title: Effects of simvastatin on pulmonary C-fiber sensitivity in rats with monocrotaline-induced pulmonary hypertension.
abstract: BACKGROUND
  The possible mechanisms of simvastatin attenuating pulmonary hypertension (PH) have been widely investigated in pulmonary vascular and hemodynamic systems, but few studies have examined the difference in respiratory response mediated by pulmonary C fibers (PCF) in animal models of PH. We hypothesized that PCF sensitivity would differ from normal in monocrotaline-induced pulmonary hypertension (MCT-PH) rats and the effects of simvastatin treatment would involve not only the pulmonary circulatory system, but also PCF sensitivity.
  
  
  METHODS
  The PCF sensitivity was investigated by measuring the apneic durations evoked by 3 chemical stimulants: capsaicin; α,β-methylene-adenosine triphosphate; and phenylbiguanide. The effects of simvastatin on PCF sensitivity were evaluated in the MCT-PH rat model.
  
  
  RESULTS
  The sensitivity of PCF was increased significantly after monocrotaline (MCT) application for 21 days. Bilateral vagatomy and high-dose perivagal capsaicin (250 μg/ml) treatment both blocked the PCF hypersensitivity induced by MCT. Three days of simvastatin (5 mg/kg) treatment significantly reduced the hypersensitive status of PCF. In MCT-PH rats, reactive oxygen species (ROS) production was significantly elevated in both blood and bronchoalveolar lavage, but both showed a significantly decrease after simvastatin treatment. These potential benefits of simvastatin were all abolished by co-application of tin protoporphyrin-IX (SnPP), a specific heme oxygenase-1 (HO-1) inhibitor.
  
  
  CONCLUSIONS
  Simvastatin treatment in MCT-PH rats not only attenuated pulmonary hypertension, but also desensitized PCF hypersensitivity and decreased the production of ROS. These cholesterol-independent effects were mainly through the HO-1 pathway and may all contribute to the therapeutic effects of PH treatment.
authors.affiliation: Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Hsao-Hsun
authors.initials: HH
authors.lastname: Hsu
authors.forename: Ting
authors.initials: T
authors.lastname: Ruan
authors.forename: Wen-Je
authors.initials: WJ
authors.lastname: Ko
authors.forename: Jo-Yu
authors.initials: JY
authors.lastname: Hsu
authors.forename: Jin-Shing
authors.initials: JS
authors.lastname: Chen
authors.forename: Yung-Chie
authors.initials: YC
authors.lastname: Lee
authors.forename: I-Rue
authors.initials: IR
authors.lastname: Lai
authors.forename: Chau-Fong
authors.initials: CF
authors.lastname: Chen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D016686:Monocrotaline; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017382:Reactive Oxygen Species; D016686:Monocrotaline; D019821:Simvastatin; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat