Rationale: Phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil) are selective pulmonary vasodilators in patients with pulmonary arterial hypertension. The mechanism(s) underlying this specificity remains unclear, but studies in genetically modified animals suggest it might be dependent on natriuretic peptide bioactivity.

Objectives: We explored the interaction between PDE5 inhibitors and the natriuretic peptide system to elucidate the (patho)physiological relationship between these two cyclic GMP (cGMP)-regulating systems and potential of a combination therapy exploiting these cooperative pathways.

Methods: Pharmacological evaluation of vascular reactivity was conducted in rat isolated conduit and resistance vessels from the pulmonary and systemic circulation in vitro, and in anesthetized mice in vivo. Parallel studies were undertaken in an animal model of hypoxia-induced pulmonary hypertension (PH).

Measurements and Main Results: Sildenafil augments vasodilatation to nitric oxide (NO) in pulmonary and systemic conduit and resistance arteries, whereas identical vasorelaxant responses to atrial natriuretic peptide (ANP) are enhanced only in pulmonary vessels. This differential activity is mirrored in vivo where sildenafil increases the hypotensive actions of ANP in the pulmonary, but not systemic, vasculature. In hypoxia-induced PH, combination of sildenafil plus the neutral endopeptidase (NEP) inhibitor ecadotril (which increases endogenous natriuretic peptide levels) acts synergistically, in a cGMP-dependent manner, to reduce many indices of disease severity without significantly affecting systemic blood pressure.

Conclusions: These data demonstrate that PDE5 is a key regulator of cGMP-mediated vasodilation by ANP in the pulmonary, but not systemic, vasculature, thereby explaining the pulmonary selectivity of PDE5 inhibitors. Exploitation of this mechanism (i.e., PDE5 and neutral endopeptidase inhibition) represents a novel, orally active combination therapy for pulmonary arterial hypertension.