title: Additive effect of tadalafil and simvastatin on monocrotaline-induced pulmonary hypertension rats.
abstract: OBJECTIVE
  Tadalafil, an oral phosphodiesterase type-5 inhibitor, induces pulmonary vasorelaxation by inhibiting the breakdown of cyclic guanosine monophosphate whereas simvastatin, an oral 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, has been shown to reverse pulmonary hypertension (PH) and attenuate vascular remodeling in animal models of pulmonary hypertension. We investigated whether the combination of tadalafil and simvastatin, which has different mechanisms of action, is superior to either drug alone in a rat model of monocrotaline-induced PH.
  
  
  METHODS
  Male Sprague-Dawley rats were randomized to gavage with a vehicle, tadalafil (10 mg/kg/day), simvastatin (2 mg/kg/day), or tadalafi + simvastatin 21 days after the monocrotaline (60 mg/kg) injections. The hemodynamic and histological changes in the pulmonary arterioles, right heart hypertrophy, interleukin 6 (IL-6) levels and perivascular inflammation in the lungs were measured 35 days after monocrotaline exposure.
  
  
  RESULTS
  The combination of tadalafil and simvastatin showed significantly more improvement in the mean pulmonary hypertension pressure (mPAP) and right ventricular hypertrophy compared with each monotherapy (p < 0.05). Combination therapy had additive effects on the increases in lung IL-6 levels and the perivascular inflammation score.
  
  
  CONCLUSIONS
  These results suggest that the combination of tadalafil and simvastatin bears promise as an approach to treat PH, especially PH associated with inflammation.
authors.affiliation: Center of International Medicine, Chinese PLA General Hospital, Beijing, PR China.
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Zhang
authors.forename: Chun-Ping
authors.initials: CP
authors.lastname: Liu
authors.forename: Yun-Jian
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Ying-Qun
authors.initials: YQ
authors.lastname: Ji
authors.forename: Wei-Xuan
authors.initials: WX
authors.lastname: Lu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zeng
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D062186:Arterial Pressure / Q000187:drug effects; D001160:Arterioles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002243:Carbolines / Q000494:pharmacology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D065627:Familial Primary Pulmonary Hypertension; D006339:Heart Rate / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D016686:Monocrotaline; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*; D000068581:Tadalafil; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D002243:Carbolines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D015850:Interleukin-6; D058986:Phosphodiesterase 5 Inhibitors; D014665:Vasodilator Agents; D016686:Monocrotaline; D000068581:Tadalafil; D019821:Simvastatin