title: Lack of synergistic effect of molsidomine and sildenafil on development of pulmonary hypertension in chronic hypoxic rats.
abstract: The present study addressed whether combined treatment with a phosphodiesterase type 5 inhibitor, sildenafil, and a nitric oxide donor, molsidomine, prevents development of pulmonary hypertension in chronic hypoxic rats. Two weeks of hypoxia increased right ventricular systolic pressure, and right ventricular and lung weight. Treatment with either sildenafil (10 mg/kg/day) or molsidomine (15 mg/kg/day) in drinking water reduced right ventricular systolic pressure and weight, while lung weight was unchanged. Combining sildenafil and molsidomine did not have additional effects compared to molsidomine alone. The number of muscularized pulmonary arteries with diameters below 50 microm was increased in vehicle and sildenafil-treated, but not in molsidomine-treated hypoxic rats. Acetylcholine relaxation was blunted in arteries from vehicle and molsidomine-treated, but not in sildenafil-treated rats. In conclusion, both sildenafil and molsidomine blunts pulmonary hypertension and right ventricular hypertrophy in chronic hypoxic rats, but no synergistic effects were observed.
authors.affiliation: Department of Pharmacology, Faculty of Health Sciences, University of Aarhus, 8000 Aarhus C, Denmark.
authors.forename: Charlotte U
authors.initials: CU
authors.lastname: Andersen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mulvany
authors.forename: Ulf
authors.initials: U
authors.lastname: Simonsen
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000199:Actins / Q000032:analysis; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000503:physiopathology / Q000517:prevention & control*; D000860:Hypoxia / Q000503:physiopathology; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D008297:Male; D008981:Molsidomine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000737:chemistry; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D011687:Purines; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones; D013599:Systole; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000199:Actins; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D010879:Piperazines; D011687:Purines; D011810:Quinoxalines; D013450:Sulfones; D014665:Vasodilator Agents; C002385:linsidomine; D009320:Atrial Natriuretic Factor; D000068677:Sildenafil Citrate; D008981:Molsidomine; D006162:Guanylate Cyclase; D000109:Acetylcholine