Ghrelin对大鼠离体心脏缺血再灌注损伤的保护作用

目的　研究促生长激素释放肽ghrelin对大鼠心脏缺血 /再灌注 (ischemia/reperfusion ,I/R)损伤的直接保护作用。方法　在大鼠离体心脏I/R模型上 ,观察ghrelin对大鼠离体心脏血流动力学和代谢改变的影响 ,及大鼠缺血和I/R损伤时心肌肌浆膜ghrelin受体变化。结果　ghrelin灌流显著减轻大鼠I/R损伤时的心功能紊乱 ,减少心肌乳酸脱氢酶及肌红蛋白漏出 ,抑制心肌脂质过氧化物生成 ,增加心肌ATP含量 ;受体结合实验表明 ,在大鼠心脏缺血及I/R损伤时 ,心肌肌浆膜ghrelin受体的结合位点增加 ,但亲和力无明显改变。结论　ghrelin对心脏I/R损伤具有非生长激素释放依赖的直接保护作用     

Possible mechanism of rottlerin induced modulation of ischemia reperfusion injury in isolated rat hearts

The present study was designed to investigate the modulatory effects of rottlerin on ischemia reperfusion induced myocardial injury. Isolated rat hearts were exposed to 30 min of global ischemia followed by 120 min of reperfusion using Langendorff apparatus. Myocardial injury was assessed in the terms of infarct size, release of lactate dehydrogenase (LDH), creatine kinase (CK) enzymes. Rottlerin, a selective PKCdelta inhibitor, did not modulate ischemia-reperfusion (I/R) induced myocardial injury at low dose (3 microM). However, at moderate dose (6 microM) it significantly produced cardioprotective effects. On the contrary, rottlerin at high dose (12 microM) significantly enhanced I/R induced myocardial injury. However, administration of FR-167653 (1.1 microM, 2.2 microM), a selective p-38 mitogen activated protein kinase (p-38 MAPK) inhibitor, attenuated rottlerin (12 microM) mediated enhancement in I/R induced myocardial injury in a dose dependent manner. Per se administration of FR-167653 (1.1 microM, 2.2 microM) also attenuated I/R induced myocardial injury in a dose dependent manner. Pretreatment with rottlerin (6 microM) did not enhance the cardioprotective effects of FR-167653 (2.2 microM). It may be concluded that rottlerin mediated cardioprotective effects at moderate dose, possible due to inhibition of PKCdelta; while at high dose it enhanced I/R induced myocardial injury which may be attributed to activation of p-38 MAPK.     

宝霍甙元对大鼠心肌缺血再灌注损伤的保护作用

目的观察宝藿甙元在大鼠心肌缺血再灌注损伤中的保护作用。方法用在体左冠状动脉前降支穿线结扎法制备心肌缺血再灌注模型。36只SD大鼠分为3组,假手术组12只,缺血再灌注组12只,宝藿甙元治疗组12只。三组SD大鼠均继续饲养三周,术后三天检测每组血清SOD浓度,三周后检测心肌梗死重量的比率。结果血清SOD浓度在宝藿甙元组较缺血再灌注组比较(6.54±0.41 vs.5.64±0.68,P=0.003)有明显升高且有统计学意义,宝藿甙元组与假手术组比较(6.54±0.41 vs.6.27±0.48,P=0.17)虽有增高,但无统计学意义。宝藿甙元治疗组较缺血再灌注组的心肌梗死重量比率有明显减少(9.03±0.22%vs.31.83±2.09%,P<0.01)且有统计学意义。结论宝藿甙元可以增加缺血再灌注后机体的抗氧化作用,从而起到对缺血再灌注损伤后的心肌有保护作用,可以减轻心肌坏死的程度。     

Cardioprotective effects of bms-180448, a prototype mitokatp channel opener, and the role of salvage kinases, in the rat model of global ischemia and reperfusion heart injury

To investigate the involvement of reperfusion-induced salvage kinases (RISK) as possible signaling molecules for the cardioprotective effects of BMS-180448, a prototype mitochondrial ATP-sensitive K+ (mitoK(ATP)) channel opener, we measured its cardioprotective effects in a rat model of ischemia/reperfusion (I/R) heart injury, together with western blotting analysis of five different signaling proteins. In isolated rat hearts subjected to 30-min global ischemia followed by 30-min reperfusion, BMS-180448 (1, 3 and 10 microM) significantly increased reperfusion left ventricular developed pressure (LVDP) and 30-min reperfusion double product (heart rate x LVDP) in a concentration-dependent manner, while decreasing left ventricular end-diastolic pressure (LVEDP) throughout reperfusion period in a concentration-dependent manner. SDS-PAGE/western blotting analysis of left ventricle reperfused for 30 min revealed that BMS-180448 significantly decreased phospho-GSK3beta at high concentration, whereas it tended to increase slightly phospho-eNOS and phospho-p70S6K with concentration. However, BMS-180448 had no effect on phospho-Akt and phospho-Bad. These results suggest that the cardioprotective effects of BMS-180448 against I/R heart injury may result from direct activation of mitoK(ATP) channel in cardiomyocytes, with the minimal role of RISK pathway in the activation of this channel and the cardioprotective effects of BMS-180448.     

Timing of erythropoietin treatment for cardioprotection in ischemia/reperfusion

Erythropoietin (EPO) is a hormone known to stimulate hematopoiesis. However, recent research suggests additional properties of EPO, such as protection against ischemia/reperfusion (I/R) injury in various tissues. We studied the effect of timing of EPO administration on cardioprotection during I/R in the heart. Male Sprague-Dawley rats were subjected to 45 minutes of coronary occlusion, followed by 24 hours of reperfusion. Animals were randomized to receive saline or single dose of EPO (5,000 IU/kg) either 2 hours before I/R, at the start of ischemia, or after the onset of reperfusion. The ratio of infarct area/area at risk (planimetry), left ventricular (LV) function (pressure development), and apoptosis (number of active caspase-3 positive cells) were determined after 24-hour reperfusion. Administration of EPO during different time points resulted in a 19 to 23% (P < 0.05) reduction in the infarct area/area at risk, which was accompanied by a trend toward better LV hemodynamic parameters. Apoptosis was significantly attenuated in groups treated with EPO at the start of ischemia (29% reduction) and after the onset of reperfusion (38%), and to a lesser extent (16%) in the group pre-treated with EPO. Thus, in vivo administration of EPO at different time points protects the myocardial structure and preserves cardiac function during I/R. Cardioprotective effect of EPO is associated with inhibition of apoptosis.     

Cardioprotective effects of ghrelin and des-octanoyl ghrelin on myocardial injury induced by isoproterenol in rats

AIM: To determine the cardioprotective action of ghrelin and des-octanoyl ghrelin in rats with isoproterenol-induced myocardial injury. METHODS: Rats were subcutaneously injected with isoproterenol (ISO; 20, 10, and 5 mg/kg) on d 1, 2 and 3, respectively, and then 3 mg/kg for the next 7 d with or without ghrelin or des-octanoyl-ghrelin (100 microg/kg, twice daily). Plasma ghrelin and growth hormone levels were assayed using radioimmunoassay methods. Growth hormone secretagogue receptor (GHSR) and ghrelin mRNA were determined using RT-PCR. The maximal binding capacity and the affinity for [3H]ghrelin were determined by receptor binding assays. RESULTS: Compared with controls, ISO-treated rats showed severe myocardial injury, cardiomegaly, infarction-like necrosis and massive fibrosis with increases in irradiated-ghrelin (ir-ghrelin) content in plasma by 67% and myocardia by 66% and in the mRNA level in the myocardia by 93% (P<0.01). ISO-treated rats had 95% (P<0.01) higher GHSR mRNA levels in the myocardia. The maximal binding capacity of [3H]ghrelin for myocardial sarcolemma was higher in ISO-treated rats than in controls. Ghrelin administration improved cardiac function and ameliorated cardiomegaly and attenuated myocardial lipid peroxidation injury and relieved cardiac fibrosis as compared with ISO treatment alone. Administration of des-octanoyl ghrelin effectively antagonized ISO-induced myocardial injury and improved all parameters measured. However, the therapeutic effect of des-octanoyl ghrelin was significantly weaker than that of ghrelin. The plasma growth hormone level increased markedly, by 1.5-fold (P<0.01), with ghrelin administration as compared with that in controls, but was unaltered in des-octanoyl ghrelin group. CONCLUSION: Myocardial ghrelin and GHSR were up-regulated during ISO-induced myocardial injury. The protective effect of ghrelin against ISO-induced cardiac function injury and fibrosis was more potent than that of des-octanoyl ghrelin, which suggests that ghrelin could be an endogenous cardioprotective factor in ischemic heart disease, and that its effects include growth hormone-dependent and -independent pathways.     

Thaliporphine protects ischemic and ischemic‐reperfused rat hearts via an NO‐dependent mechanism

In ischemia or ischemia‐reperfusion (I/R), nitric oxide (NO) can potentially exert several beneficial effects. Thaliporphine, a natural alkaloid with Ca²⁺ channel‐activating and Na⁺/K⁺ channel‐blocking activities, increased NO levels and exerted cardioprotective action in ischemic or I/R rats. The role of NO in the cardioprotective actions of thaliporphine was assessed. The severity of rhythm disturbances and mortality in anesthetized rats with either coronary artery occlusion for 30 min, or 5 min followed by 30‐min reperfusion, were monitored and compared in thaliporphine‐ vs. placebo‐treated groups. Thaliporphine treatment significantly increased NO and decreased lactate dehydrogenase (LDH) levels in the blood during the end period of ischemia or I/R. These changes in NO and LDH levels by thaliporphine were associated with a reduction in the incidence and duration of ventricular tachycardia (VT) and ventricular fibrillation (VF) during ischemic or I/R period. The mortality of animals was also completely prevented by 1 × 10^–8 moles/kg of thaliporphine. In animals subjected to 4 h of left coronary artery occlusion, 1 × 10^–7 moles/kg of thaliporphine dramatic reduced cardiac infarct zone from 46 ± 6% to 7.1 ± 1.9%. Inhibition of NO synthesis with 3.7 × 10^–6 moles/kg of N^ω ‐nitro‐L‐arginine methyl ester (L‐NAME) abolished the beneficial effects of thaliporphine during 30 min or 4 h myocardial ischemia. However, the antiarrhythmic activity and mortality reduction efficacy of thaliporphine during reperfusion after 5 min of ischemia was only partially antagonized by L‐NAME. These results showed that thaliporphine efficiently exerted the cardioprotections either in acute or prolonged coronary artery occlusion or occlusion‐reperfusion situations. The fact that thaliporphine induced cardioprotective effects were abrogated by L‐NAME indicates that NO is an important mediator for the cardioprotective effects of thaliporphine in acute or prolonged ischemia, whereas antioxidant activities may contribute to the protection of I/R injury. Drug Dev. Res. 52:446–453, 2001. © 2001 Wiley‐Liss, Inc.     

天山花楸叶总黄酮对大鼠心肌缺血/再灌注损伤的保护作用

目的观察天山花楸叶总黄酮对大鼠心肌缺血/再灌注(I/R)损伤的保护作用,探讨其作用机制。方法采用改良的Langendorff逆行恒压灌流方法,建立大鼠离体心脏I/R损伤模型,观察天山花楸叶总黄酮(4.0、6.0mg·L-1)对心脏I/R损伤后心功能、心肌组织中超氧岐化酶(SOD)活性和丙二醛(MDA)含量变化的影响。利用DPPH、羟自由基、超氧阴离子、脂质过氧化反应体系,检测了天山花楸叶总黄酮(6.25、12.5、25、50、100mg·L-1)体外抗氧化能力。结果天山花楸叶总黄酮(6.0mg·L-1)可明显改善离体心脏I/R损伤后左心室发展压(LVDP)和左室压力升高或降低最大速率(±dp/dtmax),明显增加冠脉流量;天山花楸叶总黄酮(6.0mg·L-1)处理后I/R损伤心肌组织中SOD活性升高,MDA含量减少。天山花楸叶总黄酮(6.25～100mg.L-1)可浓度依赖性地清除DPPH自由基、羟自由基和超氧阴离子自由基,并抑制脂质过氧化反应。结论天山花楸叶总黄酮对心肌缺血/再灌注损伤具有明显保护作用,与其具有较强的抗氧化活性有关。     

三七茎叶皂苷对大鼠离体心脏缺血/再灌注损伤的保护作用

目的研究三七茎叶皂苷对大鼠离体心脏缺血/再灌注(I/R)损伤的作用及其作用机制。方法 SD大鼠36只,随机分为6组(n=6),分别是空白对照组、模型组、阳性给药组(地奥心血康70 mg.kg-1)、三七茎叶皂苷低、中、高剂量组(20、40、80 mg.kg-1)。阳性给药组和三七茎叶皂苷给药组大鼠每日灌胃给药1次,连续给药7 d,空白对照组和模型组同时给予同体积生理盐水。末次给药60 min后,分离心脏置于Langendorff离体灌流装置上,平衡15 min后,全心停灌25 min,再灌注60 min,造成心肌缺血/再灌注损伤模型。于大鼠左心房插入水囊导管,记录三七茎叶皂苷对血流动力学指标的影响,测定再灌注60 min后灌流液中乳酸脱氢酶(LDH),肌酸激酶(CK)的活性及心肌组织中超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)、LDH、CK活性及丙二醛(MDA)的含量。HE染色观察组织形态学改变。结果三七茎叶皂苷不同剂量组(20、40、80 mg.L-1),可明显改善缺血/再灌注所致大鼠的心功能损伤,减少灌流液中LDH、CK释放和组织中MDA的产生,增加SOD、GSH-Px的活性。HE染色结果显示,阳性给药组与三七茎叶皂苷高、中、低剂量组均不同程度的减轻了I/R造成的心肌损伤。结论三七茎叶皂苷对心肌缺血/再灌注损伤具有保护作用,其机制可能与改善心肌舒缩功能,清除氧自由基,减少脂质过氧化反应有关。     

Fenofibrate attenuates impaired ischemic preconditioning-mediated cardioprotection in the fructose-fed hypertriglyceridemic rat heart

We investigated in this study whether or not the ischemic preconditioning (IPC)-mediated cardioprotective effect against ischemia–reperfusion (I/R) injury exists in the fructose-fed hypertriglyceridemic (HTG) rat heart. Langendorff-perfused normal and fructose-fed (10 %?w/v in drinking water, 8 weeks) HTG rat hearts were subjected to 30-min global ischemia and 120-min reperfusion. IPC protocol included four brief episodes (5 min each) of ischemia and reperfusion. Myocardial infarct size using triphenyltetrazolium chloride staining, markers of cardiac injury such as lactate dehydrogenase (LDH) and creatine kinase (CK-MB) release, coronary flow rate (CFR), and myocardial oxidative stress were assessed. High degree of myocardial I/R injury, by means of significant myocardial infarct size, elevated coronary LDH and CK-MB release, reduced CFR, and high oxidative stress, was noted in the HTG rat heart as compared to the normal rat heart. The IPC-mediated cardioprotection against I/R injury was markedly impaired in the HTG rat heart as compared to the normal rat heart. Interestingly, pharmacological reduction of triglycerides using 8-week treatment protocol with fenofibrate (80 mg/kg/day, p.o.) restored the IPC effect in the HTG rat heart that was blunted by coinfusion, during the IPC reperfusion protocol, of a specific inhibitor of phosphoinositide-3-kinase (PI3-K), wortmannin (100 nM). The IPC failed to protect the HTG rat heart against I/R injury. Fenofibrate treatment reduced high triglycerides in the fructose-fed HTG rat and subsequently restored the cardioprotective effect of IPC.     

Ghrelin protects myocardium from isoproterenol-induced injury in rats

AIM: To investigate the cardiac protective effects of ghrelin in rat with myocardial injury induced by isoproterenol (ISO). METHODS: Rats were subcutaneously injected ISO 40 mg·kg-1·d-1 with or without ghrelin 1 or 10 nmol·kg-1·d-1 for 2 d. Hemodynamic parameters including mean arterial blood pressure and left ventricular pressure were measured at 12 h after the last injection     

Physiologically tolerable insulin reduces myocardial injury and improves cardiac functional recovery in myocardial ischemic/reperfused dogs

This study was designed to examine whether physiologically tolerable insulin, which maintains lower blood glucose, can protect the myocardium against ischemia/reperfusion (I/R) injury in a preclinical large animal model. Adult dogs were subjected to 50 minutes of myocardial ischemia (80% reduction in coronary blood flow) followed by 4 hours of reperfusion and treated with vehicle, glucose-insulin-potassium (GIK; glucose, 250 g/L; insulin, 60 U/L; potassium, 80 mmol/L), GK, or low-dose insulin (30 U/L) 10 minutes before reperfusion. Treatment with GIK exerted significant cardioprotective effects as evidenced by improved cardiac function, improved coronary blood flow, reduced infarct size, and myocardial apoptosis. In contrast, treatment with GK increased blood glucose level and aggravated myocardial I/R injury. It is interesting that treatment with insulin alone at the dose that reduced blood glucose to a clinically tolerable level exerted significant cardioprotective effects that were comparable to that seen in the GIK-treated group. This low-dose insulin had no effect on coronary blood flow after reperfusion but markedly reduced coronary reactive hyperemia and switched myocardial substrate uptake from fat to carbohydrate. Our results suggest that lower glucose supply to the ischemic myocardium at early reperfusion may create a "metabolic postconditioning" and thus reduce myocardial ischemia/reperfusion injury after prolonged reperfusion.     

Possible involvement of erythropoietin in remote renal preconditioning-induced cardioprotection in rats

Remote preconditioning is a unique phenomenon in which brief episodes of ischemia and reperfusion to remote organs protect the target organ against sustained ischemia/reperfusion (I/R)-induced injury. Protective effects of remote renal preconditioning are well established in the heart, but their mechanisms still remain to be elucidated. Hence, the present study was designed to investigate the possible involvement of erythropoietin in remote renal preconditioning (RRPC)-induced cardioprotection in rats. RRPC was performed by 4 episodes of 5 min renal artery occlusion followed by 5 min reperfusion. Gentamicin (100 mg/kg intraperitoneal) was administered for 6 days for induction of renal failure. Isolated rat hearts were perfused on Langendorff apparatus and were subjected to global ischemia for 30 min ischemia followed by 120 min reperfusion. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were measured in coronary effluent to assess the degree of myocardial injury. Extent of myocardial infarct size and coronary flow rate was also measured. RRPC prevented I/R-induced myocardial injury and produced cardioprotective effects. However, cardioprotective effects of RRPC were not observed in renal failure rats, indicating the protective role of humoral factor was released from functional kidneys. In renal failure rats, exogenous administration of rhEPO (5,000 IU/kg intraperitoneal) with RRPC restored the cardioprotective effects of later. These results implicate that RRPC-induced cardioprotective effects may be mediated through release of erythropoietin from kidney.     

Cardioprotective effect of resvaratrol pretreatment on myocardial ischemia-reperfusion induced injury in rats

OBJECTIVE: The major objective of the present study was to examine the cardioprotective effect of resveratrol, an antioxidant presents in red wine, in the rat after ischemia-reperfusion (I/R). DESIGN: The left coronary artery was in occlusion for 30 min followed by a 120 min reperfusion in anesthetized rats. Animals were pretreated with and without resveratrol before occlusion. The post-ischemic ventricular function (left ventricle maximum systolic pressures and the maximal first derivative of developed pressure) and myocardial infarct size and myocardial nitric oxide (NO) and malonaldehyde (MDA) content were compared. RESULTS: Resveratrol pretreatment had dramatic cardioprotective effects on post-ischemic ventricular functional recovery and decreasing myocardial infarct size. Resveratrol pretreatment also increased NO and decreased MDA content in myocardium. CONCLUSIONS: Resveratrol has cardioprotective properties in I/R rats. The cardioprotective effects in the I/R rats may be correlated with its antioxidant activity and upregulation of NO production.     

Comparative cardioprotective effects and mechanisms of vitamin E and lisinopril against ischemic reperfusion induced cardiac toxicity

The present study was undertaken to scientifically evaluate, validate and compare the cardioprotective effects of lisinopril (Lsp), an angiotensin converting enzyme (ACE) inhibitor and vitamin E (Vit E), an antioxidant in the setting of ischemia and reperfusion (I–R) injury. An open chest left anterior descending coronary artery occlusion and reperfusion induced myocardial injury cardiotoxicity model was used in the present study. Hemodynamic, biochemical and histopathological assessment of myocardial injury was undertaken. Pre-treatment (1 month) with Lsp (50 mg/kg) and Vit E (100 mg/kg) to healthy experimental controls did not adversely affect the histopathological architecture of the myocardium as well as the baseline antioxidant parameters. Subsequent to I–R injury, Lsp demonstrated modest antioxidant effects, superior recovery in left ventricular function as compared to the control IR group. Histopathological and biochemical assessment of injury confirmed the myocardial salvaging effect of this intervention. The cardioprotection afforded by Lsp was found to be superior as compared to Vit E treatment.     

Cardioprotective effects of the novel Na<Superscript>+</Superscript>/H<Superscript>+</Superscript> exchanger-1 inhibitor KR-32560 in a perfused rat heart model of global ischemia and reperfusion: Involvement of the Akt-GSK-3β cell survival pathway and antioxidant enzyme

To investigate the cardioprotective effects and mechanism of action of KR-32560 {[5-(2-methoxy-5-fluorophenyl)furan-2-ylcarbonyl]guanidine}, a newly synthesized NHE-1 inhibitor, we evaluated the effects of KR-32560 on cardiac function in a rat model of ischemia/reperfusion (I/R)-induced heart injury as well as the role antioxidant enzymes and pro-survival proteins play these observed effects. In isolated rat hearts subjected to 25 min of global ischemia followed by 30 min of reperfusion, KR-32560 (3 and 10 μM) significantly reversed the I/Rinduced decrease in left ventricular developed pressure and increase in left ventricular enddiastolic pressure. In rat hearts reperfused for 30 min, KR-32560 (10 μM) significantly decreased the malondialdehyde content while increasing the activities of both glutathione peroxidase and catalase, two important antioxidant enzymes. Western blotting analysis of left ventricles subjected to I/R showed that KR-32560 significantly increased phosphorylation of both Akt and GSK-3β in a dose-dependent manner, with no effect on the phosphorylation of eNOS. These results suggest that KR-32560 exerts potent cardioprotective effects against I/Rinduced rat heart injury and that its mechanism involves antioxidant enzymes and the Akt-GSK-3β cell survival pathway.     

白藜芦醇预处理对心肌缺血/再灌注损伤的保护作用

目的:观察白藜芦醇预处理对心肌缺血再灌注损伤的保护作用.方法:45只雄性SD大鼠随机分为假手术组、缺血再灌组及白藜芦醇预处理组,结扎左冠状动脉制作心肌缺血再灌注模型,比较各组左室最大收缩压(LVSP)、左室等容收缩/舒张期压力上升最大速率(LVdP/dtmax),心肌一氧化氮(NO)、丙二醛(MDA)含量变化及心肌梗死范围.结果:白藜芦醇预处理组LVSP、LVdP/dtmax较缺血再灌组显著升高,心肌NO含量显著升高、MDA含量则显著降低,心肌梗死范围明显减小.结论:白藜芦醇预处理对心肌缺血再灌注损伤有明显保护作用,其机制与白藜芦醇抗氧化、清除自由基及增加NO合成有关.     

KR-31762, a novel KATP channel opener, exerts cardioprotective effects by opening SarcKATP channels in rat models of ischemia/reperfusion-induced heart injury

The cardioprotective effects of KR-31762, a newly synthesized K⁺ _ATP opener, were evaluated in rat models of ischemia/reperfusion (I/R) heart injury. In isolated rat hearts subjected to 30-min global ischemia followed by 30-min reperfusion, KR-31762 (3 and 10 μM) significantly increased the left ventricular developed pressure (LVDP) and double product (heart rate × LVDP) after 30-min referfusion in a concentration-dependent manner, while decreasing the left ventricular end-diastolic pressure (LVEDP). KR-31762 also significantly increased the time to contracture (TTC) during ischemic period (20.0, 22.4 and 26.4 min for control, 3 and 10 μM, respectively), while decreasing the release of lactate dehydrogenase (LDH) from the heart during 30 min reperfusion (30.4, 14.3 and 19.7 U/g heart weight, respectively). All these parameters except LDH release were reversed by glyburide (1 μM), a nonselective blocker of K⁺ _ATP channel, but not by 5-hydroxydecanoate, a selective blocker of mitoK⁺ _ATP channel. In anesthetized rats subjected to 45-min occlusion of left anterior descending coronary artery followed by 90-min reperfusion, KR-31762 significantly decreased the infarct size (60.8, 40.5 and 37.8% for control, 0.3 and 1.0 mg/kg, iv, respectively). KR-31762 slightly relaxed the isolated rat aorta precontracted with methoxamine (IC₅₀: 23.5 μM). These results suggest that KR-31762 exerts potent cardioprotective effects through the opening of sarcolemmal K_ATP channel in rat hearts with the minimal vasorelaxant effects.     

缝隙连接蛋白Cx43介导硫化氢后处理对大鼠心肌的保护作用

目的探讨缝隙连接蛋白Cx43是否参与硫化氢后处理减轻离体大鼠心脏缺血/再灌注(I/R)损伤。方法 72只♂SD大鼠随机分为6组(n=12):空白组(Sham组),缺血/再灌注组(I/R组),溶媒组(DMSO组),抑制剂18β-次甘草酸组(AGA组),硫化氢后处理组(NP组),硫化氢后处理+AGA组(N+A组)。采用离体心脏Langendorff灌注模型,平衡灌注20 min后,停灌30 min,复灌60 min。记录平衡末及灌注结束时的心率(HR)、左室舒张末期压(LV-EDP)、左室发展压(LVDP)、左室内压上升最大速率(+dp/dtmax)、左室内压下降最大速率(-dp/dtmax);灌注结束时,TTC染色法检测心肌梗死面积;Western blot半定量线粒体和胞质总的Cx43(total connexin 43,tCx43)和磷酸化Cx43(phosphorylated connexin 43,pCx43)表达水平。结果平衡灌注末各组间心功能指标差异无统计学意义。再灌注后,与I/R组比较,NP组明显改善再灌注损伤心功能的各项指标(P<0.05),减少心肌梗死面积[(24.4±4.8)%vs(49.4±4.2)%,P<0.05];tCx43表达在线粒体中明显升高,胞质中明显降低,pCx43表达线粒体中明显升高,胞质中明显降低。AGA逆转了硫化氢后处理产生的心肌保护效应及tCx43和pCx43在线粒体中表达的增加(P<0.05)。结论缝隙连接蛋白Cx43参与了硫化氢后处理减轻离体大鼠心脏I/R损伤过程。     

Sex Differences in Postischemic Cardiac Dysfunction and Norepinephrine Overflow in Rat Heart: The Role of Estrogen Against Myocardial Ischemia-reperfusion Damage Via an NO-mediated Mechanism

ABSTRACT:: The purpose of this study is to elucidate the relationship between sex difference and norepinephrine (NE) release in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. Isolated male and female rat hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. Compared with male hearts, I/R-induced cardiac dysfunction, such as decreased left ventricular developed pressure and dP/dtmax and increased left ventricular end diastolic pressure, was significantly attenuated in female hearts. An excessive NE overflow in the coronary effluent from the postischemic heart in females was much less than that in males. These sex differences were abolished by ovariectomy, but in vivo treatment with 17β-estradiol recovered it. This ameliorating effect of 17β-estradiol was not observed in the presence of nitric oxide (NO) synthase inhibitor N-nitro-L-arginine. When NOx (NO2/NO3) levels in the coronary effluent after onset of reperfusion were measured, reversed correlated relationships between NOx production and I/R-induced cardiac dysfunction, and NE overflow, were observed. These findings suggest that sex differences in the postischemic cardiac dysfunction are closely related to the NE overflow from the postischemic heart and that estrogen plays a key role in the cardioprotective effect against I/R injury in female rats, by suppressing NE release via the enhancement of NO production.