缺血再灌注人体模型中的最佳心肌预处理

Optimal myocardial preconditioning in a human model of ischemia and reperfusion.

作者信息

Cohen G, Shirai T, Weisel R D, Rao V, Merante F, Tumiati L C, Mohabeer M K, Borger M A, Li R K, Mickle D A

机构信息

Division of Cardiovascular Surgery, Toronto Hospital, Ontario, Canada.

出版信息

Circulation. 1998 Nov 10;98(19 Suppl):II184-94; discussion II194-6.

PMID:9852902

Abstract

BACKGROUND

Adenosine (ADE) may mediate the protective effects of preconditioning (PC). However, human data are lacking, and the optimal method of ADE administration and the mechanism of protection remain unresolved.

METHODS AND RESULTS

We have developed a model of simulated "ischemia" (I) and "reperfusion" (R) in quiescent human ventricular cardiomyocytes. Cellular injury and metabolic parameters were assessed after various interventions: Cells were preconditioned with anoxia (PC0), hypoxia (PC16), anoxic supernatant (SUP0), or hypoxic supernatant (SUP16) with or without the ADE receptor antagonist (SPT) or ADE deaminase (ADA). ADE was applied before, during, or after I or continuously with and without SPT. Cells were treated with the PKC agonist PMA. PC cells were incubated with the protein kinase-C (PKC) antagonist Calphostin-C (Cal-C). PKC translocation and PKC activity were assessed. PC0 was most protective. Protection was transferable via SUP0, which produced the highest concentrations of ADE. Protection was lost with SPT or ADA. Intracellular ATP fell after PC and prolonged I and R. Exogenous ADE was most protective when administered before I at 50 mumol. ADE during I was partially protective. No additional protection was provided with continuous ADE treatment. ADE prevented ATP degradation but increased lactate immediately after its administration. SPT abolished the protective effects of ADE. PMA conferred protection, which was abolished with Cal-C. ADE stimulated PKC translocation and PKC activity in the absence of SPT.

CONCLUSIONS

Maximal I confers maximal PC. The degree of I is reflected in supernatant ADE concentrations. The initial ATP fall with PC may account for a lack of ATP preservation after I and R. ADE reproduces the protective effects of PC, preserves ATP, and increases lactate production, perhaps by stimulating glycolysis. Clinical trials of ADE administered during cardiac surgery are necessary to further define its beneficial effects in humans.

摘要

背景

腺苷（ADE）可能介导预处理（PC）的保护作用。然而，缺乏人体数据，且ADE给药的最佳方法和保护机制仍未解决。

方法与结果

我们建立了静止的人心室心肌细胞模拟“缺血”（I）和“再灌注”（R）模型。在各种干预后评估细胞损伤和代谢参数：细胞用缺氧（PC0）、低氧（PC16）、缺氧上清液（SUP0）或低氧上清液（SUP16）进行预处理，同时使用或不使用ADE受体拮抗剂（SPT）或腺苷脱氨酶（ADA）。在I之前、期间或之后应用ADE，或在有或没有SPT的情况下持续应用。用蛋白激酶C（PKC）激动剂佛波酯（PMA）处理细胞。PC细胞与蛋白激酶C（PKC）拮抗剂Calphostin-C（Cal-C）一起孵育。评估PKC易位和PKC活性。PC0的保护作用最强。保护作用可通过产生最高浓度ADE的SUP0传递。使用SPT或ADA后保护作用消失。PC后以及延长的I和R期间细胞内ATP下降。在I之前以50μmol给药时，外源性ADE的保护作用最强。I期间的ADE具有部分保护作用。持续给予ADE没有额外的保护作用。ADE可防止ATP降解，但给药后立即增加乳酸。SPT消除了ADE的保护作用。PMA赋予保护作用，而Cal-C可消除这种作用。在没有SPT的情况下，ADE刺激PKC易位和PKC活性。