Neutral endopeptidase (NEP) inhibition is thought to blunt hypoxic
pulmonary hypertension by reducing
atrial natriuretic peptide (
ANP) metabolism, but this hypothesis has not been confirmed. We measured NEP activity,
guanosine 3',5'-cyclic monophosphate (cGMP) production, plasma
ANP levels, and cardiac
ANP synthesis in rats given an orally active NEP inhibitor (SCH-34826) during 3 wk of
hypoxia. Under normoxic conditions,
SCH-34826 had no effect on plasma
ANP levels but reduced pulmonary and renal NEP activity by 50% and increased urinary cGMP levels (60 +/- 6 vs. 22 +/- 4 pg/mg
creatinine; P < 0.05). Under hypoxic conditions, SCH-34826-treated rats had lower plasma
ANP levels (1,259 +/- 361 vs. 2,101 +/- 278 pg/ml; P < 0.05), lower right ventricular systolic pressure (53 +/- 5 vs. 73 +/- 2 mmHg; P < 0.05), lower right ventricle weight-to-left ventricle+septum weight ratio (0.47 +/- 0.04 vs. 0.53 +/- 0.03; P < 0.05), and less muscularization and percent medial wall thickness of peripheral pulmonary arteries (22 +/- 5 vs. 45 +/- 8% and 17 +/- 1 vs. 25 +/- 1%, respectively; P < 0.05 for all values) than did rats treated with vehicle alone. These values were not affected by
SCH-34826 under normoxic conditions.
SCH-34826 decreased right ventricular
ANP tissue levels in hypoxic rats (27 +/- 10 vs. 8 +/- 1 ng/mg
protein; P < 0.05) but did not affect steady-state
ANP mRNA levels. We conclude that NEP inhibition blunts
pulmonary hypertension without increasing plasma
ANP levels.(ABSTRACT TRUNCATED AT 250 WORDS)