ADENOSINE AND ENDOTHELIN IN MYOCARDIAL REPERFUSION

心肌再灌注中的腺苷和内皮素

• 批准号: 2219767
• 负责人: John J. Murray
• 金额: $ 22.44万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2219767
• 关键词: adenosine; dogs; endothelin; gene expression; heart circulation; heart pharmacology; in situ hybridization; laboratory rabbit; microcirculation; monoclonal antibody; myocardial infarct sizing; myocardial infarction; neutrophil; peptides; platelets; purinergic receptor; reperfusion; vasoconstrictors

Myocardial infarction remains a major cause of morbidity and mortality in the U.S. One important determinant of early and late mortality is the extent of left ventricular dysfunction. Although early reperfusion by either pharmacologic or mechanical means has been conclusively shown to reduce cardiac mortality, less striking beneficial effects on left ventricular function and infarct size reduction have been demonstrated. This finding, in conjunction with the observation that administration of the endogenous nucleoside Adenosine after reperfusion significantly enhances myocardial salvage in experimental models, supports the hypothesis that reperfusion per se may be detrimental to the previously ischemic but viable cardiac tissue ("REPERFUSION INJURY"). Reperfusion is associated with accelerated structural abnormalities in the vasculature resulting in progressive microcirculatory failure ("no- reflow" phenomenon). The etiology of this phenomenon remains unknown but may be produced by both hum oral and mechanical factors. ENDOTHELlN, a potent, long-acting vasoconstrictor peptide, has been shown to be significantly increased in the coronary sinus effluent in the experimental preparation of ischemia/reperfusion. Intravenous ADENOSINE, in a dose which enhances myocardial salvage, prevents this increase in the early reperfusion period. This proposal will attempt to define the role of ENDOTHELIN in the pathogenesis of reperfusion injury and the mechanisms whereby ADENOSINE modulates its release. Initial studies will determine the time course of the increase of ENDOTHELIN with various durations of ischemia. The role of ENDOTHELIN as an important mediator of reperfusion injury will be explored utilizing specific monoclonal ENDOTHELIN antibodies and a specific ENDOTHELIN receptor antagonist in the intact rabbit model. The mechanism whereby ADENOSINE attenuates the release and/or production of ENDOTHELIN will be determined utilizing both,in vivo and in vitro models. In situ hybridization techniques will be employed in both model systems to determine if ADENOSINE alters ENDOTHELIN gene production via activation of extracellular purinergic receptors. The role of activated neutrophils and platelets will be explored in an in vivo canine model of endothelial injury. The effect of ENDOTHELIN on neutrophil-endothelial interactions will be examined utilizing endothelial cell cultures. These studies will provide important information regarding the role of ENDOTHELIN in myocardial reperfusion injury and whether modulation of this peptide accounts for the beneficial effects of ADENOSINE on myocardial reperfusion injury further understanding of the mechanisms of action of ADENOSINE in protecting against reperfusion injury would allow for important advances in the treatment of evolving myocardial infarction.

心肌梗塞仍然是发病和死亡的主要原因 在美国，早期和晚期死亡率的一个重要决定因素是 左心室功能障碍的程度。尽管早期再灌注 药物或机械手段已被最终证明 降低心脏死亡率，对左侧的有益效果不太显着 心室功能和梗塞面积的减少已得到证实。 这一发现与管理的观察相结合 再灌注后内源性核苷腺苷显着升高 增强实验模型中的心肌挽救，支持 假设再灌注本身可能对先前的功能有害 缺血但存活的心脏组织（“再灌注损伤”）。再灌注 与加速结构异常有关 脉管系统导致进行性微循环衰竭（“无- 回流”现象）。这种现象的病因仍然未知，但 嗡嗡声可能是由口腔和机械因素共同产生的。内皮素，a 强效、长效的血管收缩肽，已被证明 冠状窦流出物显着增加 缺血/再灌注的实验准备。静脉注射腺苷， 以增强心肌挽救的剂量，防止这种增加 再灌注早期。该提案将尝试定义 内皮素在再灌注损伤发病机制中的作用及 腺苷调节其释放的机制。初步研究将 用各种方法确定内皮素增加的时间过程 缺血的持续时间。内皮素作为重要介质的作用 将利用特定的单克隆抗体探索再灌注损伤的机制 内皮素抗体和特定的内皮素受体拮抗剂 完整的兔子模型。腺苷减弱的机制 内皮素的释放和/或产生将利用确定 体内和体外模型。原位杂交技术将 在两个模型系统中均采用以确定腺苷是否改变 通过激活细胞外嘌呤能产生内皮素基因 受体。活化的中性粒细胞和血小板的作用是 在犬体内皮损伤模型中进行了探索。的效果 将检查内皮素对中性粒细胞-内皮相互作用的影响 利用内皮细胞培养物。这些研究将提供重要的 有关内皮素在心肌再灌注中的作用的信息 损伤以及该肽的调节是否能产生有益的作用 腺苷对心肌再灌注损伤的进一步影响 了解腺苷的保护作用机制 对抗再灌注损伤将在以下方面取得重要进展 治疗进展型心肌梗塞。

项目成果

Mechanisms and therapy of myocardial reperfusion injury.

心肌再灌注损伤的机制和治疗。

• 发表时间: 1990
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Forman,MB;Virmani,R;Puett,DW
• 通讯作者: Puett,DW

Role of endothelin in a rabbit model of acute myocardial infarction: effects of receptor antagonists.

内皮素在兔急性心肌梗死模型中的作用：受体拮抗剂的作用。

• DOI: 10.1097/00005344-199612000-00007
• 发表时间: 1996
• 期刊: Journal of cardiovascular pharmacology
• 影响因子: 3
• 作者: Vitola,JV;Forman,MB;Holsinger,JP;Kawana,M;Atkinson,JB;Quertermous,T;Jackson,EK;Murray,JJ
• 通讯作者: Murray,JJ

Reduction of myocardial infarct size in rabbits and inhibition of activation of rabbit and human neutrophils by lidocaine.

利多卡因减少兔心肌梗塞面积并抑制兔和人中性粒细胞的活化。

• DOI: 10.1016/s0002-8703(97)70226-6
• 发表时间: 1997
• 期刊: American heart journal
• 影响因子: 4.8
• 作者: Vitola,JV;Forman,MB;Holsinger,JP;Atkinson,JB;Murray,JJ
• 通讯作者: Murray,JJ