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1 Division of Pulmonary, Sleep, and Critical Care Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence, Rhode Island 02903; and 2 Department of Pathology, University of North Carolina, Chapel Hill, North Carolina 27599
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 weight- and left
ventricle plus septum weight-to-body weight ratios [RV/BW and
(LV+S)/BW, respectively], and muscularization of pulmonary
vessels were measured in wild-type mice (+/+) and in mice heterozygous
(+/
) and homozygous (/) 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 ± 2 vs.
15 ± 1 mmHg; P < 0.05) than
wild-type mice and greater RV/BW (1.22 ± 0.08 vs. 0.94 ± 0.07 and 0.76 ± 0.04 mg/g; P < 0.05)
and (LV+S)/BW (4.74 ± 0.42 vs. 3.53 ± 0.14 and 3.18 ± 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/(LV+S) in
all genotypes compared with their normoxic control animals but had no
effect on (LV+S)/BW. After 3 wk of hypoxia, homozygous mutants had
higher RVPP (29 ± 3 vs. 23 ± 1 and 22 ± 2 mmHg;
P < 0.05), RV/BW (2.03 ± 0.14 vs. 1.46 ± 0.04 and 1.33 ± 0.08 mg/g;
P < 0.05), and (LV+S)/BW (4.76 ± 0.23 vs. 3.82 ± 0.09 and 3.44 ± 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.
anoxia; cardiac hypertrophy; pulmonary circulation
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