Hormonal, renal and blood pressure effects of
SCH 39370, a selective inhibitor of neutral
metalloendopeptidase (
endopeptidase 24.11, NEP), were studied in a chronic,
congestive heart failure (CHF) model produced by coronary artery
ligation in the rat.
Sham-operated control rats and rats with CHF were treated either with vehicle or
SCH 39370, 30 mg/kg s.c. b.i.d. for 2.5 days. Plasma levels of
atrial natriuretic peptide (
ANP) and urinary excretion of
cyclic GMP (cGMP) were clearly raised in rats with CHF as compared with controls during vehicle treatment.
SCH 39370 caused a further increase in plasma
ANP in CHF rats but not in control rats. Urinary excretion of immunoreactive
ANP and cGMP increased during
SCH 39370 treatment both in CHF rats and in controls.
SCH 39370 treatment resulted in an initial increase in urine volume in rats with CHF whereas urine
sodium excretion did not change significantly. No changes in renal function due to
SCH 39370 treatment were seen in control rats. Systolic blood pressure, plasma
renin activity and urine excretion of
catecholamine metabolites (4-hydroxy-3-methoxyphenyl
acetic acid and metanephrines) did not change during
SCH 39370 treatment either in controls or in CHF rats. We conclude that the NEP-inhibitory compound
SCH 39370 is capable of increasing plasma
ANP concentration and urinary excretion of cGMP in rats with chronic CHF. In this severe
heart failure model, the possible beneficial effects of additional
ANP increments may be blunted, however. NEP inhibitors offer a novel approach to study the significance of
ANP elevation in chronic CHF.