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CARDIOVASCULAR

Tissue Kallikrein Is Involved in the Cardioprotective Effect of AT1-Receptor Blockade in Acute Myocardial Ischemia

INSERM U652/U872, Paris, France (E.M.-L., V.G.-C., A.P., M.-P.V., D.H., P.M., F.A.-G., C.R.); Université Paris-Sud, Le Kremlin-Bicêtre, France (E.M.-L., V.G.-C., C.R.); and Université de Paris-Descartes, Paris, France (D.H., P.M., F.A.-G.)

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.

Address correspondence to: Dr. Christine Richer-Giudicelli, INSERM U652/872, 15 rue de l'Ecole de Médecine, 75270 Paris, France. E-mail: christine.richer-giudicelli{at}u-psud.fr