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Sevoflurane postconditioning protects isolated rat hearts against ischemia-reperfusion injury
作者单位:Chinese Academy of Medical Sciences & Peking Union Medical College,Beijing 100037,China 
摘    要:Background Studies suggested that anesthetics administered upon the early reperfusion or "anesthetic postconditioning" could protect post-ischemic hearts against myocardial ischemia reperfusion injury (MIRI). However, the mechanism responsible for such protection was not well-elucidated. We investigated the cardioprotection induced by sevoflurane postconditioning (SpostC) in rat hearts in vitro, and the respective role of phosphatidylinositol-3-kinase (PI3K), extracellular signal-regulated kinase 1 and 2 (ERK 1/2), mitochondrial KATP channels (mitOKAme) and mitochondrial permeability transition pore (mPTP), by selectively inhibiting PI3K, ERK 1/2, mitOKATP, with LY294002 (LY), PD98059 (PD), 5-hydroxydecanoate (5-HD) and by directly opening of mPTP with atractyloside (ATR), respectively. Methods Isolated rat hearts were randomly assigned to one of the 12 groups (n=-15): Time control (continuous perfusion), ISCH (30 minutes of ischemia followed by 60 minutes of reperfusion alone), SpostC (3% sevoflurane postconditioning was administered during the first 15 minutes of reperfusion after 30 minutes of ischemia), ISCH+LY, ISCH+PD, ISCH+ATR, ISCH+5-HD and ISCH+ dimethyl sulfoxide (DMSO) groups (LY, PD, ATR, 5-HD and DMSO (the vehicle) was administered respectively during the first 15 minutes of reperfusion following test ischemia), SpostC+LY, SpostC+PD, SpostC+ATR and SpostC+5-HD groups (LY, PD, ATR and 5-HD was coadministered with 3% sevoflurane, respectively). Hemodynamics was compared within and between groups. Infarction size was determined at the end of experiments using triphenyltetrazolium chloride (TTC) staining. Lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB) and cardiac troponin I (cTnl) released from necrotic myocardium, were compared among TC, ISCH and SpostC groups. To investigate the relationships between RISK and mPTP implicated in SpostC, NAD+ content in myocardium, a marker of mPTP opening, was compared among some experimental groups (TC, ISCH, ISCH+LY, ISCH+PD, ISCH+DMSO, SpostC, SpostC+LY, SpostC+PD). To further investigate whether the anti-apoptotic mechanism is implicated in SpostC-induced cardioprotection and its association with mitochondria, TUNEL staining was performed in some experimental groups (TC, ISCH, ISCH+5-HD, ISCH+ATR, ISCH+DMSO, SpostC, SpostC+5-HD, SpostC+ATR). Results When compared with unprotected hearts subjected to 30 minutes of ischemia, exposure to 3% sevoflurane for 15 minutes during early reperfusion significantly improved functional recovery, decreased myocardial infarct size, decreased LDH, CK-MB and cTnl release, and decreased cardiomyocyte apoptosis (P 〈0.05). However, such cardioprotective effects of hemodynamic recovery and infarct size reduction by sevoflurane was completely abolished by any one of LY294002, PD98059, atractyloside and 5-hydroxydecanoate (P 〈0.05). Additionally, either LY294002 or PD98059 could reverse the inhibitory effect of SpostC over mPTP opening upon reperfusion (P 〈0.05). Both atractyloside and 5-hydroxydecanoate could abrogate the anti-apoptotic effects of SpostC (P 〈0.05). Conclusion These findings demonstrate that PI3K, ERK 1/2, mitOKATP and mPTP are key players in sevoflurane postconditioning induced cardioprotective mechanisms in isolated rat hearts subjected to MIRI.

关 键 词:sevoflurane  heart  ischemia  reperfusion

Sevoflurane postconditioning protects isolated rat hearts against ischemia-reperfusion injury
Authors:YAO Yun-tai  FANG Neng-xin  SHI Chun-xia  LI Li-huan
Institution:Department of Anesthesiology, Fuwai Cardiovascular Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100037, China
Abstract:Background Studies suggested that anesthetics administered upon the early reperfusion or "anesthetic postconditioning" could protect post-ischemic hearts against myocardial ischemia reperfusion injury (MIRI).However, the mechanism responsible for such protection was not well-elucidated.We investigated the cardioprotection induced by sevoflurane postconditioning (SpostC) in rat hearts in vitro, and the respective role of phosphatidylinositol-3-kinase (PI3K), extracellular signal-regulated kinase 1 and 2 (ERK 1/2), mitochondrial KATP channels (mitoKATP) and mitochondrial permeability transition pore (mPTP), by selectively inhibiting PI3K, ERK 1/2, mitoKATP, with LY294002 (LY), PD98059 (PD), 5-hydroxydecanoate (5-HD) and by directly opening of mPTP with atractyloside (ATR), respectively.Methods Isolated rat hearts were randomly assigned to one of the 12 groups (n=15):Time control (continuous perfusion), ISCH (30 minutes of ischemia followed by 60 minutes of reperfusion alone), SpostC (3% sevoflurane postconditioning was administered during the first 15 minutes of reperfusion after 30 minutes of ischemia), ISCH+LY,ISCH+PD, ISCH+ATR, ISCH+5-HD and ISCH+ dimethyl sulfoxide (DMSO) groups (LY, PD, ATR, 5-HD and DMSO (the vehicle) was administered respectively during the first 15 minutes of reperfusion following test ischemia), SpostC+LY, SpostC+PD, SpostC+ATR and SpostC+5-HD groups (LY, PD, ATR and 5-HD was coadministered with 3% sevoflurane, respectively).Hemodynamics was compared within and between groups.Infarction size was determined at the end of experiments using triphenyltetrazolium chloride (TTC) staining.Lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI) released from necrotic myocardium, were compared among TC, ISCH and SpostC groups.To investigate the relationships between RISK and mPTP implicated in SpostC, NAD+ content in myocardium, a marker of mPTP opening, was compared among some experimental groups (TC, ISCH, ISCH+LY, ISCH+PD,ISCH+DMSO, SpostC, SpostC+LY, SpostC+PD).To further investigate whether the anti-apoptotic mechanism is implicated in SpostC-induced cardioprotection and its association with mitochondria, TUNEL staining was performed in some experimental groups (TC, ISCH, ISCH+5-HD, ISCH+ATR, ISCH+DMSO, SpostC, SpostC+5-HD, SpostC+ATR).Results When compared with unprotected hearts subjected to 30 minutes of ischemia, exposure to 3% sevoflurane for 15 minutes during early reperfusion significantly improved functional recovery, decreased myocardial infarct size,decreased LDH, CK-MB and cTnI release, and decreased cardiomyocyte apoptosis (P <0.05).However, such cardioprotective effects of hemodynamic recovery and infarct size reduction by sevoflurane was completely abolished by any one of LY294002, PD98059, atractyloside and 5-hydroxydecanoate (P <0.05).Additionally, either LY294002 or PD98059 could reverse the inhibitory effect of SpostC over mPTP opening upon reperfusion (P <0.05).Both atractyloside and 5-hydroxydecanoate could abrogate the anti-apoptotic effects of SpostC (P <0.05).Conclusion These findings demonstrate that PI3K, ERK 1/2, mitoKATP and mPTP are key players in sevoflurane postconditioning induced cardioprotective mechanisms in isolated rat hearts subjected to MIRI.
Keywords:sevoflurane  heart  ischemia  reperfusion
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