NEUTRAL ENDOPEPTIDASE INHIBITION ATTENUATES DEVELOPMENT OF HYPOXIC PULMONARY-HYPERTENSION IN RATS

Neutral endopeptidase (NEP) inhibition is thought to blunt hypoxic pul monary hypertension by reducing atrial natriuretic peptide (ANP) metab olism, but this hypothesis has not been confirmed. We measured NEP act ivity, guanosine 3',5-cyclic monophosphate (cGMP) production, plasma A NP levels, and cardiac ANP synthesis in rats given an orally active NE P inhibitor (SCH-34826) during 3 wk of hypoxia. Under normoxic conditi ons, SCH-34826 had no effect on plasma ANP levels but reduced pulmonar y and renal NEP activity by 50% and increased urinary cGMP levels (60 +/- 6 vs. 22 +/- 4 pg/mg creatinine; P < 0.05). Under hypoxic conditio ns, 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 p ressure (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% an d 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 ventri cular ANP tissue levels in hypoxic rats (27 +/- 10 vs. 8 +/- 1 ng/mg p rotein; P < 0.05) but did not affect steady-state ANP mRNA levels. We conclude that NEP inhibition blunts pulmonary hypertension without inc reasing plasma ANP levels. This effect may be related to increased ANP activity at the local tissue level or may reflect increased activity of other vasoactive mediators metabolized by NEP.