title: Aminoguanidine inhibits mitogen-activated protein kinase and improves cardiac performance and cardiovascular remodeling in failing hearts of salt-sensitive hypertensive rats.
abstract: OBJECTIVE
  Congestive heart failure (CHF) is associated with inducible nitric oxide synthase (iNOS) expression in the failing human heart, and recently we have also demonstrated that iNOS expression was upregulated in Dahl salt-sensitive hypertensive (DS) rats with cardiac dysfunction and vascular remodeling. Thus, we evaluated whether aminoguanidine (AG), a selective iNOS inhibitor, protects against cardiac dysfunction and vascular remodeling in DS rats receiving a high-salt diet.
  
  
  METHODS
  AG (DSHF-AG, 150 mg/kg per day) or vehicle (DSHF-V) were given from left ventricular hypertrophy stage (11 weeks) to CHF stage (18 weeks) for 7 weeks. The left ventricular end-systolic pressure-volume relationship (contractility: E(es)) was measured by conductance catheter.
  
  
  RESULTS
  Decreased E(es) in DSHF-V was significantly ameliorated by AG treatment. The iNOS mRNA and protein expression and phospho-p42/p44 extracellular signal-regulated kinase (ERK) activities in the left ventricle were significantly upregulated in DSHF-V compared with control rats, and significantly suppressed in DSHF-AG compared with DSHF-V. DSHF-V showed a significant increase of perivascular fibrosis and myocardial fibrosis, with all these parameters being significantly improved by AG treatment.
  
  
  CONCLUSIONS
  We demonstrated that the selective iNOS inhibitor, AG, may be at least a potential therapeutic strategy for treating CHF and cardiovascular remodeling.
authors.affiliation: Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi, Japan. a-fukuda@dokkyomed.ac.jp
authors.forename: Naohiko
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Shigeo
authors.initials: S
authors.lastname: Horinaka
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Mita
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Yoshida
authors.forename: Takeaki
authors.initials: T
authors.lastname: Honda
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Hara
authors.forename: Toshio
authors.initials: T
authors.lastname: Nishikimi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsuoka
mesh_terms: D000818:Animals; D001794:Blood Pressure; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006333:Heart Failure / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D006973:Hypertension / Q000150:complications* / Q000209:etiology; D007550:Isothiuronium / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013318:Stroke Volume; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D012333:RNA, Messenger; D017673:Sodium Chloride, Dietary; D007550:Isothiuronium; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D020928:Mitogen-Activated Protein Kinases; C027744:S-methylisothiopseudouronium; C004479:pimagedine