title: Angiotensin II-induced myocardial fibrosis in rats: role of nitric oxide, prostaglandins and bradykinin.
abstract: OBJECTIVE
  Chronic elevations in plasma angiotensin II (AngII) are associated with an efflux of plasma macromolecules into the perivascular and contiguous interstitial space. This is followed by the appearance of macrophages and type I collagen-producing, fibroblast-like cells that precede the accumulation of fibrous tissue at these sites. Whether this perivascular and interstitial fibrosis is a direct effect of AngII on collagen turnover of these cells or an indirect response mediated by nitric oxide, prostaglandins and/or bradykinin released in response to AngII, is uncertain.
  
  
  METHODS
  We measured perivascular and interstitial fibrosis (picrosirius-stained tissue) in response to 14-day infusion of AngII (150 ng/kg/min, s.c.) in male Sprague-Dawley rats. Treated animals were compared to untreated controls and to groups receiving AngII together with either an NO-synthase inhibitor [NG-nitro-L-arginine methyl ester (L-NAME) 10 mg/kg/day in drinking water], a cyclo-oxygenase inhibitor (indomethacin, 2 mg/kg/day in drinking water), or a bradykinin B2 receptor antagonist (Hoe140, 115 ng/kg/min, s.c.).
  
  
  RESULTS
  When left and right ventricles of treated rats were compared to untreated controls, AngII led to a respective 68 and 48% increase in perivascular collagen volume fraction (PCVF) and a 54 and 22% increase in interstitial collagen volume fraction (ICVF). Co-administration of AngII + L-NAME did not attenuate either PCVF or ICVF while indomethacin significantly attenuated PCVF by 37 and 33% of left and right ventricle, respectively, but did not alter ICVF in either ventricle when compared to AngII-treated animals. Co-administration of AngII + Hoe140 completely prevented perivascular and interstitial collagen accumulation with the extent of perivascular fibrosis comparable to untreated controls.
  
  
  CONCLUSIONS
  The perivascular and interstitial fibrosis of the rat right and left ventricles seen in association with the exogenous administration of AngII is mediated by the release of bradykinin and prostaglandins, and therefore is an indirect response to elevated circulating AngII.
authors.affiliation: Department of Internal Medicine, University of Missouri Health Sciences Center, Columbia 65212, USA.
authors.forename: H H
authors.initials: HH
authors.lastname: Sigusch
authors.forename: S E
authors.initials: SE
authors.lastname: Campbell
authors.forename: K T
authors.initials: KT
authors.lastname: Weber
mesh_terms: D000804:Angiotensin II / Q000097:blood* / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D065168:Bradykinin Receptor Antagonists; D003094:Collagen / Q000032:analysis; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011453:Prostaglandins / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D065168:Bradykinin Receptor Antagonists; D016861:Cyclooxygenase Inhibitors; D011453:Prostaglandins; D000804:Angiotensin II; D009569:Nitric Oxide; C065679:icatibant; D003094:Collagen; D001120:Arginine; D019001:Nitric Oxide Synthase; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin