Renal and hormonal effects of chronic inhibition of neutral endopeptidase (EC 3.4.24.11) in normal man.
1. Acute pharmacological inhibition of the enzyme neutral endopeptidase (EC 3.4.24.11), which cleaves the cardiac hormone atrial natriuretic peptide, raises endogenous levels of the hormone. Short-term administration of inhibitors causes natriuresis and diuresis in normal and hypertensive subjects; we report here the effects of an orally active neutral endopeptidase inhibitor (candoxatril, 200 mg) given twice daily for 10 days to normal salt-replete male subjects (n = 12) in a placebo-controlled cross-over study. 2. Candoxatril administration caused a transient natriuresis on day 1 of treatment, but this was not sustained, and cumulative sodium excretion at the end of the study was not altered by active therapy [1720 +/- 40 versus 1734 +/- 57 (placebo) mmol; means +/- SEM]; exchangeable body sodium content was similarly unchanged. However, urinary cyclic GMP excretion was elevated throughout the active treatment phase when compared with placebo. 3. Although a change in plasma levels of atrial natriuretic peptide could not be demonstrated, platelet atrial natriuretic peptide binding sites were reduced by active treatment [23 +/- 3 versus 39 +/- 4 (placebo) fmol/10(9); P < 0.001]. 4. Basal blood pressure and heart rate were not affected by candoxatril treatment. After 10 days of therapy subjects were given incremental infusions of angiotensin II (2, 4 and 8 ng min-1 kg-1) followed by phenylephrine. Although active therapy had not altered basal plasma concentrations of active renin and angiotensin II, levels of angiotensin II during infusion of the octapeptide were higher during the active phase.(ABSTRACT TRUNCATED AT 250 WORDS)
O'Connell
J E
JE
MRC Blood Pressure Unit, Western Infirmary, Glasgow, U.K.
Jardine
A G
AG
Davies
D L
DL
McQueen
J
J
Connell
J M
JM
D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000097:blood* / Q000378:metabolism; D001665:Binding Sites; D001792:Blood Platelets / Q000378:metabolism; D004311:Double-Blind Method; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010656:Phenylephrine / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology*; D012016:Reference Values
D007189:Indans; D011422:Propionates; D000804:Angiotensin II; D010656:Phenylephrine; D009320:Atrial Natriuretic Factor; C062766:candoxatril; D015260:Neprilysin