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Simvastatin and sildenafil combine to attenuate pulmonary hypertension

¹ Experimental Medicine and Toxicology, Imperial College London, Hammersmith Hospital, and ² BHF Laboratories, Dept of Medicine, University College London, London, UK.

CORRESPONDENCE: L. Zhao, Experimental Medicine and Toxicology, Imperial College London, Hammersmith Hospital, Ducane Road, London W12 ONN, UK. E-mail: l.zhao{at}imperial.ac.uk

Keywords: Animal models, hypoxia, pulmonary hypertension, RhoA, sildenafil, simvastatin

Received: September 19, 2008
Accepted March 26, 2009

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·kg^–1·day^–1 by intraperitoneal injection or sildenafil 75 mg·kg^–1·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.