The detailed integrated renal, hormonal, and hemodynamic effects of acute (first dose) and established (4 days) inhibition of
endopeptidase 24.11 by
SCH 42495 (200 mg, every 12 hours) were documented in eight patients with
essential hypertension in a double-blind, balanced random-order, crossover study.
SCH 42495 suppressed plasma
endopeptidase activity (> 90%, P < .001) for the duration of the dosing period. Initially, plasma
atrial natriuretic factor levels increased markedly (+123%, P < .01) and remained elevated, although to a lesser extent (+34%, P < .01), with established
enzyme inhibition. Cyclic
guanosine monophosphate in both plasma and urine remained elevated throughout the treatment period. Significant augmentation of
sodium excretion in excess of placebo values (96 +/- 27 mmol
sodium, P < .001) was established in the initial 24 hours of dosing but later became attenuated, with a mild antinatriuresis (P < .01) in the latter 3 days of treatment. Blood pressure, heart rate, the renin-angiotensin-aldosterone system, and plasma
norepinephrine levels were all initially (first dose) unchanged. With established
enzyme inhibition (day 4), however, blood pressure was significantly lower (mean 24-hour values, 9.3 +/- 3/-3.8 +/- 1 mm Hg, P < .05 for both systolic and diastolic pressures) than matched placebo values, whereas heart rate was higher (2.7 +/- 1 beats per minute, P < .01). Mean 24-hour values of plasma
renin activity (+33%, P < .05),
aldosterone (+36%, P < .05), and
norepinephrine (+40%, P < .001) were all clearly increased above placebo values with established
enzyme inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)