Sevoflurane inhalation at sedative concentrations provides endothelial protection against ischemia-reperfusion injury in humans

BACKGROUND: Endothelial cells can be protected against cytokine-induced toxicity by volatile anesthetics. The authors tested whether inhalation of sevoflurane at subanesthetic concentrations provides protection against postocclusive endothelial dysfunction induced by ischemia-reperfusion injury of the forearm in humans. METHODS: Five healthy male volunteers were enrolled in this study with crossover design. Each subject was randomly exposed to 15 min of forearm ischemia in the presence or absence of sevoflurane. Sevoflurane was inhaled at 0.5-1 vol% end-tidal concentrations from 15 min before ischemia until 5 min after the onset of reperfusion. Hyperemic reaction, an indicator of ischemic injury and endothelial function, was determined at 15 and 30 min of reperfusion using venous occlusion plethysmography. Also, markers of leukocyte activation (CD11b, CD42b) were measured by flow cytometry during reperfusion. RESULTS: Fifteen minutes of forearm ischemia followed by reperfusion diminished postocclusive endothelium-dependent hyperemic reaction at 15 and 30 min of reperfusion. Peri-ischemic inhalation of sevoflurane, targeted at 0.5-1 vol% end-tidal concentrations, markedly improved postocclusive hyperemic reaction. In addition, inhalation of sevoflurane attenuated activation of leukocytes, as measured by CD11b expression, after ischemia-reperfusion injury. No changes in CD42b expression were observed after ischemia-reperfusion of the forearm. CONCLUSIONS: These data suggest that human endothelium, a key component of all vital organs, is receptive to protection by sevoflurane in vivo. Peri-ischemic administration of sevoflurane mimics a combination of pharmacologic preconditioning and postconditioning and protects at even low sedative concentrations (< 1 vol%). Inhibition of leukocyte adhesion is likely to be involved in the protection.     

氦气有中度抗炎作用，但在人体缺血-再灌注损伤中没有内皮保护作用

背景惰性气体氦气没有麻醉作用但对心肌有预处理的作用。我们假设氦气吸入可以对人体前臂的缺血．再灌注内皮功能不全有保护作用。方法这是一项交叉设计的研究，包括8例健康男性受检者。每个志愿者在前臂缺血15分钟时被随机分成吸氦气或不吸氦气组。氦气的呼气末浓度达50vol％。从缺血前15分钟开始吸氦气直到再灌注后5分钟（“氦气状态”）。充血反应是一种一氧化氮生物利用率和内皮功能的标记物。应用静脉阻塞体积描记术在再灌注的15分钟和30分钟时测定前臂充血反应。再灌注期用流式细胞计测定促炎症标记物CDllb、ICAM-1、PSGL-1和Dselectin（CD62L）在白细胞上的表达以及P-selectin（CD62P）、PSGL-1和CD42b在血小板上的表达。结果缺血。再灌注持续地降低再灌注15分钟和30分钟时阻塞后的内皮依赖性充血反应。围缺血期吸入50vol％氦气不能改善阻塞后充血反应。氦气降低促炎症标记物CDllb和ICAM-1在白细胞上的表达，也降低促凝标记物CD42b和PSGL-1在血小板上的表达。结论虽然吸入氦气可以消除缺血后的炎性反应，但本研究表明50vol％氦气不能保护人在体内皮。内皮是所有重要器官的主要组成成分。这与七氟醚的研究结果相反，七氟醚在低浓度、亚麻醉浓度下有人体内皮的保护作用。     

Sevoflurane before or after Ischemia Improves Contractile and Metabolic Function while Reducing Myoplasmic Ca2+ Loading in Intact Hearts

Background: Ca2+ loading occurs during myocardial reperfusion injury. Volatile anesthetics can reduce reperfusion injury. The authors tested whether sevoflurane administered before index ischemia in isolated hearts reduces myoplasmic diastolic and systolic [Ca2+] and improves function more so than when sevoflurane is administered on reperfusion.

Methods: Four groups of guinea pig hearts were perfused with crystalloid solution (55 mmHg, 37[degrees]C): (1) no treatment before 30 min global ischemia and 60 min reperfusion (CON); (2) 3.5 vol% sevoflurane administered for 10 min before ischemia (SBI); (3) 3.5 vol% sevoflurane administered for 10 min after ischemia (SAI); and (4) 3.5 vol% sevoflurane administered for 10 min before and after ischemia (SBAI). Phasic myoplasmic diastolic and systolic [Ca2+] were measured in the left ventricular free wall with the fluorescence probe indo-1.

Results: Ischemia increased diastolic [Ca2+] and diastolic left ventricular pressure (LVP). In CON hearts, initial reperfusion greatly increased diastolic [Ca2+] and systolic [Ca2+] and reduced contractility (systolic-diastolic LVP, dLVP/dtmax), relaxation (diastolic LVP, dLVP/dtmin), myocardial oxygen consumption (Mvo2), and cardiac efficiency. SBI, SAI, and SBAI each reduced ventricular fibrillation, attenuated increases in systolic and systolic-diastolic [Ca2+], improved contractile and relaxation indices, and increased coronary flow, percent oxygen extraction, Mvo2, and cardiac efficiency during 60 min reperfusion compared with CON. SBI was more protective than SAI, and SBAI was generally more protective than SAI.     

Sevoflurane and isoflurane do not enhance the pre- and postischemic eicosanoid production in guinea pig hearts

Eicosanoids and volatile anesthetics can influence cardiac reperfusion injury. Accordingly, we analyzed the effects of sevoflurane and isoflurane applied in clinically relevant concentrations on the myocardial production of prostacyclin and thromboxane A2 (TxA2) and on heart function. Isolated guinea pig hearts, perfused with crystalloid buffer, performed pressure-volume work. Between two working phases, hearts were subjected to 15 min of global ischemia followed by reperfusion. The hearts received no anesthetic, 1 minimum alveolar anesthetic concentration (MAC) isoflurane (1.2 vol%), or 0.5 and 1 MAC sevoflurane (1 vol% and 2 vol%), either only preischemically or pre- and postischemically. In additional groups, cyclooxygenase function was examined by an infusion of 1 microM arachidonic acid (AA) in the absence and presence of sevoflurane. The variables measured included the myocardial production of prostacyclin, TxA2 and lactate, consumption of pyruvate, coronary perfusion pressure, and the tissue level of isoprostane 8-iso-PGF2alpha. External heart work, determined pre- and postischemically, served to assess recovery of heart function. Volatile anesthetics had no impact on postischemic recovery of myocardial function (50%-60% recovery), perfusion pressure, lactate production, or isoprostane content. Release of prostacyclin and TxA2 was increased in the early reperfusion phase 5-8- and 2-4-fold, respectively, indicating enhanced AA liberation. Isoflurane and sevoflurane did not augment the eicosanoid release. Only 2 vol% sevoflurane applied during reperfusion prevented the increased eicosanoid formation in this phase. Infusion of AA increased prostacyclin production approximately 200-fold under all conditions, decreased pyruvate consumption irreversibly, and markedly attenuated postischemic heart work (25% recovery). None of these effects were mitigated by 2 vol% sevoflurane. In conclusion, only sevoflurane at 2 vol% attenuated the increased liberation of AA during reperfusion. Decreased eicosanoid formation had no effect on myocardial recovery in our experimental setting while excess AA was deleterious. Because eicosanoids influence intravascular platelet and leukocyte adhesion and activation, sevoflurane may have effects in reperfused tissues beyond those of isoflurane. IMPLICATIONS: In an isolated guinea pig heart model, myocardial eicosanoid release was not increased by isoflurane or sevoflurane, either before or after ischemia. Sevoflurane (2 vol%) but not isoflurane attenuated the increased release of eicosanoids during reperfusion.     

Sevoflurane and Isoflurane Protect the Reperfused Guinea Pig Heart by Reducing Postischemic Adhesion of Polymorphonuclear Neutrophils

Background: Polymorphonuclear neutrophils (PMNs) contribute to reperfusion injury. Because volatile anesthetics can reduce PMN adhesion in the reperfused, nonworking heart, the authors analyzed whether this action of volatile anesthetics affects cardiac performance after ischemia and reperfusion and further clarified the underlying mechanism.

Methods: Isolated guinea pig hearts perfused with crystalloid buffer and performing pressure-volume work were used. Hearts were subjected to 15 min global ischemia and 20 min reperfusion. In the intervention groups an intracoronary bolus of 3 x 106 PMNs was applied in the second min of reperfusion, either in the absence or presence of 0.5 or 1 minimum alveolar concentration sevoflurane or isoflurane. The number of sequestered PMNs was calculated from the difference between coronary input and output (coronary effluent) of PMNs. Performance of external heart work, determined pre- and postischemically, served as criterion for recovery of myocardial function. Additionally, the expression of the integrin CD11b on the cell surface of PMN was measured before and after coronary passage.

Results: Injection of PMN in the reperfusion phase, but not under nonischemic conditions, reduced recovery of external heart work significantly (from 55 +/- 7% to 19 +/- 11%). Addition of sevoflurane or isoflurane in concentrations of 0.5 and 1 minimum alveolar concentration to the perfusate reduced postischemic PMN adhesion from 36 +/- 8% to basal values (20 +/- 7%) and prevented decline of cardiac function. CD11b expression on PMNs increased significantly during postischemic coronary passage under control conditions. Again, both anesthetics in both concentrations inhibited that activation.     

Sevoflurane before or after ischemia improves contractile and metabolic function while reducing myoplasmic Ca(2+) loading in intact hearts.

BACKGROUND: Ca(2+) loading occurs during myocardial reperfusion injury. Volatile anesthetics can reduce reperfusion injury. The authors tested whether sevoflurane administered before index ischemia in isolated hearts reduces myoplasmic diastolic and systolic [Ca(2+)] and improves function more so than when sevoflurane is administered on reperfusion. METHODS: Four groups of guinea pig hearts were perfused with crystalloid solution (55 mmHg, 37 degrees C): (1) no treatment before 30 min global ischemia and 60 min reperfusion (CON); (2) 3.5 vol% sevoflurane administered for 10 min before ischemia (SBI); (3) 3.5 vol% sevoflurane administered for 10 min after ischemia (SAI); and (4) 3.5 vol% sevoflurane administered for 10 min before and after ischemia (SBAI). Phasic myoplasmic diastolic and systolic [Ca(2+)] were measured in the left ventricular free wall with the fluorescence probe indo-1. RESULTS: Ischemia increased diastolic [Ca(2+)] and diastolic left ventricular pressure (LVP). In CON hearts, initial reperfusion greatly increased diastolic [Ca2+] and systolic [Ca(2+)] and reduced contractility (systolic-diastolic LVP, dLVP/dt(max)), relaxation (diastolic LVP, dLVP/dt(min)), myocardial oxygen consumption (MvO(2)), and cardiac efficiency. SBI, SAI, and SBAI each reduced ventricular fibrillation, attenuated increases in systolic and systolic-diastolic [Ca(2+)], improved contractile and relaxation indices, and increased coronary flow, percent oxygen extraction, MvO(2), and cardiac efficiency during 60 min reperfusion compared with CON. SBI was more protective than SAI, and SBAI was generally more protective than SAI. CONCLUSIONS: Sevoflurane improves postischemic cardiac function while reducing Ca(2+) loading when it is administered before or after ischemia, but protection is better when it is administered before ischemia. Reduced Ca(2+) loading on reperfusion is likely a result of the anesthetic protective effect.     

七氟醚预处理对大鼠肾缺血再灌注损伤的影响

目的 评价七氟醚预处理对大鼠肾缺血再灌注损伤的影响.方法 雄性SD大鼠24只,体重250～300 g,采用随机数字表法,将大鼠随机分为3组(n=8):假手术组(S组)、肾缺血再灌注组(I/R组)和七氟醚预处理组(SP组).I/R组和SP组采用切除右肾然后夹闭左侧肾动脉45 min再开放的方法 制备肾缺血再灌注模型.SP组吸入2.2%七氟醚1 h,停止吸入后10 min时进行肾缺血.于再灌注2 h时采集静脉血样,测定血清肌酐(Cr)、尿素氮(BUN)和胱抑素C(Cys C)的浓度,取肾组织,光镜下及透射电镜下观察病理学结果,并根据肾小管病变程度进行Paller评分.结果 与S组比较,I/R组血清Cr和BUN浓度差异无统计学意义(P＞0.05),血清Cys C浓度和Paller评分明显升高(P＜0.05);与I/R组比较,SP组血清Cys C浓度和Paller评分明显降低(P＜0.05).SP组肾组织损伤程度轻于I/R组.结论 七氟醚预处理可减轻大鼠肾缺血再灌注损伤.

Abstract：

Objective To investigate the effects of sevoflurane preconditioning on renal ischemia-reperfusion(I/R)injury in rats.Methods Twenty-four adult male SD rats weighing 250-300 g were randomly divided into 3 groups(n=8 each):sham operation group (group S);I/R group; sevoflurane preconditioning group (group SP). After the rats underwent right nephrectomy, renal I/R was produced by occlusion of left renal artery for 45 min followed by reperfusion in I/R and SP groups.In group SP, the rats inhaled 2.2% sevoflurane for 1 h, then the inhalation was stopped and renal ischemia was performed 10 min later. Venous blood samples were collected at 2 h of reperfusion to determine the concentrations of serum creatinine(Cr), urea nitrogen (BUN), cystatin C (Cys C) . The renal tissues were obtained for microscopic examination, and Paller's score was recorded. Results Compared with group S, there was no significant difference in the serum Cr and BUN concentrations (P＞0.05), while the serum Cys C concentration and Paller's score for acute renal tubular injury were significantly increased in group I/R(P＜0.05). The serum Cys C concentration and Paller's score were significantly lower in group SP than in group I/R(P＜0.05).I/R-induced renal injury was significantly reduced in group SP compared with group I/R. Conclusion Preconditioning with sevoflurane can provide significant protection against renal I/R injury.     

Sevoflurane and isoflurane protect the reperfused guinea pig heart by reducing postischemic adhesion of polymorphonuclear neutrophils.

BACKGROUND: Polymorphonuclear neutrophils (PMNs) contribute to reperfusion injury. Because volatile anesthetics can reduce PMN adhesion in the reperfused, nonworking heart, the authors analyzed whether this action of volatile anesthetics affects cardiac performance after ischemia and reperfusion and further clarified the underlying mechanism. METHODS: Isolated guinea pig hearts perfused with crystalloid buffer and performing pressure-volume work were used. Hearts were subjected to 15 min global ischemia and 20 min reperfusion. In the intervention groups an intracoronary bolus of 3 x 10(6) PMNs was applied in the second min of reperfusion, either in the absence or presence of 0.5 or 1 minimum alveolar concentration sevoflurane or isoflurane. The number of sequestered PMNs was calculated from the difference between coronary input and output (coronary effluent) of PMNs. Performance of external heart work, determined pre- and postischemically, served as criterion for recovery of myocardial function. Additionally, the expression of the integrin CD11b on the cell surface of PMN was measured before and after coronary passage. RESULTS: Injection of PMN in the reperfusion phase, but not under nonischemic conditions, reduced recovery of external heart work significantly (from 55+/-7% to 19+/-11%). Addition of sevoflurane or isoflurane in concentrations of 0.5 and 1 minimum alveolar concentration to the perfusate reduced postischemic PMN adhesion from 36+/-8% to basal values (20+/-7%) and prevented decline of cardiac function. CD11b expression on PMNs increased significantly during postischemic coronary passage under control conditions. Again, both anesthetics in both concentrations inhibited that activation. CONCLUSIONS: Volatile anesthetics reduce PMN adhesion in the reperfused coronary system and thereby preserve cardiac function. Reduced expression of the adhesion molecule CD11b on PMNs in the presence of sevoflurane or isoflurane is, at least in part, responsible for the cardioprotective effect.     

七氟醚预处理对右肝癌切除患者肝脏缺血再灌注损伤的保护作用

目的：探讨七氟醚预处理对右肝癌切除患者肝脏缺血再灌注损伤的保护作用及其机制。方法：择期全麻下行右肝癌手术切除患者40例．ASAI或II级,术中经第一肝门阻断．血流阻断时间10～30min．随机分为2组（n=20）：缺血再灌注组（IR组）和七氟醚预处理组（S组）。两组麻醉维持期间均保持脑电双频谱指数40-50。s组麻醉诱导后吸入1MAC七氟醚（呼气末浓度）．30min后洗脱15min。于麻醉诱导前（T0）、缺血再灌注即刻（T1）、1h（T2）、6h（T3）抽血测血清中谷丙转氨酶（ALT）．谷草转氨酶（AST）,乳酸脱氢酶（LDH）的含量以及肝脏组织匀浆中丙二醛（MDA）含量和超氧化物岐化酶（SOD）活性,并行肝组织病理学观察。结果：与麻醉诱导前比较．两组缺血再灌注即刻．1h、6h血清ALT．AST,LDH含量均显著增加（P〈0．05）;与IR组比较,s组肝脏缺血再灌注后相应各时点血清ALT．AST、LDH含量均降低．肝组织匀浆MDA含量减少,SOD活性增加（P〈0．05）;肝组织病理学损伤减轻。结论：七氟醚预处理对右肝癌切除患者肝脏缺血再灌注损伤有保护作用．可能与其抑制氧自由基生成．减少脂质过氧化有关。     

Anesthetic preconditioning attenuates mitochondrial Ca2+ overload during ischemia in Guinea pig intact hearts: reversal by 5-hydroxydecanoic acid

Cardiac ischemia/reperfusion (IR) injury is associated with mitochondrial (m)Ca(2+) overload. Anesthetic preconditioning (APC) attenuates IR injury. We hypothesized that mCa(2+) overload is decreased by APC in association with mitochondrial adenosine triphosphate-sensitive K(+) (mK(ATP)) channel opening. By use of indo-1 fluorescence, m[Ca(2+)] was measured in 40 guinea pig Langendorff-prepared hearts. Control (CON) hearts received no treatment for 50 min before IR; APC hearts were exposed to 1.2 mM (8.8 vol%) sevoflurane for 15 min; APC + 5-hydroxydecanoate (5-HD) hearts received 200 micro M 5-HD from 5 min before to 15 min after sevoflurane exposure; and 5-HD hearts received 5-HD for 35 min. Sevoflurane was washed out for 30 min and 5-HD for 15 min before 30 min of global ischemia and 120 min of reperfusion. During ischemia, the peak m[Ca(2+)] accumulation was decreased by APC from 489 +/- 37 nM (CON) to 355 +/- 28 nM (P < 0.05); this was abolished by 5-HD (475 +/- 38 nM m[Ca(2+)]). APC resulted in improved function and reduced infarct size on reperfusion, which also was blocked by 5-HD. 5-HD pretreatment alone did not affect m[Ca(2+)] (470 +/- 34 nM) or IR injury. Thus, preservation of function and morphology on reperfusion is associated with attenuated mCa(2+) accumulation during ischemia. Reversal by 5-HD suggests that APC may be triggered by opening mK(ATP) channels. IMPLICATIONS: Myocardial ischemia/reperfusion injury is associated with mitochondrial Ca(2+) overload. Mitochondrial [Ca(2+)] and function were measured in guinea pig isolated hearts. Anesthetic preconditioning attenuated mitochondrial Ca(2+) overload during ischemia, improved function, and reduced infarct size. Reversal by 5-hydroxydecanoate suggests that anesthetic preconditioning may be triggered by mitochondrial adenosine triphosphate-sensitive K channel opening.     

Preconditioning with sevoflurane reduces changes in nicotinamide adenine dinucleotide during ischemia-reperfusion in isolated hearts: reversal by 5-hydroxydecanoic acid

BACKGROUND: Ischemia causes an imbalance in mitochondrial metabolism and accumulation of nicotinamide adenine dinucleotide (NADH). We showed that anesthetic preconditioning (APC), like ischemic preconditioning, improved mitochondrial NADH energy balance during ischemia and improved function and reduced infarct size on reperfusion. Opening adenosine triphosphate-sensitive potassium (K(atp)) channels may be involved in triggering APC. The authors tested if effects of APC on NADH concentrations before, during, and after ischemia are reversible by 5-hydroxydecanoate (5-HD), a putative mitochondrial K channel blocker. METHODS: Nicotinamide adenine dinucleotide fluorescence was measured in 60 guinea pig Langendorff-prepared hearts assigned into five groups: (1) no treatment before ischemia; (2) APC by exposure to 1.3 mm sevoflurane for 15 min; (3) 200 microm 5-HD from 5 min before to 15 min after sevoflurane exposure; (4) 35 min 5-HD alone; and (5) no treatment and no ischemia. Sevoflurane was washed out for 30 min, and 5-HD for 15 min, before 30-min ischemia and 120-min reperfusion. RESULTS: Nicotinamide adenine dinucleotide was reversibly increased during sevoflurane exposure before ischemia, and the increase and rate of decline in NADH during ischemia were reduced after APC. 5-HD abolished these changes in NADH. On reperfusion, function was improved and infarct size reduced after APC compared with other groups. CONCLUSION: Anesthetic preconditioning was evidenced by improved mitochondrial bioenergetics as assessed from NADH concentrations during ischemia and by attenuated reperfusion injury. Reversal of APC by bracketing sevoflurane exposure with 5-HD suggests that APC is triggered by mitochondrial K channel opening or, alternatively, by attenuated mitochondrial respiration without direct involvement of mitochondrial K channel opening.     

Hemodynamic and catecholamine response to a rapid increase in isoflurane or sevoflurane concentration during a maintenance phase of anesthesia in humans

Purpose The purpose of this study was to compare hemodynamic and catecholamine changes due to a sudden increase in inhalation anesthetic concentrations (isoflurane and sevoflurane) during surgery.Methods Thirty patients aged 40–70 years scheduled for lower abdominal surgery were anesthetized with either isoflurane or sevoflurane with nitrous oxide and epidural block. During surgery the isoflurane or sevoflurane concentration was kept at 0.5 minimum alveolar concentration (MAC) (end-tidal concentration) for 15 min. Then the isoflurane or sevoflurane concentration (inhalation concentration) was changed to 1.5 MAC and maintained at that level for 10 min. Thereafter, it was decreased to 0.5 MAC for 10 min. Blood pressure, heart rate, and plasma concentrations of epinephrine and norepinephrine were measured.Results The blood pressure decreased significantly in both groups after increasing the anesthetic concentration, and it increased after decreasing the concentration. The decrease in systolic blood pressure was significantly larger in the isoflurane group. The heart rate increased significantly after increasing the anesthetic concentration only in the isoflurane group. Plasma concentrations of epinephrine and norepinephrine increased significantly in the isoflurane group, whereas the epinephrine concentration (but not the norepinephrine concentration) decreased in the sevoflurane group.Conclusion During surgery a sudden increase in isoflurane concentration induced larger changes in hemodynamics and sympathetic nerve activity than sevoflurane.     

七氟烷后处理对大鼠肺缺血再灌注损伤的影响

目的 探讨七氟烷后处理对大鼠肺缺血再灌注(IR)损伤的影响及其可能机制.方法 健康SPF级雄性SD大鼠96只,体重270～330 g.随机分为4组(n=24):假手术组(S组)、缺血再灌注组(IR组)、七氟烷预处理组(SPr组)和七氟烷后处理组(SPo组).采用阻断左肺门45 min后再灌注的方法 制备大鼠单肺原位IR模型.SPr组吸入七氟烷,呼气末浓度2.1%,30 min后制备肺IR模型;SPo组于再灌注前即刻吸入七氟烷30 min,呼气末浓度2.1%.分别于再灌注30 min、1、2、4 h时测定支气管肺泡灌洗液(BALF)肿瘤坏死因子α(TNF-α)、白细胞介素1(IL-1)、IL-6浓度,并进行白细胞分类计数,计算多形核白细胞占白细胞的百分比(PMN百分比),同时测定肺组织TNF-α、IL-1、IL-6含量及细胞凋亡指数,光镜、电镜下观察肺组织病理学结果 并行损伤评分.结果 与S组比较,IR组肺组织和BALF中TNF-α、IL-1、IL-6水平、细胞凋亡指数、白细胞计数、PMN百分比和肺组织损伤评分均升高,SPr组和SPo组肺组织TNF-α、IL-1、IL-6含量升高(P<0.01);与IR组比较,SPr组和SPo组上述指标均降低(P<0.05或0.01);SPr组与SPo组各指标差异无统计学意义(P>0.05).结论 七氟烷后处理可减轻大鼠肺IR损伤,效果与其预处理无差异,其肺保护作用的机制可能与降低肺组织炎性反应,抑制细胞凋亡有关.     

Sevoflurane Preconditioning before Moderate Hypothermic Ischemia Protects against Cytosolic [Ca2+] Loading and Myocardial Damage in Part via Mitochondrial KATP Channels

Background: Brief sevoflurane exposure and washout (sevoflurane preconditioning [SPC]) before 30-min global ischemia at 37[degrees]C is known to improve cardiac function, decrease cytosolic [Ca2+] loading, and reduce infarct size on reperfusion. It is not known if anesthetic preconditioning (APC) applies as well to hypothermic ischemia and reperfusion and if KATP channels are involved. The authors examined in guinea pig isolated hearts the effect of sevoflurane exposure before 4-h global ischemia at 17[degrees]C on cardiac function, cytosolic [Ca2+] loading, and infarct size. In addition they tested the potential role of the mitochondrial KATP channel in eliciting the cardioprotection by SPC.

Methods: Hearts were randomly assigned to (1) a nontreated hypothermic ischemia group (CON), (2) a group given 3.5 vol% sevoflurane for 15 min with a 15-min washout before hypothermic ischemia (SPC), and (3) an SPC group in which anesthetic exposure was bracketed with 200 [mu]m 5-hydroxydecanoate (5-HD) from 5 min before until 5 min after sevoflurane (SPC + 5-HD). Cytosolic [Ca2+] was measured in the left ventricular (LV) free wall with the intracellularly loaded fluorescence probe indo-1.

Results: Initial reperfusion in CON hearts markedly increased systolic and diastolic [Ca2+] and reduced contractility (dLVP/dtmax), relaxation (diastolic LVP, dLVP/dtmin), myocardial oxygen consumption (Mvo2), and cardiac efficiency. In SPC hearts, cytosolic [Ca2+] overloading (especially diastolic [Ca2+]) was decreased with increased myocardial [Ca2+] influx (d[Ca2+]/dtmax) and efflux (d[Ca2+]/dtmin), improved contractility, relaxation, coronary flow, Mvo2, cardiac efficiency, and decreased infarct size. In SPC + 5HD hearts, the reduction in infarct size was antagonized by 5-HD, but functional return was less affected by 5-HD.     

Isoflurane-sevoflurane adminstration before ischemia attenuates ischemia-reperfusion-induced injury in isolated rat lungs

BACKGROUND: The effects of volatile anesthetics on ischemia-reperfusion (IR)-induced lung injury are not clear. The authors investigated the effects of preadministration of isoflurane and sevoflurane on IR-induced lung injury in an isolated buffer-perfused rat lung model. METHODS: Isolated rat lungs were designated into four groups: control group (n = 6): perfusion for 120 min without ischemia; IR group (n = 6): interruption of perfusion and ventilation for 60 min followed by reperfusion for 60 min; sevoflurane (SEVO)-IR (n = 6) and isoflurane (ISO)-IR (n = 6) groups: 1 minimum alveolar concentration (MAC) isoflurane or sevoflurane was administered for 30 min, followed by 60 min ischemia, then 60 min reperfusion. The authors measured the coefficient of filtration (Kfc) of the lung, lactate dehydrogenase (LDH) activity, tumor necrosis factor alpha, and nitric oxide metabolites (nitrite + nitrate) in the perfusate and the wet-to-dry lung weight ratio. RESULTS: IR caused significant increases in the coefficient of filtration (approximately sevenfold at 60 min of reperfusion compared with baseline; P < 0.01), the wet-to-dry lung weight ratio, the rate of increase of lactate dehydrogenase activity, and tumor necrosis factor a in the perfusate, and caused a significant decrease in nitric oxide metabolites in the perfusate. Administration of 1 MAC isoflurane or sevoflurane before ischemia significantly attenuated IR-induced increases in the coefficient of filtration and the wet-to-dry lung weight ratio, inhibited increases in the rate of increase of lactate dehydrogenase activity and tumor necrosis factor alpha in the perfusate, and abrogated the decrease in nitric oxide metabolites in the perfusate. No difference was found between the SEVO-IR and ISO-IR groups. CONCLUSION: Isoflurane and sevoflurane administered before ischemia can attenuate IR-induced injury in isolated rat lungs.     

七氟烷后处理对大鼠海马缺血性损伤及胰岛素样生长因子-1表达的影响

目的 观察不同浓度七氟烷后处理对大鼠海马缺血性损伤的保护作用及其对胰岛素样生长因子-1(insulin-like growth factor-1,IGF-1)表达的影响.方法 选取雄性SD大鼠,随机分为6组:假手术组(S)、缺血但无后处理组(C)、吸氧后处理组(O_2)、不同浓度七氟烷后处理组(Sevo1组、Sevo2组、Sevo3组);不同浓度七氟烷后处理组于脑缺血/再灌注即刻给予吸入1.5%(Sevo1组)、2.4%(Sevo2组)、3.0%(Sevo3组)的七氟烷30 min.采用大脑中动脉闭塞(MCAO)改良模型,于再灌注后的24、48、72h对海马进行组织病理学观察及IGF-1 mRNA检测.结果 与S组相比,C组各时间点大鼠海马IGF-1 mRNA的表达增加(P＜0.05)且海马组织出现病理学损伤;与C组相比,Scvo2组、Scvo3组各时间点的海马IGF-1 mRNA表达进一步增加(P＜0.05),且海马组织病理学损伤较轻;Sevo1组与C组相比,海马IGF-1mRNA的表达及病理学损伤无明显差异.结论 较高浓度的七氟烷后处理可以通过上调海马IGF-1及其受体系统而发挥中枢神经保护作用.     

Effects of halothane,isoflurane and sevoflurane on ischemiareperfusion injury in the perfused liver of fasted rats

Background : Although intraoperative ischemia-reperfusion of the liver generally occurs under general anesthesia, little is known about the direct effect of anesthetic agents on hepatic injury due to this phenomenon. The effect of volatile anesthetics on ischemia-reperfusion injury was studied using isolated liver perfusion. Methods : The liver was isolated from 24-h-fasted male Sprague-Dawley rats and perfused through the portal vein with a modified Krebs-Ringer bicarbonate solution in a recirculating perfusion-aeration system. Ischemia was induced by reducing the baseline perfusion pressure from 1.2 to 0.2 kPa followed by reperfusion to baseline level. The ischemia-reperfusion injury was assessed by LDH release from the perfused liver. We studied the effect of halothane, isoflurane and sevoflurane on the ischemia-reperfusion injury during 20 min of control conditions, exposure of the liver to 60 min of ischemia and reperfusion for 90 min. Results : Ischemia was evident by reduced portal vein flow and oxygen consumption, and caused an increase in lactate production. Reperfusion caused a transient reduction in lactate production and a significant increase in LDH release. All anesthetics reduced hepatic oxygen consumption and increased the net lactate production during control conditions. Volatile anesthetics also significantly attenuated LDH release during reperfusion. The suppression of LDH release was observed even when isoflurane was administered during the reperfusion period, but not when it was administered only during ischemia. Conclusion : These results indicate that volatile anesthetics may protect the fasted liver from early, neutrophil-independent, ischemia-reperfusion injury by acting during the reperfusion phase.     

七氟醚预处理联合后处理对大鼠心肌缺血再灌注时血栓素A2和前列腺素I2的影响

目的 评价七氟醚预处理联合后处理对大鼠心肌缺血再灌注时血栓素A2和前列腺素I2的影响.方法 健康雄性Wistar大鼠50只,体重250～280 g,采用随机数字表法,将大鼠随机分为5组(n=10):假手术组(S组)、缺血再灌注组(I/R组)、七氟醚预处理组(Spr组)、七氟醚后处理组(Spo组)和七氟醚预处理联合七氟醚后处理组(Spr+po组).I/R组、Spr组、Spo组和Spr+po组采用结扎左冠状动脉前降支30 min时进行再灌注的方法制备心肌缺血再灌注模型,S组仅在左冠状动脉前降支下穿线.Spr组进行七氟醚预处理:于缺血前30 min吸入2.5%七氟醚15 min,洗脱15 min;Spo组进行七氟醚后处理:再灌注前1 min开始吸入2.5%七氟醚,持续5 min;Spr+po组进行七氟醚预处理和后处理.再灌注2 h时取动脉血样,测定血MB型磷酸肌酸激酶同工酶(CK-MB)、乳酸脱氢酶(LDH)、心肌肌钙蛋白I(cTnI)、血栓素B2(TXB2)、6-酮-前列腺素F1α(6-keto-PGF1α)的水平和血小板最大聚集率,并计算TXB2与6-keto-PGF1α的比值(TXB2/6-keto-PGF1α).取心肌组织,电镜下观察病理学结果,进行线粒体损伤评分,并测定线粒体的比表面和面数密度.结果 与S组比较,I/R组血CK-MB、LDH、cTnI、TXB2、6-keto-PGF1α的水平、TXB2/6-keto-PGF1α血小板最大聚集率及线粒体损伤评分升高,线粒体的比表面和面数密度降低(P<0.05或0.01);与I/R组比较,Spr组和Spo组血CK-MB、LDH、cTnI的水平、TXB2/6-keto-PGF1α和线粒体损伤评分降低,血6-keto-PGF1α浓度、线粒体的比表面和面数密度升高(P<0.05或0.01);与Spr组和Spo组比较,Spr+po组血CK-MB、LDH、cTnI、TXB2的水平、TXB2/6-keto-PGF1α血小板最大聚集率和线粒体损伤评分降低,血6-keto-PGF1α浓度、线粒体的比表面和面数密度升高(P<0.05).Spr+po组心肌损伤程度轻于Spr组和Spo组.结论 与七氟醚预处理或后处理比较,两种方法联合应用可抑制血栓素A2的释放和促进前列腺素I2的释放,从而进一步减轻了大鼠心肌缺血再灌注损伤.

Abstract：

Objective To investigate the effect of sevoflurane preconditioning-postconditioning on thromboxane A2 and prostaglandin I2 during myocardial ischemia-reperfusion (I/R) in rats. Methods Fifty healthy male Wistar rats weighing 250-280 g were randomly divided into 5 groups (n = 10 each) : sham operation group (group S) , I/R group, sevoflurane preconditioning group (group Spr), sevoflurane postconditioning group (group Spo)and combination of sevoflurane preconditioning and postconditioning group (group Spr + po). Myocardial I/R was produced by occlusion of anterior descending branch of left coronary artery for 30 min followed by 2 h reperfusion in anesthetized rats. In group S the anterior descending branch was only exposed but not ligated. Group Spr received 15 min inhalation of 2.5 % sevoflurane and 15 min wash-out 30 min before ischemia. Group Spo received 5 min inhalation of 2.5% sevoflurane 1 min before reperfusion. Arterial blood samples were taken at 2 h of reperfusion for determination of the levels of MB isoenzyme of creatine kinase (CK-MB) , lactate dehydrogenase (LDH) , cardiac troponin I (cTnI), thromboxane B2(TXB2), and 6-keto-prostaglandin (6-keto-PGF1α) and platelet maximum aggregation rate. TXB2/6-keto-PGF1α ratio was calculated. The myocardial tissues were taken for microscopic examination. Mitochondria] injury was assessed by using Flameng score and stereology (Specific surface, δ and Numerical density on area, NA) .Results Compared with group S, the levels of CK-MB, LDH, cTnI, TXE2 and 6-ketoPGF1α, TXB2/6-keto-PGF1α ratio, platelet maximum aggregation rate and Flameng score were significantly increased, while δ and NA were significantly decreased in group I/R (P < 0.05 or 0.01) . The levels of CK-MB,LDH and cTnI, TXB2/6-keto-PGF1α ratio and Flameng score were significantly lower, and 6-keto-PGF1α level, δand NA were significantly higher in Spr and Spo groups than in group I/R ( P < 0.05 or 0.01) . The levels of CKMB, LDH, cTnI and TXB2 , TXB2/6-keto-PGF1α ratio, platelet maximum aggregation rate and Flameng score were significantly lower and 6-keto-PGF1α level,δ and NA were significantly higher in group Spr + po than in Spr and Spo groups(P < 0.05). Conclusion Sevoflurane preconditioning-postconditioning can reduce myocardial I/R injury through inhibiting the release of thromboxane A2 and promoting the release of prostaglandin I2 in rats.     

Anesthetic preconditioning with sevoflurane does not protect the spinal cord after an ischemic-reperfusion injury in the rat

Anesthetic preconditioning (APC) is a protective mechanism, whereby exposure to a volatile anesthetic renders a tissue resistant to a subsequent ischemic insult. We hypothesized that APC of the rat spinal cord with sevoflurane would reduce neurologic deficit after an ischemic-reperfusion injury. Rats were randomly assigned to 1 of 5 groups. The ischemic preconditioning (IPC) group (n = 14) had 3 min of IPC, 30 min of reperfusion, and 12 min of ischemia. The chronic APC (cSEVO) group (n = 14) had 1 h of APC with 3.5% sevoflurane on each of 2 days before ischemia. The acute APC (aSEVO) group (n = 14) had 1 h of APC with 3.5% sevoflurane followed by a 1-h washout period before the induction of ischemia. The controls (n = 14) underwent no preconditioning before ischemia. IPC attenuated the ischemia-reperfusion injury, whereas aSEVO and cSEVO groups were no better than control animals. Histologic evaluation of the spinal cord showed severe neurologic damage in all groups except for the IPC group and sham-operated rats. APC with sevoflurane did not reduce neurologic injury in a rat model of spinal cord ischemia. Traditional ischemic preconditioning had a strong protective benefit on neurologic outcome.     

七氟醚对肢体缺血再灌注大鼠肝损伤的影响

目的探讨七氟醚对肢体缺血再灌注大鼠肝损伤的影响。方法健康SD大鼠24只,体重200～250g,随机分为3组,各8只:假手术组(Sham组),只进行手术操作不做其他处理;肢体缺血再灌注组(IR组),双后肢缺血4h、再灌注6h;七氟醚组(S组)于再灌注前吸入2.5%七氟醚6h。IR、Sham组只吸入氧气。实验结束断头处死大鼠,于下腔静脉取血测定血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)的含量。摘取肝脏测定肝组织匀浆超氧化物歧化酶(SOD)、丙二醛(MDA)、肿瘤坏死因子α(TNF-α)和白细胞介素6(IL-6)的含量,光学显微镜下观察组织病理学结果。结果与Sham组比较,IR组和S组ALT、AST、MDA、TNF-α和IL-6含量升高,SOD含量降低(P<0.01),肝组织损伤明显;与IR组比较,S组ALT、AST、MDA、TNF-α和IL-6含量降低,SOD含量升高(P<0.05),肝组织损伤减轻。结论七氟醚对肢体缺血再灌注大鼠肝损伤具有一定程度的保护作用,其机制可能与其减少氧自由基的释放和抑制炎症反应有关。