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.