Effects of the neutral endopeptidase inhibitor, SCH 42495, on the cardiovascular remodelling secondary to chronic hypoxia in rats.
1. We have investigated the effects of inhibition of neutral endopeptidase on the cardiovascular remodelling secondary to chronic hypoxia in rats using a novel neutral endopeptidase inhibitor, SCH 42495. 2. Rats were divided into four groups, two of which were maintained in a normobaric, hypoxic chamber (10% O2) and two in room air. Animals received either neutral endopeptidase inhibitor, SCH 42495 (30 mg/kg), or aqueous methyl cellulose vehicle (0.4%) twice daily by oral gavage. 3. At 1, 3, 7, 10 and 14 days, animals (n = 4 per group for days 1, 3, 7 and 14, and n = 8 for day 10) were killed. Hearts were dissected and weighed for determination of ventricular ratios, lungs were perfused with formol saline for histological examination of the pulmonary vasculature, and blood was collected for measurement of plasma atrial natriuretic peptide level. 4. Treatment with SCH 42495 caused a significant reduction in the pulmonary vascular remodelling and ventricular hypertrophy in hypoxic rats after 10 days. Plasma atrial natriuretic peptide levels were significantly elevated in both SCH 42495-treated and control hypoxic animals (n = 8) after 10 days when compared with the normoxic groups. However, there was no difference in plasma ANP levels between SCH 42495-treated and control hypoxic groups at day 10. 5. Treatment with SCH 42495 leads to a decrease in cardiovascular remodelling secondary to chronic hypoxia in rats. A local action of atrial natriuretic peptide within the pulmonary vasculature may be responsible for this effect. Modulation of atrial natriuretic peptide may have therapeutic potential in the management of conditions characterized by pulmonary hypertension and pulmonary vascular remodelling.
Thompson
J S
JS
Department of Medicine and Pharmacology, University of Sheffield, Royal Hallamshire Hospital, U.K.
Sheedy
W
W
Morice
A H
AH
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D002908:Chronic Disease; D006352:Heart Ventricles / Q000187:drug effects; D017380:Hypertrophy, Right Ventricular / Q000097:blood / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D000860:Hypoxia / Q000097:blood / Q000150:complications / Q000473:pathology*; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011667:Pulmonary Veins / Q000187:drug effects / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar
C069018:SCH 42495; D009320:Atrial Natriuretic Factor; D008715:Methionine; D015260:Neprilysin