title: Chymase inhibition improves vascular dysfunction and survival in stroke-prone spontaneously hypertensive rats.
abstract: OBJECTIVE
  To clarify the role of chymase in hypertension, we evaluated the effect of a chymase inhibitor, TY-51469, on vascular dysfunction and survival in stroke-prone spontaneously hypertensive rats (SHR-SP).
  
  
  METHODS
  SHR-SP were treated with TY-51469 (1 mg/kg per day) or placebo from 4 to 12 weeks old or until death. Wistar-Kyoto rats were used as a normal group.
  
  
  RESULTS
  SBP was significantly higher in both the placebo and TY-51469 groups than in the normal group, but there was no significant difference between the two treatment groups. Plasma renin, angiotensin-converting enzyme activity and angiotensin II levels were not different between the placebo and TY-51469 groups. In contrast, vascular chymase-like activity was significantly higher in the placebo than in the normal group, but it was reduced by TY-51469. Acetylcholine-induced vascular relaxation was significantly higher in the TY-51469 group than in the placebo group. There was significant augmentation of the number of monocytes/macrophages and matrix metalloproteinase-9 activity in aortic tissue from the placebo group compared with the normal group, and these changes were attenuated by TY-51469. There were also significant increases in mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-α in the placebo group that were attenuated by TY-51469. Cumulative survival was significantly prolonged in the TY-51469 group compared with the placebo group.
  
  
  CONCLUSIONS
  Chymase might play an important role in vascular dysfunction via augmentation both of matrix metalloproteinase-9 activity and monocyte/macrophage accumulation in SHR-SP, and its inhibition may be useful for preventing vascular remodeling and prolonging survival.
authors.affiliation: aDepartment of Pharmacology, Osaka Medical College, Osaka, Japan bDepartment of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai, China cLaboratory of Host Defenses, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Hyogo dHirakata Ryoikuen, Osaka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.forename: Denan
authors.initials: D
authors.lastname: Jin
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Yamanishi
authors.forename: Mizuo
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Hideaki
authors.initials: H
authors.lastname: Higashino
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Yamanishi
authors.forename: Haruki
authors.initials: H
authors.lastname: Okamura
mesh_terms: D000818:Animals; D001835:Body Weight; D053818:Chymases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D006973:Hypertension / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D012083:Renin / Q000097:blood; D020521:Stroke / Q000209:etiology*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D013599:Systole / Q000187:drug effects / Q000502:physiology; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D012333:RNA, Messenger; D013449:Sulfonamides; C524344:TY 51469; D013876:Thiophenes; D053818:Chymases; D012083:Renin; D020780:Matrix Metalloproteinase 9