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(Circulation. 1999;99:605-607.)
© 1999 American Heart Association, Inc.

Brief Rapid Communication

NPR-A–Deficient Mice Show Increased Susceptibility to Hypoxia-Induced Pulmonary Hypertension

Lan Zhao, PhD; Lu Long, MB; Nicholas W. Morrell, MD; Martin R. Wilkins, MD

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

Correspondence to Dr M.R. Wilkins, Section on Clinical Pharmacology, Imperial College School of Science, Technology, and Medicine, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK. E-mail mwilkins{at}ic.ac.uk

Background—Mice in which the gene encoding NPR-A, a guanylyl cyclase–linked natriuretic peptide receptor, has been disrupted were used to examine the contribution of natriuretic peptides to maintaining pulmonary vascular homeostasis in normal- and low-oxygen environments.

Methods and Results—Wild-type (+/+), heterozygous (+/-), and homozygous null mutants (-/-) were studied. The response of the pulmonary vasculature to atrial, B-type, and C-type natriuretic peptides (ANP, BNP, and CNP) during acute hypoxia was studied in isolated perfused lungs. Right ventricular systolic pressure (RVSP), RV weight, and pulmonary vascular remodeling were measured in each genotype exposed to normal air and after 7 and 21 days in a hypoxic atmosphere (10% O₂). ANP and BNP (300 ng) reduced pulmonary artery pressure during acute hypoxia-induced pulmonary vasoconstriction in +/+ mice, but this effect was attenuated in +/- and absent in -/- mice. CNP (600 ng) had little effect in all 3 genotypes. RVSP and RV weight were similar in the 3 genotypes housed in a normal-O₂ environment. Seven and 21 days of hypoxia produced a pronounced and significantly greater increase in RVSP and RV weight in -/- mice compared with +/+ or +/- mice and more rapid muscularization of distal pulmonary arterioles.

Conclusions—ANP and BNP do not contribute to maintaining normal pulmonary artery pressure but play an important role in attenuating the pulmonary vascular response to hypoxia. NPR-A mediates the vasorelaxant effect of ANP in pulmonary vasculature.

Key Words: genes • hypertension • lung • peptides

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