Sildenafil limits monocrotaline-induced pulmonary hypertension in rats through suppression of pulmonary vascular remodeling.
We hypothesize that sildenafil attenuates pulmonary hypertension through suppressing pulmonary vascular remodeling. Thirty male adult Sprague-Dawley rats were randomized to receive saline injection (Group 1), subcutaneous monocrotaline (MCT) (60 mg/kg) (Group 2), and MCT plus oral sildenafil (30 g/kg per day) (Group 3) 5 days after MCT administration. By Day 35, Western blot showed lower connexin43 and membranous protein kinase C epsilon expressions but higher oxidative stress in right ventricle in Group 2 compared with the other groups. Additionally, pulmonary Smad1/5 was lowest, whereas connexin43 and Smad3 were highest in Group 2. Pulmonary mRNA expressions of tumor necrosis factor-alpha, caspase-3, plasminogen activator inhibitor-1, and transforming growth factor-beta were higher, whereas bone morphogenetic protein Type II receptor, Bcl-2, and endothelial nitric oxide synthase were lower in Group 2 than in the other groups. Similarly, mRNA expressions of tumor necrosis factor-alpha, caspase-3, and beta-myosin heavy chain were increased, whereas Bcl-2, endothelial nitric oxide synthase, and alpha-myosin heavy chain expressions in right ventricle were reduced in Group 2 compared with the other groups. Number of lung arterioles was lowest, whereas number of arterioles with muscularization of the medial layer was highest in Group 2. Right ventricle systolic pressure and weight were elevated in Group 2 compared with the other groups. In conclusion, sildenafil effectively alleviates MCT-induced pulmonary hypertension through suppressing pulmonary vascular remodeling.
Department of Life Science, National Pingtung University of Science and Technology, Pingtung, Taiwan.
Chia-Hung
CH
Yen
Steve
S
Leu
Yu-Chun
YC
Lin
Ying-Hsien
YH
Kao
Li-Teh
LT
Chang
Sarah
S
Chua
Morgan
M
Fu
Chiung-Jen
CJ
Wu
Cheuk-Kwan
CK
Sun
Hon-Kan
HK
Yip
D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D053148:Caspase 3 / Q000378:metabolism; D018031:Connexin 43 / Q000378:metabolism / Q000494:pharmacology; D006973:Hypertension / Q000378:metabolism / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D016686:Monocrotaline / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010879:Piperazines; D011687:Purines; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D024723:Ventricular Myosins / Q000009:adverse effects / Q000378:metabolism
D018031:Connexin 43; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D016686:Monocrotaline; D000068677:Sildenafil Citrate; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D053148:Caspase 3; D024723:Ventricular Myosins