title: Role of kinins in chronic heart failure and in the therapeutic effect of ACE inhibitors in kininogen-deficient rats.
abstract: Using Brown Norway Katholiek (BNK) rats, which are deficient in kininogen (kinin precursor) due to a mutation in the kininogen gene, we examined the role of endogenous kinins in 1) normal cardiac function; 2) myocardial infarction (MI) caused by coronary artery ligation; 3) cardiac remodeling in the development of heart failure (HF) after MI; and 4) the cardioprotective effect of angiotensin-converting enzyme inhibitors (ACEI) on HF after MI. Two months after MI, rats were randomly treated with vehicle or the ACEI ramipril for 2 mo. Brown Norway rats (BN), which have normal kininogen, were used as controls. Left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV), end-diastolic pressure (EDP), and ejection fraction (EF) as well as myocardial infarct size (IS), interstitial collagen fraction (ICF), cardiomyocyte cross-sectional area (MCA), and oxygen diffusion distance (ODD) were measured. We found that 1) cardiac hemodynamics, function, and histology were the same in sham-ligated BN and BNK rats; 2) IS was similar in BN and BNK; 3) in rats with HF treated with vehicle, the decrease in LVEF and the increase in LVEDV, LVESV, LVEDP, ICF, MCA, and ODD did not differ between BNK and BN; and 4) ACEI increased EF, decreased LVEDV and LVESV, and improved cardiac remodeling in BN-HF rats, and these effects were partially blocked by the bradykinin B(2) receptor antagonist icatibant (HOE-140). In BNK-HF rats, ACEI failed to produce these beneficial cardiac effects. We concluded that in rats, lack of kinins does not influence regulation of normal cardiac function, myocardial infarct size, or development of HF; however, kinins appear to play an important role in the cardioprotective effect of ACEI, since 1) this effect was significantly diminished in kininogen-deficient rats and 2) it was blocked by a B(2) kinin receptor antagonist in BN rats.
authors.affiliation: Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan 48202-2689, USA.
authors.forename: Y H
authors.initials: YH
authors.lastname: Liu
authors.forename: X P
authors.initials: XP
authors.lastname: Yang
authors.forename: D
authors.initials: D
authors.lastname: Mehta
authors.forename: M
authors.initials: M
authors.lastname: Bulagannawar
authors.forename: G M
authors.initials: GM
authors.lastname: Scicli
authors.forename: O A
authors.initials: OA
authors.lastname: Carretero
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002303:Cardiac Output, Low / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D002908:Chronic Disease; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007704:Kininogens / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D007705:Kinins / Q000502:physiology*; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011914:Rats, Inbred BN / Q000235:genetics
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007704:Kininogens; D007705:Kinins