To assess the efficacy of
neutral endopeptidase 24.11 inhibition in the setting of elevated plasma levels of
angiotensin II (Ang II), we studied the hemodynamic, renal, and hormonal effects of bolus
injections of the potent and specific
neutral endopeptidase inhibitor
SCH 39370 or vehicle (control) in 10 sheep with Ang II-induced
hypertension. Ang II infusion (5 ng/kg per minute for 6 days) sufficient to increase plasma Ang II levels 50% to 100% induced a consistent rise in mean arterial pressure (mean increment, 15 mm Hg; P < .0001) and increased plasma
atrial natriuretic peptide (P = .017) and its second messenger cGMP (P = .049). Compared with time-matched control observations after vehicle alone,
SCH 39370 (2.5 mg/kg) further increased plasma
atrial natriuretic peptide (P = .0006), cGMP (P = .006), and plasma Ang II (P = .054). Systolic and mean arterial pressures tended to fall after
SCH 39370, but these changes were not significant compared with control. No significant changes were observed in urinary volume and
sodium excretion. Viewed in relation to previous studies in normotensive sheep, the current findings indicate that the vasodepressor response to
neutral endopeptidase inhibition is blunted in hyperangiotensinemic sheep, in which
neutral endopeptidase inhibition further augments plasma Ang II levels.