title: Omapatrilat limits infarct size and lowers the threshold for induction of myocardial preconditioning through a bradykinin receptor-mediated mechanism.
abstract: Bradykinin is an important endogenous trigger of myocardial ischemic preconditioning (IPC). Through simultaneous inhibition of neutral endopeptidase and angiotensin converting enzyme, omapatrilat prevents enzymatic degradation of bradykinin. The aim of this study was to investigate if omapatrilat, through its ability to augment bradykinin levels, can augment a subthreshold IPC stimulus (Sub-IPC) and to compare the action of omapatrilat with the angiotensin-converting enzyme inhibitor, captopril. Langendorff perfused rat hearts were subjected to 35 min left coronary artery occlusion and 120 min reperfusion. Full IPC was induced with 5 min global ischemia/10 min reperfusion and substantially limited infarct size (21.5 +/- 3.5% of risk zone vs 53.4 +/- 2.0% in controls, P < 0.01). Sub-IPC (2 min global ischemia/10 min reperfusion) did not limit infarct size (48.4 +/- 3.8%). Omapatrilat (10 micromol/L) or captopril (200 micromol/L) were administered alone or in conjunction with Sub-IPC. Reduced infarct size comparable to that observed with the full IPC protocol was seen when sub-IPC was combined with either omapatrilat (19.7 +/- 2.5%) or captopril (20.3 +/- 4.9%). Omapatrilat alone caused modest reduction of infarct size (34.6 +/- 1.5%, P < 0.01 v control), an effect not observed with captopril. Hoe140, a selective kinin B(2) receptor antagonist, eliminated the cardioprotective effect of omaptrilat alone or in combination with sub-IPC. We conclude that omapatrilat elicits cardioprotection via inhibition of bradykinin degradation and that dual inhibition of angiotensin-converting enzyme and neutral endopeptidase may have beneficial effects beyond standard angiotensin-converting enzyme inhibitor therapy in patients with acute coronary syndromes who are at risk of myocardial infarction.
authors.affiliation: The Hatter Institute, UCL Hospitals and Medical School, London, UK.
authors.forename: Z
authors.initials: Z
authors.lastname: Ebrahim
authors.forename: G F
authors.initials: GF
authors.lastname: Baxter
authors.forename: D M
authors.initials: DM
authors.lastname: Yellon
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002216:Captopril / Q000627:therapeutic use; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D009929:Organ Size / Q000187:drug effects; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018002:Receptors, Bradykinin / Q000187:drug effects*; D013841:Thiazepines / Q000627:therapeutic use*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D011725:Pyridines; D018002:Receptors, Bradykinin; D013841:Thiazepines; C106266:omapatrilat; D002216:Captopril