Combination of sildenafil and simvastatin ameliorates monocrotaline-induced pulmonary hypertension in rats.
Sildenafil, a phosphodiesterase-5 inhibitor, and simvastatin, a cholesterol lowering drug, both have therapeutic effects on PAH; however, the combination of these drugs has not been tested in the treatment of PAH. The purpose of this study was to determine whether the combination of sildenafil and simvastatin is superior to each drug alone in the prevention of MCT-induced PAH. Phosphorylated Smad levels were decreased in lung tissue in MCT-injected rats, whereas ERK protein levels were increased. This indicates a possible role for an increase in mitogenic ERK activity in addition to decreased proapoptotic Smad signaling in the MCT model of PAH. Combination sildenafil and simvastatin treatment prevented the MCT-induced increases in right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH), exerted an anti-proliferative effect on pulmonary artery smooth muscle cells (PASMC). Our results indicate that combination therapy with sildenafil and simvastatin attenuated the development of pulmonary hypertension more than either treatment alone.
Kuang
Tuguang
T
Department of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital and Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing, China.
Wang
Jun
J
Pang
Baosen
B
Huang
Xiuxia
X
Burg
Elyssa D
ED
Yuan
Jason X-J
JX
Wang
Chen
C
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D016686:Monocrotaline; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*
D000924:Anticholesteremic Agents; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D016686:Monocrotaline; D019821:Simvastatin; D000068677:Sildenafil Citrate