感觉神经肽对缺血后处理保护作用的影响及机制研究
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摘要
研究背景：
随着心脏体外循环、冠状动脉搭桥术、经皮冠状动脉介入治疗等技术的推广应用,心肌缺血--再灌注损伤(I/R)已成为临床麻醉面临的一种常见的病理生理变化,其成为阻碍心脏血管外科手术疗效的主要难题。2003年缺血后处理(Ischemia postconditioning,IpostC)概念的提出,使得IpostC对缺血--再灌注损伤保护作用及相关机制的研究成为近年研究热点。降钙素基因相关肽(calcitonin gene-related peptide,CGRP)和P物质(substance P, SP)是支配心脏的感觉神经纤维中共存的两种重要的神经肽,参与调节机体多种生命活动。大量研究提示SP和CGRP参与心脏功能的调节,但对二者在缺血后处理中的作用缺乏系统研究,详细作用机制还不是十分清楚。心脏感觉神经及其主要递质SP和CGRP是否参与缺血后处理的保护作用?其作用机制又是如何?本实验拟对此进行研究。
研究目的：
1.确定成年大鼠在体心脏急性心肌缺血后即刻给予缺血后处理能否促进感觉神经肽CGRP和SP的表达和释放；
2.评价内源性CGRP和SP是否参与缺血后处理的保护作用,即其对再灌后心肌梗死面积,再灌后心脏血流动力学,室性心律失常的影响及其可能的作用机制。
研究内容及方法：采用体重为350-380g的健康雄性SD大鼠,建立急性心肌缺血再灌注模型和缺血后处理模型,实验共分为四个部分
第一部分利用酶联免疫吸附试验(enzyme linked immunosorbent assay, ELISA),对大鼠心脏缺血再灌注及缺血后处理再灌后不同时点(15min,2.5H)缺血心肌组织和血清中CGRP和SP表达进行检测,分析缺血再灌注及缺血后处理心肌组织和血清中SP、CGRP表达的变化；
第二部分在大鼠心脏缺血再灌注前分别给予CGRP受体拮抗剂CGRP8-37(10-6,10-7mol·L-1), SP受体拮抗剂RP67580(10-5,10-6mol·L-1)及联合应用CGRP8-37(10-6mol·L-1)和RP67580(10-6mol·L-1),观察内源性CGRP和SP对缺血后处理再灌后心肌梗死面积的影响；
第三部分在大鼠心脏缺血再灌注前分别给予CGRP受体拮抗剂CGRP8-37(10-6,10-7mol·L-1), SP受体拮抗剂RP67580(10-5,10-6mol·L-1)及联合应用CGRP8-37(10mol·L-1)和RP67580(10-6mol·L-1),观察内源性CGRP和SP对大鼠心脏缺血后处理再灌注血流动力学的影响；
第四部分在大鼠心脏缺血再灌注前分别给予CGRP受体拮抗剂CGRP8-37(10-6,10-7mol·L-1), SP受体拮抗剂RP67580(10-5,10-6mol·L-1)及联合应用CGRP8-37(10-6mol·L-1)和RP67580(10-6mol·L-1),观察心肌缺血后处理对心肌缺血再灌注诱发室性心律失常的影响及内源性CGRP和SP在其中的作用。
研究结果：
1.心肌缺血再灌注以及缺血后处理心肌组织和血清中SP和CGRP浓度的变化。
与I/R组相比,IpostC组可以使再灌后(15min,2.5H)心肌组织和血清中CGRP和SP的表达上调。
2.内源性CGRP和SP对大鼠心脏缺血后处理再灌后心肌梗死面积的影响。
实验各组缺血危险区面积百分比AAR/LV%无差异。与I/R组相比,IpostC组可以显著降低再灌后心肌梗死区面积百分比IS/AAR%;与IpostC组相比,给予CGRP8-37, RP67580以及联合应用二者都可以明显增加梗死区面积百分比IS/AAR%。
3.内源性CGRP和SP对大鼠心脏缺血后处理再灌注后血流动力学的影响。
与I/R组相比,IpostC组可以显著降低再灌后SAP和DAP,降低再灌后PAP,增加再灌后HR；与IpostC组相比,给予CGRP8-37可以增加再灌后SAP和DAP,降低PAP,同时可以降低HR；给予RP67580可以显著增加再灌后SAP和DAP,降低PAP,降低HR；二者联合应用可以显著增加再灌后SAP和DAP,降低HR。4.心肌缺血后处理对心肌缺血再灌注诱发室性心律失常的影响及内源性CGRP和SP在其中的作用。
与I/R组相比,IpostC组可以显著降低再灌注后室性心律失常发生,峰值降低,时限延后；与IpostC组相比,不同浓度的CGRP8-37,RP67580以及联合应用二者均可以增加再灌注后室性心律失常的发生,出现峰值增高,时限提前。
结论：缺血后处理可以增加再灌注后内源性感觉神经肽CGRP和SP的表达,改善再灌注血流动力学,降低室性心律失常的发生以及心肌梗死面积,其机制可能与内源性感觉神经肽其相应受体途径有关,相关机制有待进一步研究阐明。
Background:With the popularization and application of the technology of the heartduring cardiopulmonary bypass,coronary artery bypass graft,percutaneous coronaryintervention, myocardial ischemia-reperfusion has become a commonpathophysiological change, meanwhile which become the challenge ofcardiovascular surgery. In2003,with the concept of IpostC Ischemiapostconditioning has been proposing, making the cardioprotection of IpostC and therelated mechanism to be a research hotspot. CGRP calcitonin gene-related peptide and SP substance P are important neuropeptides of the sensory nerve fibers, whichinvolving in the regulation of the life activities. The existing research shows thatCGRP and SP involved in the regulation of the cardiovascular system, little is knownabout the role of them on the the regulatory effects and the mechanism of IpostC. Sowe established the current study to investigate whether the sensory nerve and itsneurotransmitters (CGRP and SP) are involved in the protective effect of IpostCwhich further explore the neurogenic mechanism of IpostC in rats.
Object we established the current study to determine:
1. whether ischemic-postconditioning applied at the beginning of reperfusion couldup-regulated the expression of CGRP and SP;
2. To evaluate whether endogenous CGRP and SP are involved in the cardioprotectionof ischemic-postconditioning, including cardiac hemodynamics, ventriculararrhythmias and myocardial infarct size after reperfusion, which further explore theneurogenic mechanism of the organ injury in rats.
Method: Making the model of acute myocardial ischemia-reperfusion andischemia-postconditioning with the healthy male SD rats, the experiment has beendivided into four parts:
1. The eluates were processed using ELISA enzyme linked immunosorbent assay for measurement of SP, CGRP concentrations in myocardium and serum at ischemicreperfusion15min and2.5H after IpostC.
2. Observed pretreatment with CGRP_(8-37)(10-6mol L-1,10-7mol L-1), RP6758010~(-5)10~(-6)mol·L~(-1)） or joint application CGRP8-37(10-6mol L-1) and RP67580(10-6mol L-1), the change of myocardial infarct size of reperfusion after IpostC.
3. Observed pretreatment with CGRP_(8-37)(10-6mol L-1,10-7mol L-1), RP6758010~(-5),10~(-6)mol·L~(-1) or joint application CGRP_(8-37)(10-6mol L-1) and RP67580(10-6mol L-1), the change of hemodynamic of reperfusion after IpostC.
4. Observed pretreatment with CGRP_(8-37)(10-6mol L-1,10-7mol L-1), RP6758010-5è10-6mol·L-1or joint application CGRP_(8-37)(10-6mol L-1) and RP67580(10-6mol L-1), the change of ventricular arrhythmia of reperfusion after IpostC.
Result:
1.The change of concentration of CGRP and SP in myocardium and serum at differenttime of ischemic reperfusion after IpostC:
Compared with group IR èthe concentrations of CGRP and SP in myocardiumand serum were significantly up-regulated at ischemic reperfusion15min and2.5Hafter IpostC.
2. The effection of CGRP and SP to myocardial infarct size of reperfusion afterIpostC:
Compared with group IR èthe myocardial infarct size(IS/AAR%) wassignificantly decreased in group IpostC. Compared with group IpostC, pretreatmentwith the different concentration of CGRP_(8-37),RP67580and CGRP_(8-37)+RP67580can significantly enhance AAR/LV%.
3. The effection of CGRP and SP to cardiac hemodynamics of reperfusion afterIpostC:
Compared with group IR èIpostC significantly reduce SAP,DAP and PAP,significantly enhanced HR; compared with group IpostC, pretreatment with CGRP_(8-37)can significantly increased SAP and DAP, prominently reduce HR and PAP;pretreatment with RP67580can significantly increased SAP and DAP, prominentlyreduce HR and PAP; pretreatment with CGRP_(8-37)+RP67580can significantlyenhanced LVSP and DAP, produced lower HR.
4.The effection of CGRP and SP to ventricular arrhythmia of reperfusion after IpostC:
Compared with group IR ècardiac ventricular arrhythmia was significantlydecreased in group IpostC., the duration of arrhythmias was late; compared withgroup IpostC, pretreatment with the different concentration of CGRP_(8-37),RP67580and CGRP_(8-37)+RP67580can significantly increase ventricular arrhythmia, theduration of arrhythmias was bring forward.
Conclusions: Results from the present study indicate that IpostC could increase theexpress of endogenous CGRP and SP, regulate cardiac functions, arrhythmias andmyocardial infarction after Ischemia-reperfusion, endogenous CGRP and SP might beinvolved in the regulation of the effect through their specific receptor.However, theprecise mechanisms involved remain elusive.
随着心脏体外循环、冠状动脉搭桥术、经皮冠状动脉介入治疗等技术的推广应用,心肌缺血--再灌注损伤(I/R)已成为临床麻醉面临的一种常见的病理生理变化,其成为阻碍心脏血管外科手术疗效的主要难题。2003年缺血后处理(Ischemia postconditioning,IpostC)概念的提出,使得IpostC对缺血--再灌注损伤保护作用及相关机制的研究成为近年研究热点。降钙素基因相关肽(calcitonin gene-related peptide,CGRP)和P物质(substance P, SP)是支配心脏的感觉神经纤维中共存的两种重要的神经肽,参与调节机体多种生命活动。大量研究提示SP和CGRP参与心脏功能的调节,但对二者在缺血后处理中的作用缺乏系统研究,详细作用机制还不是十分清楚。心脏感觉神经及其主要递质SP和CGRP是否参与缺血后处理的保护作用?其作用机制又是如何?本实验拟对此进行研究。
研究目的：
1.确定成年大鼠在体心脏急性心肌缺血后即刻给予缺血后处理能否促进感觉神经肽CGRP和SP的表达和释放；
2.评价内源性CGRP和SP是否参与缺血后处理的保护作用,即其对再灌后心肌梗死面积,再灌后心脏血流动力学,室性心律失常的影响及其可能的作用机制。
研究内容及方法：采用体重为350-380g的健康雄性SD大鼠,建立急性心肌缺血再灌注模型和缺血后处理模型,实验共分为四个部分
第一部分利用酶联免疫吸附试验(enzyme linked immunosorbent assay, ELISA),对大鼠心脏缺血再灌注及缺血后处理再灌后不同时点(15min,2.5H)缺血心肌组织和血清中CGRP和SP表达进行检测,分析缺血再灌注及缺血后处理心肌组织和血清中SP、CGRP表达的变化；
第二部分在大鼠心脏缺血再灌注前分别给予CGRP受体拮抗剂CGRP8-37(10-6,10-7mol·L-1), SP受体拮抗剂RP67580(10-5,10-6mol·L-1)及联合应用CGRP8-37(10-6mol·L-1)和RP67580(10-6mol·L-1),观察内源性CGRP和SP对缺血后处理再灌后心肌梗死面积的影响；
第三部分在大鼠心脏缺血再灌注前分别给予CGRP受体拮抗剂CGRP8-37(10-6,10-7mol·L-1), SP受体拮抗剂RP67580(10-5,10-6mol·L-1)及联合应用CGRP8-37(10mol·L-1)和RP67580(10-6mol·L-1),观察内源性CGRP和SP对大鼠心脏缺血后处理再灌注血流动力学的影响；
第四部分在大鼠心脏缺血再灌注前分别给予CGRP受体拮抗剂CGRP8-37(10-6,10-7mol·L-1), SP受体拮抗剂RP67580(10-5,10-6mol·L-1)及联合应用CGRP8-37(10-6mol·L-1)和RP67580(10-6mol·L-1),观察心肌缺血后处理对心肌缺血再灌注诱发室性心律失常的影响及内源性CGRP和SP在其中的作用。
研究结果：
1.心肌缺血再灌注以及缺血后处理心肌组织和血清中SP和CGRP浓度的变化。
与I/R组相比,IpostC组可以使再灌后(15min,2.5H)心肌组织和血清中CGRP和SP的表达上调。
2.内源性CGRP和SP对大鼠心脏缺血后处理再灌后心肌梗死面积的影响。
实验各组缺血危险区面积百分比AAR/LV%无差异。与I/R组相比,IpostC组可以显著降低再灌后心肌梗死区面积百分比IS/AAR%;与IpostC组相比,给予CGRP8-37, RP67580以及联合应用二者都可以明显增加梗死区面积百分比IS/AAR%。
3.内源性CGRP和SP对大鼠心脏缺血后处理再灌注后血流动力学的影响。
与I/R组相比,IpostC组可以显著降低再灌后SAP和DAP,降低再灌后PAP,增加再灌后HR；与IpostC组相比,给予CGRP8-37可以增加再灌后SAP和DAP,降低PAP,同时可以降低HR；给予RP67580可以显著增加再灌后SAP和DAP,降低PAP,降低HR；二者联合应用可以显著增加再灌后SAP和DAP,降低HR。4.心肌缺血后处理对心肌缺血再灌注诱发室性心律失常的影响及内源性CGRP和SP在其中的作用。
与I/R组相比,IpostC组可以显著降低再灌注后室性心律失常发生,峰值降低,时限延后；与IpostC组相比,不同浓度的CGRP8-37,RP67580以及联合应用二者均可以增加再灌注后室性心律失常的发生,出现峰值增高,时限提前。
结论：缺血后处理可以增加再灌注后内源性感觉神经肽CGRP和SP的表达,改善再灌注血流动力学,降低室性心律失常的发生以及心肌梗死面积,其机制可能与内源性感觉神经肽其相应受体途径有关,相关机制有待进一步研究阐明。
Background:With the popularization and application of the technology of the heartduring cardiopulmonary bypass,coronary artery bypass graft,percutaneous coronaryintervention, myocardial ischemia-reperfusion has become a commonpathophysiological change, meanwhile which become the challenge ofcardiovascular surgery. In2003,with the concept of IpostC Ischemiapostconditioning has been proposing, making the cardioprotection of IpostC and therelated mechanism to be a research hotspot. CGRP calcitonin gene-related peptide and SP substance P are important neuropeptides of the sensory nerve fibers, whichinvolving in the regulation of the life activities. The existing research shows thatCGRP and SP involved in the regulation of the cardiovascular system, little is knownabout the role of them on the the regulatory effects and the mechanism of IpostC. Sowe established the current study to investigate whether the sensory nerve and itsneurotransmitters (CGRP and SP) are involved in the protective effect of IpostCwhich further explore the neurogenic mechanism of IpostC in rats.
Object we established the current study to determine:
1. whether ischemic-postconditioning applied at the beginning of reperfusion couldup-regulated the expression of CGRP and SP;
2. To evaluate whether endogenous CGRP and SP are involved in the cardioprotectionof ischemic-postconditioning, including cardiac hemodynamics, ventriculararrhythmias and myocardial infarct size after reperfusion, which further explore theneurogenic mechanism of the organ injury in rats.
Method: Making the model of acute myocardial ischemia-reperfusion andischemia-postconditioning with the healthy male SD rats, the experiment has beendivided into four parts:
1. The eluates were processed using ELISA enzyme linked immunosorbent assay for measurement of SP, CGRP concentrations in myocardium and serum at ischemicreperfusion15min and2.5H after IpostC.
2. Observed pretreatment with CGRP_(8-37)(10-6mol L-1,10-7mol L-1), RP6758010~(-5)10~(-6)mol·L~(-1)） or joint application CGRP8-37(10-6mol L-1) and RP67580(10-6mol L-1), the change of myocardial infarct size of reperfusion after IpostC.
3. Observed pretreatment with CGRP_(8-37)(10-6mol L-1,10-7mol L-1), RP6758010~(-5),10~(-6)mol·L~(-1) or joint application CGRP_(8-37)(10-6mol L-1) and RP67580(10-6mol L-1), the change of hemodynamic of reperfusion after IpostC.
4. Observed pretreatment with CGRP_(8-37)(10-6mol L-1,10-7mol L-1), RP6758010-5è10-6mol·L-1or joint application CGRP_(8-37)(10-6mol L-1) and RP67580(10-6mol L-1), the change of ventricular arrhythmia of reperfusion after IpostC.
Result:
1.The change of concentration of CGRP and SP in myocardium and serum at differenttime of ischemic reperfusion after IpostC:
Compared with group IR èthe concentrations of CGRP and SP in myocardiumand serum were significantly up-regulated at ischemic reperfusion15min and2.5Hafter IpostC.
2. The effection of CGRP and SP to myocardial infarct size of reperfusion afterIpostC:
Compared with group IR èthe myocardial infarct size(IS/AAR%) wassignificantly decreased in group IpostC. Compared with group IpostC, pretreatmentwith the different concentration of CGRP_(8-37),RP67580and CGRP_(8-37)+RP67580can significantly enhance AAR/LV%.
3. The effection of CGRP and SP to cardiac hemodynamics of reperfusion afterIpostC:
Compared with group IR èIpostC significantly reduce SAP,DAP and PAP,significantly enhanced HR; compared with group IpostC, pretreatment with CGRP_(8-37)can significantly increased SAP and DAP, prominently reduce HR and PAP;pretreatment with RP67580can significantly increased SAP and DAP, prominentlyreduce HR and PAP; pretreatment with CGRP_(8-37)+RP67580can significantlyenhanced LVSP and DAP, produced lower HR.
4.The effection of CGRP and SP to ventricular arrhythmia of reperfusion after IpostC:
Compared with group IR ècardiac ventricular arrhythmia was significantlydecreased in group IpostC., the duration of arrhythmias was late; compared withgroup IpostC, pretreatment with the different concentration of CGRP_(8-37),RP67580and CGRP_(8-37)+RP67580can significantly increase ventricular arrhythmia, theduration of arrhythmias was bring forward.
Conclusions: Results from the present study indicate that IpostC could increase theexpress of endogenous CGRP and SP, regulate cardiac functions, arrhythmias andmyocardial infarction after Ischemia-reperfusion, endogenous CGRP and SP might beinvolved in the regulation of the effect through their specific receptor.However, theprecise mechanisms involved remain elusive.
引文
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