title: Effects of everolimus in combination with sildenafil in monocrotaline-induced pulmonary hypertension in rats.
abstract: In our study, we investigated the efficacy of everolimus in combination with sildenafil on hemodynamic and morphological parameters in rats with monocrotaline-induced pulmonary hypertension (PH). Right ventricular pressure (RVP), right ventricular hypertrophy, and the response to vasoconstrictor and vasodilator agents in pulmonary arteries as evaluated by myography and histopathological changes were compared among the groups. RVP and right ventricle/body weight ratios were increased in non-treated monocrotaline groups versus the controls; these increased ratios were decreased in the treated groups and were similar to control values. The contractile responses to endothelin-1 in the pulmonary arteries were decreased in the non-treated monocrotaline groups versus the control. In the treatment groups, contractile responses were similar to those in the controls. Responses to acetylcholine and sodium nitroprusside relaxation were decreased in non-treated monocrotaline groups but were improved significantly in the everolimus groups. Upon histopathological examination, the vascular hypertrophy and cardiac hypertrophy observed in monocrotaline groups were improved by the sildenafil and everolimus treatment. In particular, these improvements became remarkable, including the inflammatory changes, in the everolimus treatment groups. In the light of these results, sildenafil and everolimus in combination were more effective than sildenafil treatment alone in reversing the remodelling process without any cardiovascular toxic effects in the monocrotaline-induced PH model.
authors.affiliation: Department of Pharmaceutical Toxicology, Anadolu University, Eskisehir, Turkey. silgin@anadolu.edu.tr
authors.forename: Sinem
authors.initials: S
authors.lastname: Ilgin
authors.forename: Dilek
authors.initials: D
authors.lastname: Burukoglu
authors.forename: Ozlem
authors.initials: O
authors.lastname: Atli
authors.forename: Basar
authors.initials: B
authors.lastname: Sirmagul
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D019332:Endothelin-1 / Q000494:pharmacology; D000068338:Everolimus; D005260:Female; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016686:Monocrotaline / Q000633:toxicity*; D009599:Nitroprusside / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage*; D011687:Purines / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013450:Sulfones / Q000008:administration & dosage*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D018497:Ventricular Dysfunction, Right; D020257:Ventricular Remodeling
chemical_list: D019332:Endothelin-1; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D016686:Monocrotaline; D000068338:Everolimus; D000068677:Sildenafil Citrate; D000109:Acetylcholine; D020123:Sirolimus