title: Effects of captopril and omapatrilat on early post-myocardial infarction survival and cardiac hemodynamics in rats: interaction with cardiac cytokine expression.
abstract: The purpose of this study was to evaluate and compare the effects of simultaneous angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP) inhibition by the vasopeptidase inhibitor omapatrilat (10 and 40 mg x kg(-1) x day(-1)) with those of the selective ACE inhibitor captopril (160 mg x kg(-1) x day(-1)) on survival, cardiac hemodynamics, and cytokine mRNA expression in left ventricular (LV) tissues 4 days after myocardial infarction (MI) in rats. The effects of the co-administration of both B1 and B2 kinin receptor antagonists (2.5 mg x kg(-1) x day(-1) each) with and without omapatrilat were also evaluated to assess the role of bradykinin (BK) during this post-MI period. Both omapatrilat and captopril treatments improve early (4 days) post-MI survival when started 4 h post-MI. The use of kinin receptor antagonists had no significant effect on survival in untreated MI rats and omapatrilat-treated MI rats. This improvement in survival with omapatrilat and captopril is accompanied by a reduced LV end-diastolic pressure (LVEDP) and pulmonary congestion. The use of kinin receptor antagonists had little effect on cardiac hemodynamics or morphologic measurements. Acute MI significantly increased the expression of cardiac cytokines (TNF-alpha, TGF-beta1, and IL-10). Captopril significantly attenuated this activation, while omapatrilat had variable effects: sometimes increasing but generally not changing activation depending on the cytokine measured and the dose of omapatrilat used. The co-administration of both kinin receptor antagonists attenuates the increase in expression of cardiac TNF-alpha and TGF-beta1 after omapatrilat treatment. Taken together, these results would suggest that despite very marked differences in the way these drugs modified the expression of cardiac cytokines, both omapatrilat and captopril improved early (4 days) post-MI survival and cardiac function to a similar extent.
authors.affiliation: Faculté de Pharmacie, Université de Montréal, Centre-ville, QC, Canada.
authors.forename: Charles
authors.initials: C
authors.lastname: Blais
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lapointe
authors.forename: Jean-Lucien
authors.initials: JL
authors.lastname: Rouleau
authors.forename: Robert
authors.initials: R
authors.lastname: Clément
authors.forename: Dimcho R
authors.initials: DR
authors.lastname: Bachvarov
authors.forename: Albert
authors.initials: A
authors.lastname: Adam
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D065168:Bradykinin Receptor Antagonists; D002216:Captopril / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis*; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D016753:Interleukin-10 / Q000096:biosynthesis; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013841:Thiazepines / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D016207:Cytokines; D011725:Pyridines; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D013841:Thiazepines; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C106266:omapatrilat; D002216:Captopril