconditioning and whether inhibition of protein kinase C (PKC) and mitochondrial K(ATP) channels attenuated this enhanced cardioprotection. The effects of regular ethanol consumption on expression of inducible (iNOS) and endothelial (eNOS) nitric oxide synthase were determined.


METHODS
Isolated perfused guinea pig hearts underwent 30-min global ischemia and 120-min reperfusion (


METHODS
CTL). The ethanol group (EtOH) received 2.5% ethanol in their drinking water for 6 wk. Anesthetic preconditioning was elicited by 10-min exposure to sevoflurane (1 minimum alveolar anesthetic concentration; 2%) in ethanol (EtOH + SEVO) or nonethanol (SEVO) hearts. PKC and mitochondrial K(ATP) channels were inhibited with chelerythrine and 5-hydroxydecanoate pretreatment, respectively. Contractile recovery was assessed by monitoring of left ventricular developed and end-diastolic pressures. Infarct size was determined by triphenyltetrazolium chloride staining. Expression of iNOS and eNOS were determined by Western blot analysis.


RESULTS
After ischemia-reperfusion, hearts from the EtOH, sevoflurane (SEVO), and EtOH + SEVO groups had higher left ventricular developed pressure and lower left ventricular end-diastolic pressure compared with CTL. Infarct size was reduced in EtOH and SEVO hearts compared with CTL (27% and 23% vs 45%, respectively, P < 0.001). Sevoflurane further reduced infarct size in EtOH hearts (27% vs 15%, P < 0.001). Chelerythrine and 5-hydroxydecanoate abolished cardioprotection in both SEVO and EtOH cardioprotected hearts. iNOS expression was reduced and eNOS expression was increased in EtOH hearts.


CONCLUSIONS
Sevoflurane enhances cardiac preconditioning induced by regular EtOH consumption. This effect is mediated in part by modulation of PKC and mitochondrial K(ATP) channels, and possibly by altered modulation of NOS expression.
Kaneda
Kazuhiro
K
Department of Anesthesiology, Osaka Dental University, Osaka, Japan.
Miyamae
Masami
M
Sugioka
Shingo
S
Okusa
Chika
C
Inamura
Yoshitaka
Y
Domae
Naochika
N
Kotani
Junichiro
J
Figueredo
Vincent M
VM
D018685:Anesthetics, Inhalation / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D053119:Benzophenanthridines / Q000494:pharmacology; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003652:Decanoic Acids / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D004789:Enzyme Activation; D000431:Ethanol / Q000494:pharmacology* / Q000627:therapeutic use; D006168:Guinea Pigs; D006439:Hemodynamics; D006880:Hydroxy Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology* / Q000627:therapeutic use; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000077149:Sevoflurane; D016277:Ventricular Function, Left
D018685:Anesthetics, Inhalation; D053119:Benzophenanthridines; D002316:Cardiotonic Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D008738:Methyl Ethers; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D047428:Protein Kinase Inhibitors; C117780:mitochondrial K(ATP) channel; D009569:Nitric Oxide; D000077149:Sevoflurane; D000431:Ethanol; C052853:5-hydroxydecanoic acid; C016299:chelerythrine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011493:Protein Kinase C