Neutral endopeptidase (NEP) inhibition in rats with established pulmonary hypertension secondary to chronic hypoxia.
1. Atrial natriuretic peptide (ANP) causes vasorelaxation in the pulmonary vasculature. ANP levels are elevated in conditions characterized by pulmonary hypertension and it has been hypothesized that ANP may be autoregulatory in the pulmonary circulation. 2. One route of ANP metabolism in vivo is by the action of the enzyme neutral endopeptidase (NEP). We have studied the effects of the NEP inhibitor, SCH 42495, in rats with established pulmonary hypertension secondary to chronic hypoxia. 3. Rats (n = 32) were divided into 4 groups. Normoxic controls were kept in air for 10 days (NC10) and all other animals were placed in a normobaric hypoxic chamber (F1 O2 10%). Chronic hypoxic controls were studied at 10 days (CHC10). After 10 days hypoxia the two remaining groups received oral treatment for a further 10 days, consisting of either SCH 42495 (30 mg kg-1, twice daily CHT20) or methyl cellulose vehicle (0.4%, twice daily, CHV20). 4. Animals were anaesthetized and blood collected for measurement of plasma ANP. Hearts were dissected and ventricles weighed and the histology of the pulmonary vasculature examined. 5. CHC10 rats had significant right ventricular hypertrophy (0.53 +/- 0.08) and pulmonary vascular remodelling (29.0 +/- 0.01%) and had gained significantly less body weight (33.2 +/- 5.5 g) than NC10 rats (0.31 +/- 0.04, 10.9 +/- 0.01%, and 59.2 +/- 11.9 g respectively). CHC10 rats had significantly elevated plasma ANP levels (58.4 +/- 9.9 pM) compared with NC10 rats (23.9 +/- 32 pM). Treatment with SCH 42495 caused a significant reduction in pulmonary vascular remodelling (25.0 +/- 0.01%) and right ventricular hypertrophy (0.52 +/- 0.09) in CHT20 rats compared with CHV20 controls (33.0 +/- 0.02% and 0.61 +/- 0.09 respectively). Pulmonary vascular remodelling was also significantly lower in CHT20 rats than CHC1O animals.6. Thus, short term inhibition of NEP causes regression of established pulmonary vascular remodelling and may be a useful therapeutic strategy in pulmonary hypertension.
Thompson
J S
JS
Department of Medicine and Pharmacology, University of Sheffield, Royal Hallamshire Hospital.
Sheedy
W
W
Morice
A H
AH
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D002908:Chronic Disease; D006976:Hypertension, Pulmonary / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000473:pathology; D000860:Hypoxia / Q000150:complications* / Q000473:pathology; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D009206:Myocardium / Q000473:pathology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
C069018:SCH 42495; D009320:Atrial Natriuretic Factor; D008715:Methionine; D015260:Neprilysin