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Apstatin, a selective inhibitor of aminopeptidase P, reduces myocardial infarct size by a kinin‐dependent pathway
Author(s) -
Wolfrum S,
Richardt G,
Dominiak P,
Katus H A,
Dendorfer A
Publication year - 2001
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704236
Subject(s) - bradykinin , kinin , ace inhibitor , ramipril , cardioprotection , pharmacology , angiotensin converting enzyme , chemistry , bradykinin receptor , enzyme inhibitor , pentobarbital , medicine , ischemia , endocrinology , enzyme , receptor , biochemistry , blood pressure
Inhibitors of the angiotensin converting enzyme (ACE) have been shown to exert their cardioprotective actions through a kinin‐dependent mechanism. ACE is not the only kinin degrading enzyme in the rat heart. Since aminopeptidase P (APP) has been shown to participate in myocardial kinin metabolism to the same extent as ACE, the aims of the present study were to investigate whether (a) inhibition of APP leads to a reduction of myocardial infarct size in a rat model of acute ischaemia and reperfusion, (b) reduction of infarct size is mediated by bradykinin, and (c) a combination of APP and ACE inhibition leads to a more pronounced effect than APP inhibition alone. Pentobarbital‐anaesthetized rats were subjected to 30 min left coronary artery occlusion followed by 3 h reperfusion. The APP inhibitor apstatin, the ACE‐inhibitor ramiprilat, or their combination were administered 5 min before ischaemia. Rats receiving HOE140, a specific B 2 receptor antagonist, were pretreated 5 min prior to enzyme inhibitors. Myocardial infarct size (IS) was determined by tetrazolium staining and expressed as percentage of the area at risk (AAR). IS/AAR% was significantly reduced in rats that received apstatin (18±2%), ramiprilat (18±3%), or apstatin plus ramiprilat (20±4%) as compared with those receiving saline (40±2%), HOE (43±3%) or apstatin plus HOE140 (49±4%). Apstatin reduces IS in an in vivo model of acute myocardial ischaemia and reperfusion to the same extent than ramiprilat. Cardioprotection achieved by this selective inhibitor of APP is mediated by bradykinin. Combined inhibition of APP and ACE did not result in a more pronounced reduction of IS than APP‐inhibition alone.British Journal of Pharmacology (2001) 134 , 370–374; doi: 10.1038/sj.bjp.0704236