Endopeptidase 24.11 inhibition by SCH 42495 in essential hypertension.
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)
Department of Cardiology, Princess Margaret Hospital, Christchurch, New Zealand.
A M
AM
Richards
I G
IG
Crozier
T
T
Kosoglou
M
M
Rallings
E A
EA
Espiner
M G
MG
Nicholls
T G
TG
Yandle
H
H
Ikram
C
C
Frampton
D000328:Adult; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000652:urine; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D006157:Guanosine Monophosphate / Q000097:blood / Q000652:urine; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008875:Middle Aged; D009318:Natriuresis / Q000187:drug effects; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000097:blood; D009638:Norepinephrine / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects; D012964:Sodium / Q000652:urine; D013564:Sympathetic Nervous System / Q000187:drug effects; D013997:Time Factors
C069018:SCH 42495; D006157:Guanosine Monophosphate; D009320:Atrial Natriuretic Factor; D012964:Sodium; D008715:Methionine; D015260:Neprilysin; D009638:Norepinephrine