title: Cardioprotective effect of a combination of Rho-kinase inhibitor and p38 MAPK inhibitor on cardiovascular remodeling and oxidative stress in Dahl rats.
abstract: OBJECTIVE
  Rho-kinase plays a critical role in various cellular functions. p38 mitogen-activated protein kinase (p38 MAPK) plays a central role in the inflammatory cytokine response to immune challenge. We evaluated the effects of a combination of fasudil, a Rho-kinase inhibitor, and FR167653, a p38 MAPK inhibitor, on cardiovascular remodeling, inflammation, and oxidative stress in Dahl salt-sensitive hypertensive (DS) rats.
  
  
  METHODS
  DS and Dahl salt-resistant (DR) rats were fed a high-salt diet at 6 weeks of age. Vehicle, fasudil (100 mg/kg per day), FR167653 (2 mg/kg per day), and a combination of fasudil and FR167653 were administered to 6-week-old DS rats for 5 weeks.
  
  
  RESULTS
  At the age of 11 weeks, in the left ventricle, DS rats were characterized by increased myocardial fibrosis, phosphorylation of p38 MAPK, and myosin phosphatase targeting subunit (MYPT-1), and NAD(P)H oxidase p22(phox), p47(phox), gp91(phox), tumor necrosis factor-α and interleukin-1β expression compared with DR rats. Fasudil improved cardiovascular remodeling, inflammation, NAD(P)H oxidase subunits, and phosphorylation of p38 MAPK and MYPT-1. FR167653 also similarly ameliorated these indices but not MYPT-1 phosphorylation. Compared with either agent alone, a combination of fasudil and FR167653 was more effective for the improvement of myocardial damage, inflammation and oxidative stress.
  
  
  CONCLUSIONS
  These findings suggest that the Rho-kinase and p38 MAPK pathways may play a pivotal role in ventricular hypertrophy; thus, we obtained the first evidence that a combination of Rho-kinase inhibitor and p38 MAPK inhibitor may provide a potential therapeutic target in hypertension with cardiovascular remodeling.
authors.affiliation: Department of Hypertension and Cardiorenal Medicine, Dokkyo Medical University School of Medicine, Tochigi, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeshima
authors.forename: Naohiko
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Wataru
authors.initials: W
authors.lastname: Koguchi
authors.forename: Mayuko
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sugiyama
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ishimitsu
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D008297:Male; D018384:Oxidative Stress; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D020303:Rats, Inbred Dahl; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; C104334:FR 167653; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C049347:fasudil