title: Effects of bradykinin on cardiovascular remodeling in renovascular hypertensive rats.
abstract: Angiotensin converting enzyme (ACE) inhibitors inhibit both the formation of angiotensin II and the catabolism of bradykinin (BK). They prevent not only hypertension but also cardiac hypertrophy and fibrosis. An increase in BK level stimulates the expression of nitric oxide (NO) synthase (NOS) and induces prostaglandins, both of which are powerful vasodilator factors. The direct effect of BK against cardiac hypertrophy is still unclear. This study was performed to examine the cardioprotective effects of BK in hypertrophic models. Renovascular hypertensive (RHT) rats were treated with BK (1,000 ng/kg/day), BK+D-arginyl-[Hyp(3), Thi(5), D-Tic(7), Oic(8)]-bradykinin (HOE140) (a BK B(2) receptor antagonist), and BK+N(omega)-nitro-L-arginine methyl ester (L-NAME) (a NOS inhibitor) for 3 weeks. Blood pressure was measured and echocardiographic analysis performed during the treatment. Histological data were analyzed to confirm the hypotrophic effect of BK. Treatment with BK improved cardiac remodeling, reducing both the heart weight/body weight ratio and the left ventricular wall thickness. However, co-treatment with HOE140 or L-NAME reversed the anti-hypertrophic action of BK. In particular, cardiac fibrosis or perivascular fibrosis, along with collagen accumulation, were inhibited by treatment with BK, while HOE140 and L-NAME counteracted these changes. In addition, expressions of atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP), which are markers of cardiac abnormalities, were down-regulated by treatment with BK. These effects were reversed by co-treatment with HOE140 and L-NAME. Together, these results indicate that BK directly inhibits the progression of cardiac hypertrophy and cardiac fibrosis due to NO release via the BK B(2) receptor. The BK-NO pathway may play an important role in the progression of cardiac remodeling.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Makoto
authors.initials: M
authors.lastname: Nagai
authors.forename: Taro
authors.initials: T
authors.lastname: Date
authors.forename: Takuya
authors.initials: T
authors.lastname: Okada
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Abe
authors.forename: Shingo
authors.initials: S
authors.lastname: Seki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Ikuo
authors.initials: I
authors.lastname: Taniguchi
authors.forename: Seibu
authors.initials: S
authors.lastname: Mochizuki
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003326:Coronary Circulation; D004452:Echocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D006977:Hypertension, Renal / Q000150:complications / Q000188:drug therapy*; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009206:Myocardium / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000319:Adrenergic beta-Antagonists; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D020097:Natriuretic Peptide, Brain; C065679:icatibant; D009320:Atrial Natriuretic Factor; D019001:Nitric Oxide Synthase; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester