Messadi-Laribi Erij, Griol-Charhbili Violaine, Pizard Anne, Vincent Marie-Pascale, Heudes Didier, Meneton Pierre, Alhenc-Gelas François, Richer Christine
INSERM U652/872, 15 rue de l'Ecole de Médecine, 75270 Paris, France.
J Pharmacol Exp Ther. 2007 Oct;323(1):210-6. doi: 10.1124/jpet.107.124859. Epub 2007 Jul 16.
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-5-yl)biphenyl-4-yI)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 by 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)-4,5,6,7-tetrahydro-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 B2 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 B2 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.
血管紧张素转换酶抑制剂在心肌缺血再灌注损伤的动物模型中可限制梗死面积。已表明这种作用是由于抑制缓激肽降解而非抑制血管紧张素II的形成。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受体是否能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。我们对麻醉的小鼠进行30分钟冠状动脉闭塞，随后再灌注3小时，并在再灌注后立即评估梗死面积。在开始再灌注前5分钟给予氯沙坦（Los）或EXP3174 [2-正丁基-4-氯-1-[(2'-(1H-四氮唑-5-基)联苯-4-基)甲基]咪唑-5-羧酸]，剂量根据血压效应和抑制血管紧张素升压反应的初步研究确定。与生理盐水相比，两种药物均使心肌梗死面积显著减少约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-咪唑并(4,5-c)吡啶-6-羧酸]预处理小鼠，在无氯沙坦时不影响梗死面积，但消除了氯沙坦提供的梗死面积减少作用。在组织激肽释放酶基因缺陷小鼠（TK-/-）中，氯沙坦不再减少梗死面积。用B2受体拮抗剂艾替班特预处理野生型小鼠再现了TK缺陷的效应。我们得出结论，阻断AT1受体通过刺激AT2受体提供对心肌缺血再灌注损伤的心脏保护作用。激肽释放酶和B2受体是氯沙坦这种心脏保护作用的主要决定因素。我们的结果支持在阻断AT1受体期间AT2受体与激肽释放酶之间存在偶联的假说，这在心脏保护中起主要作用。
