Jr. Klinger et al., NEUTRAL ENDOPEPTIDASE INHIBITION ATTENUATES DEVELOPMENT OF HYPOXIC PULMONARY-HYPERTENSION IN RATS, Journal of applied physiology, 75(4), 1993, pp. 1615-1623
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.