Clearance of brain natriuretic peptide in patients with chronic heart failure: indirect evidence for a neutral endopeptidase mechanism but against an atrial natriuretic peptide clearance receptor mechanism.
1. Brain natriuretic peptide is a new natriuretic hormone with striking similarity to atrial natriuretic peptide, but there are no previous data concerning its clearance in man. Two pathways of clearance for atrial natriuretic peptide are recognized: degradation by neutral endopeptidase and binding to atrial natriuretic peptide clearance receptors. We have examined the effect of candoxatril, an inhibitor of neutral endopeptidase (dose range 10-200 mg), and the effect of an infusion of a pharmacological dose [45 micrograms (90 micrograms in two patients)] of synthetic human atrial natriuretic peptide on plasma human brain natriuretic peptide-like immunoreactivity levels in seven patients with mild to moderate chronic heart failure. 2. Plasma human brain natriuretic peptide-like immunoreactivity levels were elevated in all patients (mean +/- SEM 22.0 +/- 6.2 pmol/l) compared with healthy control subjects (1.3 +/- 0.2 pmol/l, n = 11). 3. In all patients, candoxatril increased both plasma atrial natriuretic peptide (P less than 0.05) and plasma human brain natriuretic peptide-like immunoreactivity (P less than 0.05) levels. 4. By contrast, an exogenous infusion of atrial natriuretic peptide had no effect on plasma human brain natriuretic peptide-like immunoreactivity levels despite increasing the plasma atrial natriuretic peptide concentration to 424 +/- 74 pmol/l, which is a level of atrial natriuretic peptide which would have 'swamped' all atrial natriuretic peptide clearance receptors. 5. We have therefore shown that plasma human brain natriuretic peptide-like immunoreactivity levels in chronic heart failure are increased by a neutral endopeptidase inhibitor, but are unchanged by an exogenous infusion of atrial natriuretic peptide.(ABSTRACT TRUNCATED AT 250 WORDS)
Lang
C C
CC
Department of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee, U.K.
Motwani
J G
JG
Coutie
W J
WJ
Struthers
A D
AD
D000368:Aged; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000097:blood*; D006801:Humans; D007189:Indans / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain; D009419:Nerve Tissue Proteins / Q000097:blood*; D011422:Propionates / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D017461:Receptors, Atrial Natriuretic Factor; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology
D007189:Indans; D009419:Nerve Tissue Proteins; D011422:Propionates; D011480:Protease Inhibitors; D011956:Receptors, Cell Surface; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; C062766:candoxatril; D017461:Receptors, Atrial Natriuretic Factor