Editors' ChoicePulmonary Hypertension

Sildenafil: Bench to Bedside and Back Again

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Science Translational Medicine  16 Mar 2011:
Vol. 3, Issue 74, pp. 74ec34
DOI: 10.1126/scitranslmed.3002361

A conceptual melding of the heart and breathlessness has generally positive connotations. Not so if the shortness of breath comes from heart failure (HF) rather than a caress. Heart function is closely tied to pulmonary blood vessels (the vasculature), and left-sided HF thus can result in abnormally high blood pressure in the lungs. This condition—called "pulmonary hypertension"—increases the load on the right side of the heart and eventually can give rise to right-sided HF. Small clinical trials have shown that the drug sildenafil—commonly known as Viagra—reduces pulmonary hypertension and increases exercise capacity in patients with HF. Now, Yin et al. move from bedside to bench to investigate the mechanism behind this effect in a rat model of HF.

Although the underlying causes of left-sided HF vary, the effect on the pulmonary vasculature is similar: Smooth muscle tone is enhanced, which increases vascular constriction, derangement of the dilation and constriction abilities of the endothelial cells that line the blood vessels (endothelial dysfunction), and vascular remodeling. All of these changes contribute to impeding blood flow, which leads to high blood pressure in the lungs.

Although best known for its ability to treat erectile dysfunction, sildenafil—an inhibitor of the enzyme phosphodiesterase type 5 (PDE-5)—is approved for the treatment of another lung condition, pulmonary arterial hypertension (PAH). PDE-5 is responsible for the degradation of cyclic guanosine monophosphate (cGMP), a molecule that regulates signal transduction pathways in the cell. Sildenafil treatment increases cGMP concentrations, which causes smooth muscle relaxation. Although the causes of PAH differ from those of pulmonary hypertension that results from left-sided HF, the two conditions sport similar pathophysiologies (endothelial dysfunction and vascular remodeling) and, therefore, treatment of either should benefit from the vasorelaxant effects of sildenafil.

In the current study, rats were subjected to either a sham surgical procedure (controls) or aortic banding in order to cause pressure overload on the left ventricle of the heart and eventual HF. When rats with HF were given sildenafil, they exhibited reductions in pulmonary vascular remodeling, blood flow resistance, pulmonary hypertension, and right ventricular hypertrophy and dysfunction compared with rats in HF that were not given sildenafil. The sildenafil-treated HF rats appeared to be clinically similar to the sham-operated controls, except that the HF rats had significantly higher concentrations of plasma cGMP, as expected.

This work adds to the growing body of evidence that sildenafil may be an important therapeutic agent for patients with left ventricular HF and elevated pulmonary pressure. Presently, we await results from the RELAX study, a randomized trial of sildenafil in patients with diastolic HF, a condition caused by stiffness of the left ventricle and subsequent pulmonary hypertention.

J. Yin et al., Sildenafil preserves lung endothelial function and prevents pulmonary vascular remodeling in a rat model of diastolic heart failure. Circ. Heart Fail. 7 January 2011 (10.1161.CIRCHEARTFAILURE.110.957050). [Abstract]

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