Apstatin, a selective inhibitor of aminopeptidase P, reduces myocardial infarct size by a kinin-dependent pathway

1 Inhibitors of the angiotensin converting enzyme (ACE) have been shown to exert their cardioprotective actions through a kinin-dependent mechanism. A CE is not the only kinin degrading enzyme in the rat heart. 2 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 w ere to investigate whether (a) inhibition of APP leads to a reduction of my ocardial infarct size in a rat model of acute ischaemia and reperfusion, (b ) reduction of infarct size is mediated by bradykinin, and (c) a combinatio n of APP and ACE inhibition leads to a more pronounced effect than APP inhi bition alone. 3 Pentobarbital-anaesthetized rats were subjected to 30 min left coronary a rtery occlusion followed by 3 h reperfusion. The APP inhibitor apstatin, th e ACE-inhibitor ramiprilat, or their combination were administered 5 min be fore 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 t he area at risk (AAR). 4 IS/AAR% was significantly reduced in rats that received apstatin (18 +/- 2%), ramiprilat (18 +/- 3%), or apstatin plus ramiprilat (20 +/- 4%) as com pared with those receiving saline (40 +/- 2%), HOE (43 +/- 3%) or apstatin plus HOE140 (49 +/- 4%). 5 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 inhi bition of APP and ACE did not result in a more pronounced reduction of IS t han APP-inhibition alone.