Wang P, Downey J M, Cohen M V
Department of Physiology, University of South Alabama College of Medicine, Mobile 36688, USA.
Basic Res Cardiol. 1996 Nov-Dec;91(6):458-67. doi: 10.1007/BF00788727.
Preconditioning the heart with a short period of ischemia makes it resistant to infarction from a subsequent ischemic insult. We have proposed that preconditioning is triggered by the release of endogenous substances including adenosine which activate protein kinase C through receptormediated cell signaling pathways. However, it has also been proposed that the initial brief ischemia may result in mast cell degranulation without significant myocardial damage, making it less likely that the toxic granule contents could be released to irreversibly damage vulnerable myocardial cells during the subsequent prolonged ischemia. To study the role of mast cells in ischemic preconditioning (PC) isolated rabbit hearts were subjected to 30 min of regional ischemia followed by 120 min of reperfusion. Infarct size was measured with triphenyltetrazolium chloride. In control hearts infarction was 31.9 +/- 2.6% of the risk zone. Preconditioning with 5 min of global ischemia and 10 min of reperfusion reduced infarct size to 5.6 +/- 6.1% (p < 0.01). When disodium cromoglycate (DSCG)(10 microM), a mast cell stabilizer, was infused shortly before the long ischemia it did protect the heart (12.8 +/- 2.9% infarction, p < 0.01 vs control) which supports the mast cell theory. However, a mast cell degranulating agent, compound 48/80 (24 mg/L), added to the perfusate prior to the 30 min ischemic period could not mimic PC (39.7 +/- 5.6% infarction). Mast cell granules are rich in histamine, and the latter was assayed in myocardium by immunoassay as a marker of intact granules. In homogenized left ventricle from normal rabbit hearts and those following a standard PC protocol of 5-min global ischemia/10-min reperfusion, histamine contents were 9.3 +/- 1.4 and 8.9 +/- 1.4 ng/g wet tissue, respectively. Compound 48/80 reduced histamine levels to 2.9 +/- 0.6 ng/g (p < 0.05 vs control). Although baseline histamine contents were 10-fold higher in rats, PC also had no effect, but compound 48/80 reduced content by 91%. Therefore, histamine tissue content and presumably mast cell granules were unaffected by a PC protocol which successfully protected ischemic myocardium, while pharmacological myocardial histamine depletion was not associated with protection. Hence, mast cells do not appear to be important in ischemic preconditioning. Although a mast cell stabilizer such as DSCG can protect ischemic myocardium, it may do so by one of its other properties, e.g., membrane stabilization.
用短时间缺血预处理心脏可使其对随后的缺血性损伤产生梗死抵抗。我们曾提出，预处理是由内源性物质的释放所触发，这些物质包括通过受体介导的细胞信号通路激活蛋白激酶C的腺苷。然而，也有人提出，最初的短暂缺血可能导致肥大细胞脱颗粒而无明显心肌损伤，因此在随后的长时间缺血期间，毒性颗粒内容物不太可能释放出来对易损心肌细胞造成不可逆损伤。为了研究肥大细胞在缺血预处理（PC）中的作用，对离体兔心脏进行30分钟的局部缺血，随后再灌注120分钟。用氯化三苯基四氮唑测定梗死面积。在对照心脏中，梗死面积占危险区的31.9±2.6%。用5分钟全心缺血和10分钟再灌注进行预处理可使梗死面积降至5.6±6.1%（p<0.01）。当在长时间缺血前不久注入肥大细胞稳定剂色甘酸钠二钠（DSCG）（10μM）时，它确实对心脏起到了保护作用（梗死面积为12.8±2.9%，与对照组相比p<0.01），这支持了肥大细胞理论。然而，在30分钟缺血期之前加入灌注液中的肥大细胞脱颗粒剂化合物48/80（24mg/L）并不能模拟预处理（梗死面积为39.7±5.6%）。肥大细胞颗粒富含组胺，通过免疫测定法测定心肌中的组胺作为完整颗粒的标志物。在正常兔心脏以及按照5分钟全心缺血/10分钟再灌注的标准预处理方案处理后的兔心脏的左心室匀浆中，组胺含量分别为9.3±1.4和8.9±1.4ng/g湿组织。化合物48/80将组胺水平降至2.9±0.6ng/g（与对照组相比p<0.05）。虽然大鼠的基线组胺含量高10倍，但预处理也没有效果，但化合物48/80使含量降低了91%。因此，成功保护缺血心肌的预处理方案并未影响组胺组织含量以及推测的肥大细胞颗粒，而药理学上使心肌组胺耗竭与保护作用无关。因此，肥大细胞在缺血预处理中似乎并不重要。虽然像DSCG这样的肥大细胞稳定剂可以保护缺血心肌，但它可能是通过其其他特性之一，如膜稳定作用来实现的。
