ADENOSINE AND ENDOTHELIN IN MYOCARDIAL REPERFUSION

心肌梗死仍然是发病率和死亡率的主要原因。 在美国，早期和晚期死亡率的一个重要决定因素是 左心功能不全的程度。虽然早期再灌流通过 无论是药物手段还是机械手段都已被确凿地证明 降低心脏死亡率，对左侧的有益影响不那么显著 已经证实了心功能和梗塞面积的缩小。 这一发现，连同观察到的政府 再灌流后内源性核苷腺苷显著升高 增强实验模型中的心肌挽救，支持 假设再灌流本身可能对之前的 缺血但存活的心脏组织(“再灌注损伤”)。再灌流 与地球内部加速的结构异常有关 导致进行性微循环衰竭的血管系统(“NO- 回流现象)。这一现象的原因尚不清楚，但 可能是由嗡嗡声和机械因素造成的。Endothellln，a 强效、长效的血管收缩肽，已被证明是 冠状静脉窦流出物显著增加 缺血/再灌注的实验制备。静脉注射腺苷， 在增加心肌挽救的剂量中，防止这种增加 再灌注期早期。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 腺苷调节其释放的机制。初步研究将 用不同的方法测定内皮素升高的时间进程 缺血持续时间。内皮素作为一种重要的介质的作用 将利用特定的单抗来探索再灌注损伤的机制 内皮素抗体及其受体拮抗剂的研究进展 完整的兔子模型。腺苷减弱血管紧张素转换酶的机制 内皮素的释放和/或产生将通过 无论是体内模型还是体外模型。原位杂交技术将 在两个模型系统中用于确定腺苷是否改变 胞外嘌呤能激活产生内皮素基因 感受器。激活的中性粒细胞和血小板的作用将是 在活体犬内皮损伤模型中进行了探索。的影响 将研究内皮素对中性粒细胞-内皮细胞相互作用的影响。 利用内皮细胞培养。这些研究将提供重要的 内皮素在心肌再灌注中作用的研究进展 损伤以及这种多肽的调节是否有益于 腺苷对心肌再灌注损伤的进一步作用 对腺苷保护作用机制的认识 抗再灌流损伤将允许重要的进展 进展性心肌梗死的治疗。

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.