Neutral endopeptidase inhibition attenuates development of hypoxic pulmonary hypertension in rats.
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)
Klinger
J R
JR
Division of Pulmonary and Critical Care Medicine, Brown University School of Medicine, Providence, Rhode Island.
Petit
R D
RD
Warburton
R R
RR
Wrenn
D S
DS
Arnal
F
F
Hill
N S
NS
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis; D001794:Blood Pressure / Q000187:drug effects; D002908:Chronic Disease; D006152:Cyclic GMP / Q000652:urine; D004148:Dioxolanes / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
D004148:Dioxolanes; D004151:Dipeptides; D007093:Imidazoles; D011719:Pyrazines; D012333:RNA, Messenger; C056319:Sch 34826; C042837:3-amino-2-methyl-8-phenylmethoxyimidazo(1,2-a)pyrazine; D009320:Atrial Natriuretic Factor; D015260:Neprilysin; D006152:Cyclic GMP