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. ACE 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 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. 3. 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). 4. 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%). 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 inhibition of APP and ACE did not result in a more pronounced reduction of IS than APP-inhibition alone.
Wolfrum
S
S
Medical Clinic II, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. wolfrum@medinf.mu-luebeck.de
Richardt
G
G
Dominiak
P
P
Katus
H A
HA
Dendorfer
A
A
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007705:Kinins / Q000502:physiology*; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D010455:Peptides / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D017257:Ramipril / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043782:Receptor, Bradykinin B2
D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D007705:Kinins; D010455:Peptides; D011480:Protease Inhibitors; D043782:Receptor, Bradykinin B2; C052549:ramiprilat; C065679:icatibant; D000626:Aminopeptidases; C022750:X-Pro aminopeptidase; C097277:apstatin; D017257:Ramipril; D001920:Bradykinin