ERK1/2参与丙泊酚预处理对肾性高血压大鼠离体心肌缺血再灌注损伤的作用

目的探讨丙泊酚预处理对肾性高血压大鼠离体缺血再灌注心肌的作用及细胞外信号调节激酶(ERK1/2)活化在其中的可能机制。方法在Langendorff离体心脏灌注模型上,64只肾性高血压大鼠随机分为8组(n=8):对照组(CTRL组),缺血再灌注组(ISCH组),DMSO组,30、100和300μmol.L-1丙泊酚预处理组(P30、P100和P300组),ERK1/2激酶抑制剂PD98059组(PD组)及PD98059+100μmol.L-1丙泊酚预处理组(PD+P100组)。持续监测心功能指标,实验末生化比色法检测心肌细胞超氧化物歧化酶(SOD)活性和丙二醛(MDA)含量,W estern B lotting方法半定量测定p-ERK1/2蛋白表达水平。结果再灌注60 m in末,ISCH组心功能较CTRL组恶化(P<0.01),DMSO组、P30组、P300组和PD组心功能指标与ISCH组相比未见差异,P100组心功能恢复程度高于ISCH组(P<0.01),PD98059能拮抗100μmol.L-1丙泊酚预处理引起的心功能改善。P100组MDA含量低于ISCH组和PD+P100组,SOD活性高于ISCH组和PD+P100组。P100组胞浆p-ERK1、胞核p-ERK1/2活性较ISCH组升高,PD+P100组较P100组胞核p-ERK1/2活性明显降低(P<0.01)。结论100μmol.L-1丙泊酚预处理减轻了肾性高血压大鼠离体心肌缺血再灌注损伤,其机制可能涉及心肌细胞p-ERK1/2,尤其是细胞核p-ERK1/2活性的增加。     

丙泊酚预处理对大鼠离体心肌缺氧/再给氧损伤线粒体细胞色素C释放的影响

目的探讨丙泊酚预处理对大鼠离体心肌缺氧再给氧损伤时心肌细胞凋亡及线粒体细胞色素C释放的影响。方法50只SD大鼠随机分为5组:对照组(C组),DMSO预处理组(D组),25、50、100μmol.L-1丙泊酚预处理组(P1、P2、P3组)。应用Langendorff离体心脏灌注模型,经主动脉用K-H液逆行灌注。各组均缺氧30min,再给氧60min。DMSO组、P1、P2、P3组在缺氧前分别以含DMSO、相应浓度丙泊酚的K-H液灌注10min,再冲洗5min,重复2次。记录平衡灌注末、缺氧前即刻、再给氧30、60min时的心功能指标。再给氧60min时用DNA原位末端缺口标记技术(TUNEL法)测定凋亡细胞,提取心肌线粒体,免疫印迹法测定线粒体和胞质的细胞色素C水平。结果D组与C组相比差异无显著性;与D组相比,P1、P2、P3组再给氧30min、60min时LVEDP降低、LVDP升高(P<0.05),再给氧末心肌细胞凋亡率降低(P<0.05或0.01),心肌线粒体细胞色素C释放减少,胞质细胞色素C的量明显降低(P<0.05或0.01)。结论丙泊酚预处理能够通过抑制心肌线粒体细胞色素C释放到胞质降低心肌细胞凋亡率,减轻心肌缺氧再给氧损伤。     

Coronary vascular hemodynamic and permeability changes during reperfusion after no-flow ischemia in isolated, diltiazem-treated rabbit hearts

Effects of diltiazem on coronary vascular functional integrity were assessed in isolated rabbit hearts during reperfusion after 30 min of global, no-flow ischemia. External detection of radiolabeled albumin, [125I]bovine serum albumin ([125I]BSA), and compartmental-model analysis were used to estimate the mean transit time of [125I]BSA (tBSA), vascular volume (V1), and vascular into extravascular space clearance (F21) for [125I]BSA. Perfusion pressure, left ventricular (LV) end-diastolic pressure, LV developed pressure, maximum +dP/dt, and V1 remained constant during 5 h of continuous perfusion, while tBSA and F21 gradually increased (1.5 and 2.4 times baseline, respectively). Diltiazem, 4 microM, increased total water content (8.5%) and decreased perfusion pressure (11%), LV developed pressure (22%), and +dP/dt (24%) in nonischemic control experiments, but did not significantly affect estimates of V1, extracellular space, tBSA, or albumin permeation. During reperfusion after 30 min of ischemia, V1 increased 40% and perfusion pressure increased 60%, while tBSA and F21 increased three and eight times baseline, respectively. LV developed pressure and +dP/dt returned to control levels, even though the water content and extracellular space of ischemic hearts were increased significantly. Diltiazem, 4 microM, blocked ischemia-reperfusion-induced increases in water content, extracellular space, vascular resistance, V1, and vascular permeability to [125I]BSA, without reducing LV developed pressure or +dP/dt relative to nonischemic diltiazem controls. These results suggest that protection of ischemic myocardium by diltiazem is mediated, at least in part, by preservation of vascular functional integrity.     

Enhanced Na+/H+ exchange during ischemia and reperfusion impairs mitochondrial bioenergetics and myocardial function

Inhibition of Na+/H+ exchange (NHE) during ischemia reduces cardiac injury due to reduced reverse mode Na+/Ca2+ exchange. We hypothesized that activating NHE-1 at buffer pH 8 during ischemia increases mitochondrial oxidation, Ca2+ overload, and reactive O2 species (ROS) levels and worsens functional recovery in isolated hearts and that NHE inhibition reverses these effects. Guinea pig hearts were perfused with buffer at pH 7.4 (control) or pH 8 +/- NHE inhibitor eniporide for 10 minutes before and for 10 minutes after 35- minute ischemia and then for 110 minutes with pH 7.4 buffer alone. Mitochondrial NADH and FAD, [Ca2+], and superoxide were measured by spectrophotofluorometry. NADH and FAD were more oxidized, and cardiac function was worse throughout reperfusion after pH 8 versus pH 7.4, Ca2+ overload was greater at 10-minute reperfusion, and superoxide generation was higher at 30-minute reperfusion. The pH 7.4 and eniporide groups exhibited similar mitochondrial function, and cardiac performance was most improved after pH 7.4+eniporide. Cardiac function on reperfusion after pH 8+eniporide was better than after pH 8. Percent infarction was largest after pH 8 and smallest after pH 7.4+eniporide. Activation of NHE with pH 8 buffer and the subsequent decline in redox state with greater ROS and Ca2+ loading underlie the poor functional recovery after ischemia and reperfusion.     

Effects of Young's solution (YNG solution) on cardiac function and mitochondrial function during one hour ischemia at 30 degrees C and after reperfusion

In a previous paper from this laboratory, protective effects of YNG solution on the myocardial mechanical function and metabolism of the heart arrested at 10 degrees C ascribable to the presence of Mg2+ were demonstrated. In order to further clarify the role played by Mg2+ in the protection, the present experiment was conducted using the isolated perfused guinea pig heart arrested at 30 degrees C. While the time to arrest of the contraction was equally short both with YNG (K+ + Mg2+) and K (K+) solutions, the time to resumption of contraction was significantly longer with K solution than with YNG solution, and the regular contraction was not resumed with the former solution. The recovery of the coronary flow, left ventricular pressure and dp/dt after reperfusion was around 100% with YNG solution, while the recovery was significantly poorer with K solution. Although the mitochondrial function was well maintained during the arrest both with YNG and K solution, the recovery of the mitochondrial function after reperfusion was observed only with YNG solution; severe damage was noted in mitochondria of the hearts arrested with K solution. There was a good correlation between the changes in mitochondrial function and those in cardiac function.(ABSTRACT TRUNCATED AT 250 WORDS)     

降钙素基因相关肽介导的离体大鼠心脏缺血预处置

降钙素基因相关肽介导的离体大鼠心脏缺血预处置１肖洲生，李元建２，邓汉武（湖南医科大学药理教研室，长沙４１００７８，中国）关键词降钙素基因相关肽；心肌再灌注损伤；心功能试验；肌酸激酶目的：研究降钙素基因相关肽（ＣＧＲＰ）在离体大鼠心脏缺血预处置（ＰＣ）...     

Discrepancies between inotropic responses and beta-adrenoceptor characteristics after global ischemia in isolated hearts.

The influence of global ischemia on cardiac beta-adrenoceptors was studied in rat and guinea pig Langendorff hearts (LH), both by functional and binding experiments using the specific beta-adrenoceptor ligand (-)-[125I]-iodocyanopindolol. Neither ischemia (30 or 60 min) nor postischemic reperfusion caused any change in beta-adrenoceptor density, affinity or in the beta 1/beta 2 ratio in LH of normal rats or in LH of rats pretreated with reserpine or 6-hydroxydopamine (6-OHDA), or in guinea pig LH, whereas perfusion of rat LH with 10(-5) M isoprenaline (15 min) caused the expected decrease in beta-adrenoceptor density. After ischemia, isoprenaline was no longer able to influence beta-adrenoceptor density, suggesting that the internalization mechanism is impaired. In functional studies, perfusion of the rat LH with 10(-5) M isoprenaline (15 min) shifted the concentration-response curve for isoprenaline to the right. Thirty-minute global ischemia virtually abolished the inotropic but not the chronotropic response to isoprenaline. Ischemia did not impair the inotropic response to ouabain or to calcium, indicating that the contractile apparatus itself was still largely intact. Our results suggest that the contractile failure after ischemia is not caused by a decrease in beta-adrenoceptor density or by a defect in the contractile apparatus but by an impaired second-messenger system.     

Role of histamine H3 receptors during ischemia/reperfusion in isolated rat hearts

Histamine H3 receptors are involved in regulating the release of norepinephrine (NE), in both central and peripheral nervous systems. We investigated the effect of R-alpha-methylhistamine (R-HA), a selective H3 receptor agonist, and thioperamide (Thiop), a selective H3 receptor antagonist, on ischemia/reperfusion-induced changes in carrier-mediated NE release and cardiac function in isolated rat heart. Hearts were subjected to 40-minute ischemia followed by 30-minute reperfusion. Ischemia/reperfusion evoked massive NE release, which was markedly suppressed by the treatment with desipramine (DMI), a neuronal NE transporter blocker. Ischemia/reperfusion-induced cardiac dysfunction (decreases in left ventricular developed pressure, LVDP, and the first derivative of left ventricular pressure, dP/dt, and a rise in left ventricular end diastolic pressure, LVEDP) was also improved by the DMI treatment. The treatment with R-HA also significantly decreased the excessive NE release induced by the ischemia/reperfusion, improved the recovery of LVDP and dP/dt, and suppressed the rise in LVEDP. Thiop did not affect NE release and cardiac function after the reperfusion. When R-HA was administered concomitantly with Thiop, R-HA failed to attenuate ischemia/reperfusion-induced NE release and cardiac dysfunction. Thus, it seems likely that the ischemia/reperfusion-induced carrier-mediated NE release in rat hearts is negatively regulated by the activation of H3 receptors, probably located on cardiac noradrenergic nerve endings.     

二氢槲皮素预处理对心肌缺血/再灌注损伤抗氧化作用的影响

目的探讨二氢槲皮素(dihydroquercetin,DDQ)对大鼠离体心脏缺血/再灌注损伤抗氧化作用的影响。方法SD大鼠40只,随机分为正常组、模型组、二氢槲皮素低剂量组(5 mg·L~(-1))、二氢槲皮素高剂量组(10 mg·L~(-1))4组。使用Langendorff逆行恒压灌流方式建立离体大鼠心脏I/R模型。观察I/R期间DDQ对左心室舒张压、左心室收缩压、室内压最大上升速率、室内压最大下降速率和心率的影响。乳酸脱氢酶(LDH)水平和血清肌酸激酶(CK)的含量均采用酶联免疫吸附法进行分析,TTC染色法评价心肌梗死程度,测定心肌组织中超氧化物歧化酶(SOD)、还原型谷胱甘肽/氧化型谷胱甘肽(GSH/GSSG)和丙二醛(MDA)含量,HE染色观察心肌组织学结构的病变。结果与模型组比,DDQ预处理组能够明显改善血流动力学的各项指标;DDQ预处理组可使心肌组织中的SOD和GSH/GSSG的含量明显增加;CK,LDH和MDA的含量明显降低,同时降低心肌梗死程度,减轻心肌组织学病变。结论 DDQ对离体大鼠缺血/再灌注损伤具有明显的保护作用,此保护作用可能与DDQ提高氧自由基清除能力,减少氧自由基产生,降低脂质过氧化损伤的作用机制有关。     

内源性抗氧化酶在异氟烷预处理离体大鼠心肌保护作用中的变化

目的观察不同浓度异氟烷预处理离体大鼠心肌的保护作用及其与内源性抗氧化酶变化的关系。方法建立大鼠离体心脏Langendorff灌流模型,随机分为6组(n=14):空白对照组(CON组)、1.44MAC异氟烷对照组(ISO组)、缺血/再灌注组(I/R组)、0.72MAC(I1组)、1.08MAC(I2组)和1.44MAC(I3组)异氟烷处理组。除CON组和ISO组外,其余各组大鼠心脏均缺血30min,再灌注60min。异氟烷预处理在心脏缺血前25min时进行,用不同浓度异氟烷充分饱和的K-H液预处理20min,冲洗5min。记录平衡末,缺血前即刻,再灌注30、60min时的心功能指标,测定再灌注末心肌组织中内源性抗氧化酶的活性,计算心肌梗死面积。并检测I2组大鼠心肌在平衡末,缺血前即刻,缺血后即刻及再灌30min组织中内源性抗氧化酶的活力。结果心肌缺血/再灌注使离体大鼠心脏的LVEDP明显升高,HR、LVDP、dp/dtmin及dp/dtmax明显降低(P<0.05)。与I/R组比较,再灌注末,I2组和I3组LVEDP和心肌梗死面积均明显降低,HR、dp/dtmin、dp/dtmax以及各抗氧化酶活性明显升高(P<0.05)。与平衡末相比,在缺血后即刻心肌组织各内源性抗氧化酶的活性明显降低;而在再灌注30和60min时,其活性较缺血后即刻升高(P<0.05),但仍未达到平衡末水平。结论异氟烷预处理可以增强内源性抗氧化酶的活性,明显改善心功能,并减少心肌梗死面积,对大鼠离体缺血/再灌注心肌有保护作用。     

Ischemic preconditioning: triggering role of nitric oxide-derived oxidants in isolated hearts

There is evidence that oxidants generated during ischemic preconditioning (IPC) trigger or mediate cardioprotection. We examined whether a causal relationship exists between oxidant formation during ischemic preconditioning and cardioprotection. We monitored formation of dityrosine in crystalloid-perfused guinea pig isolated hearts after a preconditioning protocol and after prolonged ischemia. Superoxide dismutase, catalase, and glutathione (SCG), or the L-arginine analogue NGnitro L-arginine methyl ester (L-NAME) were given during preconditioning. Dityrosine was observed in the coronary effluent immediately after both stimuli, but not after bracketing with SCG or L-NAME. After prolonged ischemia, dityrosine was significantly lower in the IPC group than in other groups. IPC was evidenced by improved mechanical and metabolic function on reperfusion, and by reduced infarction. These effects were abrogated by either SCG or L-NAME. These data support the hypothesis that the formation of nitric oxide-derived oxidants during ischemic preconditioning is causally related to myocardial adaptation to reperfusion injury.     

Cardiovascular responses to the stereoisomers of dobutamine in isolated rat hearts 48 hours after acute myocardial infarction.

Effects of acute myocardial infarction (48 h) on cardiovascular responses to (+/-)-, (-)-, and (+)-dobutamine were studied in isolated perfused rat hearts. The effects of the racemate and the isomers on ventricular pressure were measured simultaneously in infarcted left ventricle and noninfarcted right ventricle. Administration of (+/-)-, (-)-, and (+)-dobutamine resulted in dose-dependent increases in inotropic parameters and coronary flow (CF) in both control and in infarcted hearts. As compared with the (+)-isomer, the racemate and the (-)-isomer in both control and infarcted hearts were approximately 1.5 and 15 times weaker with respect to inotropic parameters. For (+/-)-, (-)-, and (+)-dobutamine, there was no significant difference in pD2 values in any of the inotropic measurements between the infarcted group and the corresponding control group. The maximal obtainable responses were significantly lower in the infarcted groups as compared with their corresponding control group. In control hearts, effects of isoproterenol and methoxamine as compared with (+/-)-dobutamine were approximately 2 log units more and 2 log units less in potency, respectively. The inotropic effects of (-)-dobutamine but not those of methoxamine were completely antagonized by propranolol (0.3 microM). Although the results provide evidence for the existence of myocardial alpha 1-adrenoceptors, all forms of dobutamine exerted positive inotropic effects through activation of beta-adrenoceptors both in control and in infarcted in rat hearts.     

Cardioprotection by polysaccharide sulfate against ischemia/reperfusion injury in isolated rat hearts

Aim:

Polysaccharide sulfate (PSS) is a new type of heparinoid synthesized with alginic acid as the basic material and then by chemical introduction of effective groups. Although PSS is successfully applied in ischemic cardio-cerebrovascular disease, its effect on cardiac function after ischemia/reperfusion (I/R) injury has previously not been investigated. The aim of the present study was to investigate whether PSS can protect the heart from I/R injury and the underlying mechanism of protection.

Methods:

Isolated rat hearts were perfused (Langendorff) and subjected to 20 min global ischemia followed by 60 min reperfusion with Kreb''s Henseleit solution or PSS (0.3–100 mg/L). Myocardial contractile function was continuously recorded. Creatine kinase (CK) and lactate dehydrogenase (LDH) leakage were measured. Tumor necrosis factor-α (TNF-α) expression in cardiomyocytes was investigated. Western blot analysis for extracellular regulated kinases (ERKs), c-jun amino-terminal kinase (JNKs) and p38 mitogen-activated protein kinase (MAPK) activity was performed.

Results:

After I/R, cardiac contractility decreased, CK and LDH levels increased in the coronary effluent, and TNF-α expression increased in cardiomyocytes. PSS administration at concentrations of 1–30 mg/L improved cardiac contractility, reduced CK and LDH release and inhibited TNF-α production. Phosphorylated-p38MAPK (p-p38MAPK) and p-p54/p46-JNK increased in I/R rat hearts but diminished in PSS (1–30 mg/L) treated hearts. P-p44/p42-ERK levels were unchanged. In contrast, high concentrations of PSS (100 mg/L) had adverse effects that caused a worsening of heart function.

Conclusion:

PSS has dose-dependent cardioprotective effects on the rat heart after I/R injury. The beneficial effects may be mediated through normalization of the activity of p38 MAPK and JNK pathways as well as controlling the level of TNF-α expression.     

Cardioprotection by polysaccharide sulfate against ischemia/ reperfusion injury in isolated rat hearts

Aim： Polysaccharide sulfate （PSS） is a new type of heparinoid synthesized with alginic acid as the basic material and then by chemical introduction of effective groups. Although PSS is successfully applied in ischemic cardio-cerebrovascular disease, its effect on cardiac function after ischemia/reperfusion （I/R） injury has previously not been investigated. The aim of the present study was to investigate whether PSS can protect the heart from I/R injury and the underlying mechanism of protection. Methods： Isolated rat hearts were perfused （Langendorff） and subjected to 20 min global ischemia followed by 60 min reperfusion with Kreb＇s Henseleit solution or PSS （0.3-100 mg/L）. Myocardial contractile function was continuously recorded. Creatine kinase （CK） and lactate dehydrogenase （LDH） leakage were measured. Tumor necrosis factor-α （TNF-α） expression in cardiomyocytes was investigated. Western blot analysis for extracellular regulated kinases （ERKs）, c-jun aminoterminal kinase （JNKs） and p38 mitogen-activated protein kinase （MAPK） activity was performed.
Results： After I/R, cardiac contractility decreased, CK and LDH levels increased in the coronary effluent, and TNF-α expression increased in cardiomyocytes. PSS administration at concentrations of 1-30 mg/L improved cardiac contractility, reduced CK and LDH release and inhibited TNF-α production. Phosphorylated-p38MAPK （p-p38MAPK） and p-p54/p46- JNK increased in I/R rat hearts but diminished in PSS （1-30 mg/L） treated hearts. P-p44/p42-ERK levels were unchanged. In contrast, high concentrations of PSS （100 mg/L） had adverse effects that caused a worsening of heart function. Conclusion： PSS has dose-dependent cardioprotective effects on the rat heart after I/R injury. The beneficial effects may be mediated through normalization of the activity of p38 MAPK and JNK pathways as well as controlling the level of TNF-α expression.     

Evidence for the involvement of peroxynitrite in ischaemic preconditioning in rat isolated hearts

1. The aim of this study was to investigate the involvement of peroxynitrite, reactive metabolite originating from nitric oxide and superoxide, in preconditioning of the ischaemic myocardium in rat isolated hearts. 2. Isolated hearts perfused with Krebs-Henseleit solution were preconditioned either by 3 min of coronary artery occlusion (CAO) or by peroxynitrite administration at three different concentrations (0.1, 1, 10 microM) for 3 min, followed by 10 min reperfusion and 30 min of CAO. Peroxynitrite, at 1 microM concentration, decreased the incidence of VT from 100% (n=14) to 62% (n=13) and abolished the occurrence of VF (50% in the control group). 3. N-2-mercaptopropionylglycine (MPG, 1 microM - 10 mM) produced a concentration-dependent inhibition of peroxynitrite signals in luminol chemiluminescence and 67+/-1% inhibition was observed at 100 microM (n=7). MPG (at 300 microM, n=7) added to the perfusate 10 min prior to ischaemic preconditioning or peroxynitrite infusion and maintained until CAO, significantly reversed the beneficial effects of the ischaemic and peroxynitrite-treated groups. MPG administration in the peroxynitrite-treated group increased the incidence of VT from 62% (n=13) to 100% (n=10) and total VF from 0% (n=0) to 67% (n=10). Similarly, MPG elevated the incidence of VT from 50% (n=10) to 100% (n=8) in the ischaemic preconditioned group. On its own, MPG did not affect the severity of cardiac arrhythmias. 4. These results suggest that endogenously produced peroxynitrite plays a significant role in the antiarrhythmic effect of ischaemic preconditioning in the rat isolated hearts.     

Low-dose calcium antagonists reduce energy demand and cellular damage of isolated hearts during both ischemia and reperfusion

Calcium antagonists may protect against postischemic reperfusion injury of the heart, but neither the time and mode of action leading to cardioprotection is resolved, nor is the generality of this effect proven. Accordingly, the functional and metabolic influence of four different Ca2+-antagonists (diltiazem, 3x10(-8) M; nifedipine, 3x10(-9) M; amlodipine, 3x 10(-9) M; barnidipine, 3x10(-11) M) was examined in preparations of guinea pig hearts (n=7/group) performing pressure-volume work after being subjected to low-flow ischemia (30 min) and reperfusion (35 min). The drugs were applied throughout the study at concentrations without negative inotropic or chronotropic effect, as would be mandatory for any therapeutic application, and without overt coronary dilatation. All calcium antagonists improved postischemic recovery of external heart work: from 42% in controls (post- vs. preischemic value) to 59% for diltiazem, 61% for nifedipine, 65% for amlodipine, and 73% for barnidipine (all P<0.05). Efficiency of myocardial performance (work in relation to oxygen consumption) was low in postischemic controls (8% of total energy equivalents), but significantly improved in treated hearts, especially by barnidipine (15% efficiency). Release of lactate dehydrogenase in the first 5 min of reperfusion, a sign of cell damage, increased from basal (65 mU/min) to 208 mU/min in controls. This increase was fully suppressed by all drugs tested. Myocardial release of lactate and of purine catabolites of adenine nucleotides (markers of anaerobic metabolism) was markedly reduced by Ca2+-antagonists. Interestingly, these metabolic effects were evident not only in the reperfusion phase, but already in the period of low-flow ischemia. Oxidative consumption of pyruvate was enhanced, whereas coronary flow and heart rate showed no postischemic effect of treatment. These findings on isolated guinea pig hearts suggest that Ca2+-antagonists generally improve postischemic pump function and aerobic metabolism without any requirements for negative inotropic action or coronary dilatation. The protective effects seemed to rely on an attenuation of both ischemic stress and reperfusion damage. This could implicate a benefit from prophylactic use of Ca2+-antagonists in patients at risk for myocardial ischemia.     

Inhibition of cardiac tumor necrosis factor-alpha production by calcitonin gene-related peptide-mediated ischemic preconditioning in isolated rat hearts

Previous investigations have demonstrated that calcitonin gene-related peptide (CGRP) plays an important role in the mediation of ischemic preconditioning in rats. In the present study, we examined signal transduction pathways of CGRP-mediated ischemic preconditioning. Thirty minutes of global ischemia and 40 min of reperfusion caused a dramatic decrease in myocardial function, and a significant increase in the release of cardiac creatine kinase in the coronary effluent and in the content of tumor necrosis factor-alpha (TNF-alpha) in myocardial tissues. However, ischemic preconditioning (three cycles of 5-min ischemia and 5-min reperfusion) or pretreatment with CGRP for 5 min dramatically improved the recovery of cardiac function, and reduced the release of cardiac creatine kinase and the TNF-alpha content. The effect of ischemic preconditioning was abolished by CGRP-(8-37), the selective CGRP receptor antagonist, and by capsaicin, which depletes sensory nerve neurotransmitter content, but was unaltered by treatment with glibenclamide, a blocker of the ATP-sensitive potassium (K(ATP)) channel. The protective effects of exogenous CGRP-induced preconditioning were also not blocked by glibenclamide. These results suggest that the cardioprotective effects afforded by CGRP-mediated ischemic preconditioning are related to inhibition of cardiac TNF-alpha production, but not to activation of the K(ATP) channel.     

缺血预处理对离体大鼠心脏肌钙蛋白T释放的影响

目的 :探讨缺血预处理对离体大鼠再灌注期释放心肌肌钙蛋白 T(Tn T)的影响。方法 :实验采用L angendorff灌流装置 ,单次 5 m in缺血 ,继 10 min再灌注作为预处理模型。于 2 0 min缺血后 6 0 min再灌注 ,测定冠流液Tn T、磷酸肌酸激酶 (CK)、乳酸脱氢酶 (L DH)和左室内压 (L VP)。结果 :缺血预处理能明显减少 Tn T、CK、L DH的释放 ,也能改善左室心肌收缩功能。∑Tn T或再灌注 6 0 m in时的 Tn T与 L VP有明显相关性。结论 :Tn T可以作为一个有效的生化指标来判断左室功能障碍和心肌受损程度 ,缺血预处理能减轻心肌缺所致的心肌损伤并改善左室功能