Simvastatin and sildenafil combine to attenuate pulmonary hypertension.
Statins have been proposed to be a potential treatment for pulmonary arterial hypertension. If introduced into clinical practice, the statin would have to be used in conjunction with established therapy. We investigated the effects of combining simvastatin with a phosphodiesterase type-5 inhibitor, sildenafil, in the rat model of hypoxia-induced pulmonary hypertension. Rats were allocated to either: 1) a prevention protocol, to receive simvastatin 20 mg x kg(-1) x day(-1) by intraperitoneal injection or sildenafil 75 mg x kg(-1) x day(-1) orally or the combination (or vehicle) for 2 weeks beginning at the start of exposure to hypoxia (10% inspired oxygen); or 2) a treatment protocol, where the same agents were administered in the last 2 weeks of a 4-week period of hypoxia. In both protocols, the combination of sildenafil and simvastatin lowered pulmonary artery pressure and produced a significantly greater reduction in right ventricular hypertrophy and pulmonary vascular muscularisation than either drug alone. Moreover, the combination augmented significantly endothelial nitric oxide synthase expression and cGMP levels in the lung and right ventricle above that produced by either drug independently and resulted in greater inhibition of RhoA activity. These data suggest that simvastatin can be usefully combined with sildenafil in the treatment of pulmonary arterial hypertension to achieve greater therapeutic benefit.
Experimental Medicine and Toxicology, Imperial College London, Hammersmith Hospital, London, UK. l.zhao@imperial.ac.uk
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L
Zhao
A
A
Sebkhi
O
O
Ali
B
B
Wojciak-Stothard
L
L
Mamanova
Q
Q
Yang
J
J
Wharton
M R
MR
Wilkins
D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D000860:Hypoxia / Q000150:complications; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate; D019821:Simvastatin / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D019821:Simvastatin; D000068677:Sildenafil Citrate; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D020742:rhoA GTP-Binding Protein; D006152:Cyclic GMP