Published Online
on December 30, 2002

A more recent version of this article appeared on January 21, 2003

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Submitted on September 19, 2002
Revised on November 15, 2002
Accepted on November 15, 2002

Beneficial Effects of Phosphodiesterase 5 Inhibition in Pulmonary Hypertension Are Influenced by Natriuretic Peptide Activity

Lan Zhao PhD, Nicola A. Mason PhD, Julian W. Strange MRCP, Hamish Walker MRCP, and Martin R. Wilkins MD^*

From the Section on Clinical Pharmacology, Imperial College School of Science, Technology and Medicine, Hammersmith Hospital, London, England.

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

Background—Phosphodiesterase type 5 (PDE5) inhibitors (eg, sildenafil) are a novel, orally active approach to the treatment of pulmonary arterial hypertension. The role of natriuretic peptides in the response to sildenafil was examined in mice lacking NPR-A, a guanylyl cyclase-linked natriuretic peptide receptor, in which pulmonary hypertension was induced by hypoxia.

Methods and Results—Mice homozygous for NPR-A (NPR-A^+/+) and null mutants (NPR-A^-/-) were studied. Sildenafil inhibited the pressor response to acute hypoxia in the isolated perfused lungs of both genotypes. This effect was greater in the presence of atrial natriuretic peptide in the perfusate in NPR-A^+/+ mice but not NPR-A^-/- animals. In vivo, NPR-A mutants had higher basal right ventricular (RV) systolic pressures (RVSPs) than did NPR-A^+/+ mice, and this was not affected by 3 weeks of treatment with sildenafil (25 mg · kg^-1 · d^-1). Both genotypes exhibited a rise in RVSP and RV weight with chronic hypoxia (10% O₂ for 21 days); RVSP and RV weight were reduced by continuous sildenafil administration in NPR-A^+/+ mice, but only RVSP showed evidence of a response to the drug in NPR-A^-/- mice. The effect of sildenafil on hypoxia-induced pulmonary vascular muscularization and cyclic GMP levels was also blunted in NPR-A^-/- mice.

Conclusions—The natriuretic peptide pathway influences the response to PDE5 inhibition in hypoxia-induced pulmonary hypertension, particularly its effects on RV hypertrophy and vascular remodeling.

Key words: hypertension, pulmonary • natriuretic peptides • remodeling

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