ENDOPEPTIDASE INHIBITION IN ANGIOTENSIN-INDUCED HYPERTENSION - EFFECT OF SCH-39370 IN SHEEP

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.