降钙素基因相关肽介导硝酸甘油增强心停搏液的保护作用(英文)

目的:研究硝酸甘油增强心停搏液的保护作用与促进降钙素基因相关肽释放的关系。方法:在StThomas Hospital心停搏液条件下,离体心脏低温缺血4h后再灌40min,记录心率、冠脉流量及心功能,并测定灌注液中降钙素基因相关肽(CGRP)的浓度及肌酸激酶(CK)的释放量。结果:硝酸甘油(0.1或1μmol/L)改善心功能,降低CK释放,同时促进CGRP的释放。CGRP(5或10nmol/L)也改善心功能及降低CK释放。预先用辣椒素耗竭感觉神经递质后。硝酸甘油的心肌保护和升高灌注液中CGRP浓度作用消失。选择性CGRP受体拮抗剂CGRP_(8-37)也能取消硝酸甘油的心肌保护作用。格列苯脲对硝酸甘油和CGRP的心保护作用均无影响。结论:硝酸甘油增强心停搏液的保护作用是通过内源性CGRP所介导,其保护作用与ATP敏感的钾通道无关。     

羟基红花黄色素A对大鼠心肌缺血再灌注损伤的保护作用及机制

目的:探讨羟基红花黄色素A(HSYA)是否具有缺血预适应样心肌保护作用及其作用机制。方法:建立在体大鼠心肌缺血再灌注损伤模型和缺血预适应模型,化学比色法测定血清CK水平,NBT染色测定心肌梗死面积,放免法测定血浆降钙素基因相关肽(CGRP)、6-酮基-前列腺素F1α等指标的变化。结果:缺血预适应组和HSYA治疗组心肌梗死面积分别为:(15.4±2.2)%,(12.0±3.3)%,(16.6±2.4)%,(22.0±3.4)%,较缺血再灌注损伤组(41.7±9.8)%明显降低(P<0.05)。缺血预适应组和HSYA治疗组较缺血再灌注组CGRP、6-酮基-前列腺素F1α显著升高,CK-MB含量降低。结论:羟基红花黄色素A可对大鼠心肌缺血再灌注损伤产生保护作用,其作用与心肌缺血预适应的保护作用相似。     

吴茱萸次碱对心脏过敏损伤的保护作用

目的 观察吴茱萸次碱对心脏过敏损伤的保护作用与激活辣椒素受体。剌激内源性降钙素基因相关肽(CGRP)释放的关系。方法 预致敏的离体心脏用K-H液恒压逆行灌流,从侧管中注入牛血清白蛋白(5 mg),造成过敏损伤。测定冠脉流出液中CGRP和心肌组织中肿瘤坏死因子(TNF-α)的浓度。结果预致敏的豚鼠心脏受抗原(牛血清蛋白)攻击引起冠脉流量(CF)显著减少,左室内压(LVP)和左室内压最大变化速率(±dp/dtmax)降低,同时伴有心率(HR)的增加和P-R间期的延长。两个浓度吴莱萸次碱(0.3或1.0 μmol·L-1)均能显著抑制抗原攻击所致的心功能抑制,表现为LVP、±dp/dtmax和CF升高,P-R间期明显缩短,并能同时促进CGRP的释放和降低心肌组织TNF-α的浓度。昊茱萸次碱对窦性心动过速无明显影响。吴茱萸次碱对心脏过敏损伤的保护作用能被一种选择性CGRP受体拮抗剂CGRP8-37所取消。结论 吴茱萸次碱对心脏过敏损伤的保护作用是通过促进CGRP释放所介导,其心脏保护作用可能与抑制心肌组织TNF-α产生有关。     

降钙素基因相关肽在一氧化氮介导热应激诱导心肌延迟预适应中的作用

目的：研究一氧化氮－降钙素基因相关肽途径是否参与热应激诱导的心肌延迟预适应。方法：采用Langendorff装置灌注离体心脏。心脏低温（4℃）保存4h后,再灌注40min(37℃）。实验前24h大鼠进行高温处理（直肠温度42℃,15min)。记录心率,冠脉流量、左室内压以及最大变化速率,并测定血浆降钙素基因相关肽（CGRP）浓度和冠脉流出液中肌酸激酶（CK）释放量。结果：热应激能显著增强心肌停搏液的保护作用,减少CK释放量,并升高血浆CGRP浓度。这些作用能被预先给予亚硝基精氨酸甲酯及辣椒素所取消。结论：一氧化氮参与了对大鼠心脏的延迟保护,其作用是由内源性CGRP所介导。     

降钙素基因相关肽:一种调节预适应的内源性中介物(英文)

心脏遭受短暂缺血或高温处理后均产生早期和延迟保护效应.缺血预适应的心脏保护作用与内源性活性物质有关.辣椒素敏感的感觉神经的主要递质降钙素基因相关肽(CGRP)介导缺血预适应的早期和延迟保护作用.CGRP介导的预适应能保护内皮细胞.热应激的早期和延迟保护也与内源性CGRP释放有关.某些药物如硝酸甘油诱导的预适应可能与其促CGRP释放有关.这些结果表明CGRP可能是一种内源性心肌保护物质,并在预适应的保护效应中起重要作用.     

Cardioprotection of bradykinin-induced preconditioning mediated by prostaglandin1

在大鼠离体心脏观察了前列腺素介导缓激肽诱导的预适应对缺血再灌心肌的保护作用. 30 min缺血和30 min再灌引起心功能降低（左室内压和左室内压最大上升速率下降）,冠脉流量和心率降低以及肌酸激酶（CPK）释放增加. 缺血预适应（5min 缺血,5min再灌,重复3次）能显著改善心功能,促进心率和冠脉流量的恢复,减少CPK释放. 其作用不受吲哚美辛（10μmol     

缓激肽与硝酸甘油对心脏过敏反应的保护作用

研究了外源性缓激肽与硝酸甘油对豚鼠心脏过敏反应的保护作用. 豚鼠致敏后,离体心脏抗原攻击能显著降低冠脉流量,左室内压和左室内压最大变化速率以及延缓房室传导. 缓激肽（50和500 nmol·L^-1）与硝酸甘油（300 nmol·L^-1）能显著增加冠脉流出液中降钙素基因相关肽（CGRP）的含量,同时减轻心脏过敏所致的心功能下降和房室传导阻滞。结果提示：外源性缓激肽与硝酸甘油对心脏过敏反应有保护作用,其作用可能与促进CGRP释放有关.     

辣椒辣素对大鼠再灌注损伤的心肌早期和延迟保护作用(英文)

目的:研究辣椒辣素预处理的早期和延迟心肌保护。方法:采用Langendorff装置灌注离体心脏,记录心率、冠脉流量、左室内压以及最大变化速率,并测定降钙素基因相关肽(CGRP)的血浆浓度及灌注液中肌酸激酶(CK)的释放量。结果:辣椒辣素(50mg·kg~(-1),sc)改善心功能、降低CK释放,并升高CGRP的血浆浓度。预先用辣椒辣素耗竭感觉神经递质后,辣椒辣素的心肌保护和升高CGRP血浆浓度作用消失,应用辣椒辣素24h或48h后,其对缺血心肌仍具有保护作用。结论:辣椒辣素能诱导早期和延迟心肌保护,其保护作用可能与促进CGRP释放有关。     

缓激肽与硝酸甘油对心脏过敏反应的保护作用(英文)

研究了外源性缓激肽与硝酸甘油对豚鼠心脏过敏反应的保护作用 .豚鼠致敏后 ,离体心脏抗原攻击能显著降低冠脉流量 ,左室内压和左室内压最大变化速率以及延缓房室传导 .缓激肽 ( 50和 50 0nmol·L-1)与硝酸甘油 ( 30 0 nmol·L-1)能显著增加冠脉流出液中降钙素基因相关肽 ( CGRP)的含量 ,同时减轻心脏过敏所致的心功能下降和房室传导阻滞。结果提示 :外源性缓激肽与硝酸甘油对心脏过敏反应有保护作用 ,其作用可能与促进 CGRP释放有关 .     

前列腺素介导缓激肽诱导预适应对缺血再灌心肌的保护作用(英文)

在大鼠离体心脏观察了前列腺素介导缓激肽诱导的预适应对缺血再灌心肌的保护作用．３０ｍｉｎ缺血和３０ｍｉｎ再灌引起心功能降低（左室内压和左室内压最大上升速率下降）,冠脉流量和心率降低以及肌酸激酶（ＣＰＫ）释放增加．缺血预适应（５ｍｉｎ缺血,５ｍｉｎ再灌,重复３次）能显著改善心功能,促进心率和冠脉流量的恢复,减少ＣＰＫ释放．其作用不受吲哚美辛（１０μｍｏｌ·Ｌ－１预先灌流３０ｍｉｎ）影响．预先用缓激肽（０．５μｍｏｌ·Ｌ－１）处理５ｍｉｎ产生缺血预适应样心肌保护作用,表现为促进心功能恢复,减少ＣＰＫ释放．该作用被预先灌流吲哚美辛取消．对照组,缺血再灌组,缓激肽组,吲哚美辛加缓激肽组的ＣＰＫ分别为（０．２８±０．０３）,（２．２３±０．０６）,（０．３９±０．０９）,（１．８７±０．０５）μｍｏｌ·ｍｉｎ－１·ｇ－１湿组织．结果提示：缓激肽诱导预适应对缺血再灌心肌的保护作用与促前列腺素生成有关     

The cardioprotection of rutaecarpine is mediated by endogenous calcitonin related-gene peptide through activation of vanilloid receptors in guinea-pig hearts

Previous investigations have shown that calcitonin gene-related peptide (CGRP) protects against myocardial ischemia-reperfusion injury and that rutaecarpine activates vanilloid receptors to evoke CGRP release. In the present study, we examined whether rutaecarpine enhances preservation with cardioplegia in guinea-pig hearts, and whether the protective effects of rutaecarpine are related to stimulation of endogenous CGRP release via activating vanilloid receptors. The isolated guinea-pig heart was arrested using St. Thomas Hospital solution, and then reperfused with normothermic Krebs-Henseleit solution for 30 min after a 4-h hypothermic ischemic period. Hypothermic ischemia caused a decline in cardiac function (left ventricular pressure, +/-dp/dt(max), heart rate and coronary flow) and an increased release of creatine kinase during reperfusion. Rutaecarpine at the concentration of 1.0 microM significantly improved the recovery of cardiac function and reduced the release of creatine kinase during reperfusion after hypothermic ischemia. Rutaecarpine at the concentration of 3.0 microM significantly reduced the release of creatine kinase and increased the coronary flow, but only caused a slight improvement of left ventricular pressure, +/-dp/dt(max), heart rate during reperfusion. The cardioprotective effects of rutaecarpine were abolished by capsazepine, a competitive vanilloid receptor antagonist, or by CGRP (8-37), a selective CGRP receptor antagonist. Rutaecarpine at the concentration of 1.0 or 3.0 microM significantly increased the release of CGRP, which was also abolished by capsazepine. These results suggest that rutaecarpine enhances preservation with cardioplegia in guinea-pig hearts and that the protective effects of rutaecarpine are due to stimulation of endogenous CGRP release via activating vanilloid receptors.     

Mediation of calcitonin gene-related peptide in protection of ischemic preconditioning in rat hindlimbs.

AIM: To study modulation of calcitonin gene-related peptide (CGRP) in the protective effect of ischemic preconditioning on endothelial cells. METHODS: Rat hindlmbs were subjected to ischemia for 2 h, and endothelium-dependent vasorelaxation to acetylcholine (ACh) was examined in rat hindlimbs. RESULTS: Two hours of ischemia elicited no effect on vasoconstrictor responses to norepinephrine, but markedly impaired vasodilator responses to ACh. Ischemic preconditioning induced by 5-min aortic occlusion and 10-min blood reperfusion prevented the impairment of vasorelaxation to ACh due to long-term ischemia. The protection of ischemic preconditioning was abolished by repeated pretreatments with capsaicin to deplete CGRP. Acute application of capsaicin to evoke CGRP release or CGRP caused an ischemic preconditioning-like protection. CONCLUSION: Capsaicin-sensitive sensory nerves are involved in the protective effect of ischemic preconditioning on endothelial cells in the rat hindlimbs, and CGRP can mimic the protective effect of ischemic preconditioning in blood vessels.     

Protective effects of calcitonin gene-related peptide-mediated evodiamine on guinea-pig cardiac anaphylaxis

Previous investigations have indicated that the pharmacological effects of evodiamine, a major alkaloidal component of the dried, unripe fruit of Evodia rutaecarpa Bentham (Rutaceae), are associated with stimulation of calcitonin gene-related peptide (CGRP) release and CGRP prevents cardiac anaphylactic injury. In the present study, the protective effects of evodiamine on cardiac anaphylaxis were examined. Presensitized guinea-pig hearts challenged with specific antigen (bovine serum albumin) caused a marked decrease in coronary flow, left ventricular pressure and its derivatives (+/-dp/dt(max)), an increase in heart rate, and prolongation of P-R interval. Evodiamine (0.3 microM or 1 microM) markedly increased the content of CGRP in the coronary effluent concomitantly with a significant improvement of cardiac function and alleviation of the extension of P-R interval. Evodiamine at the concentration of 1 microM also inhibited the sinus tachycardia. The protective effect of evodiamine on cardiac anaphylaxis was abolished by CGRP(8-37), the selective CGRP receptor antagonist. These results suggest that evodiamine possesses a protective effect of cardiac anaphylactic injury and that the effect of evodiamine is related to stimulation of CGRP release.     

Protection of calcitonin gene-related peptide-mediated preconditioning against lysophosphatidylcholine-induced myocardial injury in isolated rat hearts

研究心脏缺血预适应（ＰＣ）对溶血性磷脂酰胆碱（ＬＰＣ）损伤心肌作用的影响，并探讨降钙素基因相关肽（ＣＧＲＰ）在ＰＣ中的作用．离体大鼠心脏Ｌａｎｇｅｎｄｏｒｆ法灌流，记录心率，冠脉流量，左室压和左室压最大上升速率（＋ｄｐ／ｄｔｍａｘ），并测定灌流液中肌酸磷酸激酶（ＣＰＫ）含量．结果显示，ＬＰＣ能降低各项心功能指标，并使ＣＰＫ释放增加；ＰＣ（缺血５ｍｉｎ，再灌５ｍｉｎ，重复３次）能减轻ＬＰＣ的损伤作用；ＰＣ的心肌保护作用可被选择性ＣＧＲＰ受体拮抗剂ＣＧＲＰ８－３７所取消；预先给予ＣＧＲＰ或辣椒素能产生与ＰＣ相同的心肌保护作用．对照组，ＬＰＣ，ＰＣ＋ＬＰＣ，ＣＧＲＰ８－３７，ＣＧＲＰ８－３７＋ＰＣ＋ＬＰＣ，ＣＧＲＰ＋ＬＰＣ，ＣＧＲＰ８－３７＋ＣＧＲＰ＋ＬＰＣ，辣椒素＋ＬＰＣ组ＣＰＫ释放量分别为０．２６±０．０５，２．３０±０．２２，０．２５±０．０３，０．３０±０．０８，２．６０±０．１５，０．２４±０．０５，２．７０±０．２０和０．２５±０．０７μｍｏｌ·ｍｉｎ－１·ｇ－１湿组织．这些结果提示：１）ＰＣ对ＬＰＣ所致心肌损伤具有保护作用；２）ＰＣ的保护作用是由ＣＧＲＰ所介导；３）ＣＧＲＰ或辣椒素可模拟ＰＣ的保护作?     

Monophosphoryl lipid A-induced delayed preconditioning is mediated by calcitonin gene-related peptide

The delayed preconditioning of the heart by monophosphoryl lipid A is mediated by endogenous nitric oxide (NO), and the cardioprotection afforded by nitroglycerin is related to stimulation of calcitonin gene-related peptide (CGRP) release. The objective of this study was to explore whether improvement of preservation with cardioplegia by monophosphoryl lipid A is mediated by CGRP. In addition, we examined the effect of monophosphoryl lipid A on the tumor necrosis factor-alpha (TNF-alpha) content of myocardial tissues. The isolated rat heart was perfused in the Langendorff mode. Heart rate, coronary flow, left-ventricular pressure, and its first derivatives (+/-dp/dt(max)) were recorded, and plasma levels of NO and CGRP, the release of creatine kinase in coronary effluent and the content of TNF-alpha in myocardial tissues were measured. Hypothermic ischemia for 4 h caused a decline in cardiac function, and an increase in the release of creatine kinase and in the content of TNF-alpha. Pretreatment with monophosphoryl lipid A (500 microg/kg, i.p.) for 24 h improved the recovery of cardiac function and reduced the release of creatine kinase concomitantly with a decrease in the content of cardiac TNF-alpha. Monophosphoryl lipid A markedly increased plasma concentrations of CGRP and NO. After pretreatment with L-nitroarginine methyl ester (L-NAME), the cardioprotection and the increased release of NO and CGRP induced by monophosphoryl lipid A were abolished. Capsaicin also abolished the cardioprotection and the increased release of CGRP induced by monophosphoryl lipid A, but did not affect the content of NO. The results suggest that monophosphoryl lipid A-induced preconditioning enhances preservation with cardioplegia and that the protective effects of monophosphoryl lipid A are related to stimulation of CGRP release.     

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.     

The role of calcitonin gene-related peptide (CGRP) in ischemic preconditioning in isolated rat hearts

Brief coronary artery occlusion can protect the heart against damage during subsequent prolonged coronary artery occlusion; ischemic preconditioning. The role of calcitonin gene-related peptide (CGRP) in ischemic preconditioning is investigated in isolated perfused rat hearts, by measuring CGRP release during ischemic preconditioning and mimicking this by exogenous CGRP infusion, either in the absence or presence of the CGRP antagonist BIBN4096BS. CGRP increased left ventricular pressure and coronary flow in a concentration dependent manner, which was effectively antagonized by BIBN4096BS. Rat hearts (n=36) were subjected to 45 min coronary artery occlusion and 180 min reperfusion, which was preceded by: (1) sham pretreatment, (2) BIBN4096BS infusion (1 microM), (3) preconditioning by 15 min coronary artery occlusion and10 min reperfusion, (4) as 3, but with BIBN4096BS, (5) 15 min CGRP infusion (5 nM) and 10 min washout, (6) as 5, but with BIBN4096BS. Cardiac protection was assessed by reactive hyperaemia, creatine kinase release, infarct size related to the area at risk (%), and left ventricular pressure recovery. Preconditioning increased CGRP release into the coronary effluent from 88+/-13 to 154+/-32 pg/min/g, and significantly protected the hearts by decreasing reactive hyperaemia (35%), reducing creatine kinase release (53%), limiting infarct size (48%), and improving left ventricular pressure recovery (36%). Exogenous CGRP induced preconditioning-like cardioprotection. BIBN completely abolished the cardioprotection induced by preconditioning as well as by exogenous CGRP. In conclusion, since cardioprotection of preconditioning-induced CGRP release can be mimicked by exogenous CGRP, and both can be blocked by a CGRP antagonist, results indicate an important role for CGRP in ischemic preconditioning.     

Protective effects of rutaecarpine in cardiac anaphylactic injury is mediated by CGRP

Previous investigations have indicated that rutaecarpine activates the vanilloid receptor to evoke calcitonin gene-related peptide (CGRP) release. CGRP has been shown to alleviate cardiac anaphylactic injury. In the present study, the effect of rutaecarpine on cardiac anaphylaxis was examined. Challenge of presensitized guinea-pig hearts with a specific antigen caused marked decreases in coronary flow (CF), left ventricular pressure (LVP) and its derivatives (+/- dp/dt(max)), an increase in heart rate, and prolongation of the P-R interval. Rutaecarpine (0.3 or 1 microM) markedly increased the content of calcitonin gene-related peptide (CGRP) in the coronary effluent and decreased the content of tumor necrosis factor-alpha (TNF-alpha) in myocardial tissues concomitantly with a significant improvement of cardiac function and alleviation of the extension of the P-R interval. Rutaecarpine at the concentration of 1 microM also inhibited the sinus tachycardia. The protective effects of rutaecarpine on cardiac anaphylaxis were abolished by CGRP (8-37), a selective CGRP receptor antagonist. These results suggest that the protective effects of rutaecarpine on cardiac anaphylactic injury are related to inhibition of TNF-alpha production by stimulation of CGRP release.     

Delayed cardioprotection by intestinal preconditioning is mediated by calcitonin gene-related peptide

Previous studies have shown that nitric oxide and calcitonin gene-related peptide (CGRP) are involved in mediation of the delayed cardioprotection of ischemic or pharmacological preconditioning, and nitric oxide can evoke the release of CGRP. In the present study, we examined the role of CGRP in nitric oxide-mediated delayed cardioprotection by brief intestinal ischemia in rats. The serum concentration of creatine kinase and infarct size were measured after 45-min coronary artery occlusion and 180-min reperfusion. Ischemic preconditioning was induced by six cycles of 4-min ischemia and 4-min reperfusion of the small intestine. Pretreatment with intestinal ischemic preconditioning for 24, 48, or 72 h significantly reduced infarct size and creatine kinase release, and the effects of ischemic preconditioning were completely abolished by L-nitroarginine methyl ester (L-NAME, 10 mg/kg, i.p.), an inhibitor of nitric oxide synthase, or by pretreatment with capsaicin (50 mg/kg, s.c.), which selectively depletes transmitters in capsaicin-sensitive sensory nerves. Intestinal preconditioning caused a significant increase in plasma concentrations of CGRP, and the effect was also abolished by L-NAME or capsaicin. These results suggest that the delayed cardioprotection afforded by intestinal ischemic preconditioning is mediated by endogenous CGRP via the nitric oxide pathway.     

The cardioprotective effects of nitroglycerin-induced preconditioning are mediated by calcitonin gene-related peptide

Previous investigations have shown that endogenous calcitonin gene-related peptide (CGRP) may play an important role in the mediation of ischemic preconditioning and that nitroglycerin evokes the release of CGRP. In the present study, we examined whether nitroglycerin provides a preconditioning stimulus, and whether the cardioprotective effects of nitroglycerin-induced preconditioning involve endogenous CGRP. Thirty minutes of global ischemia and 30 min of reperfusion caused a significant impairment of cardiac contractile function and an increased release of creatine kinase. Pretreatment with nitroglycerin at the concentration of 3x10(-7) or 10(-6) M for 5 min produced a significant improvement of cardiac function and a decrease in the release of creatine kinase. The content of CGRP-like immunoreactivity in coronary effluent was increased during nitroglycerin perfusion. However, the cardioprotection afforded by nitroglycerin was abolished by CGRP-(8-37) (10(-7) M), a selective CGRP receptor antagonist. Pretreatment with capsaicin (50 mg/kg, s.c.), which specifically depletes the transmitter content of sensory nerves, also abolished the protective effects of nitroglycerin and markedly reduced the release of CGRP from the heart during nitroglycerin perfusion. These findings suggest that nitroglycerin-induced preconditioning is related to stimulation of CGRP release in rat hearts.