Chronic inhibition of endopeptidase 24.11 in essential hypertension: evidence for enhanced atrial natriuretic peptide and angiotensin II.
OBJECTIVE
To determine the renal, endocrine and haemodynamic effects of an orally active inhibitor of the neutral endopeptidase EC 3.4.24.11 in essential hypertension.


METHODS
Two groups of 12 white male patients with essential hypertension were treated with candoxatril at 25 mg every 12 h (group 1) or at 200 mg every 12 h (group 2) for 5 days in double-blind, placebo-controlled, crossover studies.


RESULTS
Candoxatril enhanced natriuresis over the initial 48 h of treatment. Twenty-four-hour diurnal hormone profiles (day 4) showed modest elevations in plasma atrial natriuretic factor (ANF) concentrations and more clear-cut increases in plasma and urinary cyclic GMP. Plasma angiotensin II and aldosterone concentrations were also significantly increased. Plasma catecholamine concentrations were significantly increased by the higher dose of candoxatril. Blood pressure (day 4, 24-h intra-arterial recordings) fell significantly with both doses. The infusions of exogenous ANF and angiotensin II on day 5 showed that candoxatril impaired the metabolic clearance of both ANF and angiotensin II with consequent enhancement of the biological effects of both effector peptides.


CONCLUSIONS
Candoxatril augments the effects of ANF and lowers blood pressure in patients with hypertension. However, the antihypertensive effects may be offset by increased angiotensin-aldosterone and sympathetic nervous system activity. The blood pressure response to endopeptidase inhibition in hypertensive patients may depend on the relative effects on humoral vasodilator (including ANF) and vasoconstrictor (including the angiotensin-aldosterone and sympathetic) systems.
Department of Cardiology, Princess Margaret Hospital, Christchurch, New Zealand.
A M
AM
Richards
G A
GA
Wittert
I G
IG
Crozier
E A
EA
Espiner
T G
TG
Yandle
H
H
Ikram
C
C
Frampton
D000328:Adult; D000804:Angiotensin II / Q000008:administration & dosage / Q000097:blood; D009320:Atrial Natriuretic Factor / Q000008:administration & dosage / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D007189:Indans / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009318:Natriuresis / Q000187:drug effects; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011422:Propionates / Q000494:pharmacology*; D013997:Time Factors
D007189:Indans; D011422:Propionates; D000804:Angiotensin II; D009320:Atrial Natriuretic Factor; C062766:candoxatril; D015260:Neprilysin