ALUNG May 20/5

Klinger, James R., Rod R. Warburton, Linda A. Pietras, Oliver Smithies, Richard Swift, and Nicholas S. Hill. Genetic disruption of atrial natriuretic peptide causes pulmonary hypertension in normoxic and hypoxic mice. Am. J. Physiol. 276 (Lung Cell. Mol. Physiol. 20): L868–L874, 1999.—To determine whether atrial natriuretic peptide (ANP) plays a physiological role in modulating pulmonary hypertensive responses, we studied mice with gene-targeted disruption of the ANP gene under normoxic and chronically hypoxic conditions. Right ventricular peak pressure (RVPP), right ventricle weightand left ventricle plus septum weight-tobody weight ratios [RV/BW and (LV1S)/BW, respectively], and muscularization of pulmonary vessels were measured in wild-type mice (1/1) and in mice heterozygous (1/2) and homozygous (2/2) for a disrupted proANP gene after 3 wk of normoxia or hypobaric hypoxia (0.5 atm). Under normoxic conditions, homozygous mutants had higher RVPP (22 6 2 vs. 15 6 1 mmHg; P , 0.05) than wild-type mice and greater RV/BW (1.22 6 0.08 vs. 0.94 6 0.07 and 0.76 6 0.04 mg/g; P , 0.05) and (LV1S)/BW (4.74 6 0.42 vs. 3.53 6 0.14 and 3.18 6 0.18 mg/g; P , 0.05) than heterozygous or wild-type mice, respectively. Three weeks of hypoxia increased RVPP in heterozygous and wild-type mice and increased RV/BW and RV/(LV1S) in all genotypes compared with their normoxic control animals but had no effect on (LV1S)/BW. After 3 wk of hypoxia, homozygous mutants had higher RVPP (29 6 3 vs. 23 6 1 and 22 6 2 mmHg; P , 0.05), RV/BW (2.03 6 0.14 vs. 1.46 6 0.04 and 1.33 6 0.08 mg/g; P , 0.05), and (LV1S)/BW (4.76 6 0.23 vs. 3.82 6 0.09 and 3.44 6 0.14 mg/g; P , 0.05) than heterozygous or wild-type mice, respectively. The percent muscularization of peripheral pulmonary vessels was greater in homozygous mutants than that in heterozygous or wild-type mice under both normoxic and hypoxic conditions. We conclude that endogenous ANP plays a physiological role in modulating pulmonary arterial pressure, cardiac hypertrophy, and pulmonary vascular remodeling under normoxic and hypoxic conditions.