Published Online
on June 9, 2003

A more recent version of this article appeared on July 1, 2003

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Submitted on November 26, 2002
Revised on March 17, 2003
Accepted on March 21, 2003

Phosphodiesterase Type 5 as a Target for the Treatment of Hypoxia-Induced Pulmonary Hypertension

A. Sebkhi PhD, Julian W. Strange MB, Steven C. Phillips PhD, John Wharton PhD, and Martin R. Wilkins ^*

From the Section on Clinical Pharmacology (A.S., J.W.S., J.W., M.R.W.), Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, and Pfizer Global Research & Development (S.C.P.), Sandwich, Kent, United Kingdom.

^* To whom correspondence should be addressed. E-mail: m.wilkins{at}ic.ac.uk.

Background--Phosphodiesterase type 5 (PDE5) is a novel therapeutic target for the treatment of pulmonary hypertension. This study examined the distribution of PDE5 in normal and hypoxic lung and the effect of chronic PDE5 inhibition with sildenafil, initiated before and during exposure to hypoxia, on pulmonary artery pressure (PAP) and structure.

Methods and Results--Sprague-Dawley rats were exposed to hypoxia (10% O₂) for up to 42 days. PAP, measured continuously by telemetry, increased gradually by 20 to 40 mm Hg, reaching a plateau between 10 and 14 days, and declined to normal levels on return to normoxia. PDE5 immunoreactivity was localized to smooth muscle cells in the medial layer of pulmonary arteries and veins in the normal lung and in distal muscularized arteries (<25 µm diameter) after hypoxia-induced pulmonary hypertension. Sildenafil (25 or 75 mg · kg^-1 · d^-1) given before hypoxia produced marked dose-dependent inhibition in the rise of PAP (60% to 90% reduction; P<0.0001) and vascular muscularization (28.4±5.0% reduction; P<0.001). When begun after 14 days of hypoxia, sildenafil significantly reduced PAP (30% reduction; P<0.0001) and partially reversed pulmonary artery muscularization (39.9±4.9% reduction; P<0.001).

Conclusions--PDE5 is found throughout the muscularized pulmonary vascular tree, including in newly muscularized distal pulmonary arteries exposed to hypoxia. PDE5 inhibition attenuates the rise in PAP and vascular remodeling when given before chronic exposure to hypoxia and when administered as a treatment during ongoing hypoxia-induced pulmonary hypertension.

Key words: inhibitors • hypertension, pulmonary • hypoxia • telemetry

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