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.

心肌梗死仍然是发病率和死亡率的主要原因

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