title: 3-Hydroxy-3-methylglutaryl (HMG)-COA reductase inhibitors and phosphodiesterase type V inhibitors attenuate right ventricular pressure and remodeling in a rat model of pulmonary hypertension.
abstract: OBJECTIVE
  We examined the inhibitory effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors and a phosphodiesterase type V inhibitor on hemodynamic function and cardiac remodeling in rats with monocrotaline-induced pulmonary hypertension.
  
  
  METHODS
  The rat model of pulmonary hypertension was created by administration of monocrotaline (70 mg/kg, s.c.) to male Wistar rats. A polyethylene tube was introduced into a femoral artery for measurement of mean arterial pressure, another into the right ventricle via the right jugular vein for measurement of right ventricular systolic pressure (RVSP), and another into a femoral vein for administration of test drugs.
  
  
  RESULTS
  Repeated administration of atorvastatin (2 mg/kg/day, p.o. 0 - 28 days) and simvastatin (2 mg/kg/day, p.o. 0 - 28 days) significantly reduced RVSP and right ventricular weight (RV)/left ventricular + septum weight (LV + S) without a change in heart rate. However, repeated administration of pravastatin (4 mg/kg/day, p.o. 0 - 28 days) did not reduce the monocrotaline-induced elevation of RVSP and RV/(LV + S) significantly. The reduction of RVSP and RV/(LV + S)) induced by a combination of a prostacyclin analogue, beraprost (100 mg/kg/day, 0 - 28 days) and simvastatin (2 mg/kg/day, 0 - 28 days), was more potent than the effect induced by each drug alone. Sildenafil (5 mg/kg/day, 0 - 28 days) tended to reduce RVSP and RV/(LV + S). Repeated combined administration of atorvastatin (2 mg/kg/day, p.o. 0 - 28 days) + sildenafil (5 mg/kg/day, p.o. 0 - 28 days) significantly reduced Lung/BW.
  
  
  CONCLUSIONS
  Our present results suggest that repeated administration of the lipophilic HMG-CoA reductase inhibitors, atorvastatin and simbastatin, selectively attenuates the elevation of RVSP, development of pulmonary hypertension and right ventricular remodeling in rats with monocrotaline-induced pulmonary hypertension, and that a combination of HMG-CoA reductase inhibitor and beraprost has a more potent effect than each agent alone.
authors.affiliation: Department of Toxicology and Pharmacology, Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba, 274-8510, Japan.
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Satoh
authors.forename: Akira
authors.initials: A
authors.lastname: Satoh
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D006538:Heptanoic Acids / Q000627:therapeutic use; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D016686:Monocrotaline; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use; D017035:Pravastatin / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000187:drug effects* / Q000503:physiopathology; D011758:Pyrroles / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000627:therapeutic use
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010726:Phosphodiesterase Inhibitors; D011758:Pyrroles; D016686:Monocrotaline; D000069059:Atorvastatin; D019821:Simvastatin; D017035:Pravastatin