Tissue kallikrein is involved in the cardioprotective effect of AT1-receptor blockade in acute myocardial ischemia
Tissue kallikrein is involved in the cardioprotective effect of AT1-receptor blockade in acute myocardial ischemia
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DOI：
10.1124/jpet.107.124859
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发表时间：
2007-10-01
影响因子：
3.5
通讯作者：
Richer, Christine
中科院分区：
文献类型：
--
作者：
Messadi-Laribi, Erij;Griol-Charhbili, Violaine;Richer, Christine
血管紧张素转换酶抑制剂可限制心肌缺血再灌注损伤动物模型中的梗死面积。该效应已被证明是由于抑制缓激肽降解而不是抑制血管紧张素 II 形成。本研究的目的是确定氯沙坦或其活性代谢物 EXP3174 阻断血管紧张素 AT1 受体是否可以保护小鼠免受心肌缺血再灌注损伤，以及这种保护是否由激肽释放酶激肽系统介导。我们对麻醉小鼠进行 30 分钟的冠状动脉闭塞，然后再灌注 3 小时，并在再灌注后立即评估梗塞面积。开始再灌注前 5 分钟给予洛沙坦 (Los) 或 EXP3174 [2-正丁基-4-氯-1-[(2'-(1H-四唑-5基)联苯-4-基)甲基]咪唑-5-羧酸]，剂量由血压效应和血管紧张素升压反应抑制的初步研究确定。与生理盐水相比，两种药物均能显着减少心肌梗塞面积约 40%（P < 0.001）。用选择性 AT2 受体拮抗剂 PD123,319 [S-(+)-1-([4-(二甲氨基)-3-甲基苯基]甲基)-5-(二苯乙酰基)-4,5,6,7四氢-1H-咪唑(4,5-c)吡啶-6-羧酸]预处理小鼠，在没有氯沙坦的情况下不影响梗塞面积，但消除了氯沙坦所提供的梗塞面积的减小。在组织激肽释放酶基因缺陷小鼠（TK-/-）中，氯沙坦不再减少梗塞面积。用 B 2 受体拮抗剂艾替班特预处理野生型小鼠，重现了 TK 缺乏的影响。我们得出结论，AT1 受体阻断通过刺激 AT2 受体提供针对心肌缺血再灌注损伤的心脏保护作用。激肽释放酶和B 2 受体是氯沙坦心脏保护作用的主要决定因素。我们的结果支持了 AT1 受体阻断期间 AT2 受体和激肽释放酶之间存在偶联的假设，这在心脏保护中发挥着重要作用。
Angiotensin-converting enzyme inhibitors limit infarct size in animal models of myocardial ischemia reperfusion injury. This effect has been shown to be due to inhibition of bradykinin degradation rather than inhibition of angiotensin II formation. The purpose of this study was to determine whether angiotensin AT1 receptor blockade by losartan or its active metabolite EXP3174 protects against myocardial ischemia-reperfusion injury in mice and whether this protection is mediated by the kallikrein kinin system. We subjected anesthetized mice to 30 min of coronary artery occlusion followed by 3 h of reperfusion and evaluated infarct size immediately after reperfusion. Losartan ( Los) or EXP3174 [ 2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid] were administered 5 min before starting reperfusion at dosages determined by preliminary studies of blood pressure effect and inhibition of angiotensin pressor response. Compared with saline, both drugs significantly reduced myocardial infarct size roughly 40% ( P < 0.001). Pretreatment of mice with the selective AT2 receptor antagonist PD123,319 [S-(+)-1-([4-(dimethylamino)-3-methylphenyl] methyl)-5-(diphenylacetyl)-4,5,6,7tetrahydro- 1H-imidazo(4,5-c) pyridine-6-carboxylic acid] did not affect infarct size in the absence of losartan but abolished the reduction in infarct size provided by losartan. In tissue kallikrein gene-deficient mice (TK-/-), losartan no longer reduced infarct size. Pretreatment of wild-type mice with the B 2 receptor antagonist icatibant reproduced the effect of TK deficiency. We conclude that AT1 receptor blockade provides cardioprotection against myocardial ischemia-reperfusion injury through stimulation of AT2 receptors. Kallikrein and B 2 receptor are major determinants of this cardioprotective effect of losartan. Our results support the hypothesis of a coupling between AT2 receptors and kallikrein during AT1 receptor blockade, which plays a major role in cardioprotection.