Neutral endopeptidase 24.11 inhibition may not exhibit beneficial haemodynamic effects in patients with congestive heart failure.
OBJECTIVE
Inhibition of neutral endopeptidase 24.11 (NEP) prevents degradation of plasma atrial natriuretic peptide (ANP), a substance with vasodilatory and natriuretic properties. The aim of the study was to investigate the haemodynamic and endocrine effects of the NEP inhibitor candoxatril in patients with congestive heart failure (CHF).


METHODS
In a randomized double-blind, parallel group study design, 24 patients with CHF received a 10-day oral drug treatment with candoxatril (25, 100 or 400 mg b.i.d.) or placebo. Invasive haemodynamics and laboratory parameters were measured on days 1 and 10.


RESULTS
On the first treatment day, candoxatril produced a dose-dependent increase in plasma cyclic GMP, the second messenger of ANP. At doses of 100 and 400 mg, candoxatril induced an increase (!) in systemic vascular resistance (SVR) and a decrease in cardiac index (CI), which was not observed with placebo and the lower candoxatril dose.


CONCLUSIONS
Despite significant activation of the ANP system, reflected by a dose-dependent increase in plasma cyclic GMP concentrations, high doses of candoxatril induced systemic vasoconstrictory rather than vasocilatory effects in patients with CHF. Therefore NEP inhibition by candoxatril may not exhibit beneficial haemodynamic effects in CHF.
Kentsch
M
M
Department of Internal Medicine, Hansestadt Stralsund, Germany.
Otter
W
W
Drummer
C
C
Nötges
A
A
Gerzer
R
R
Müller-Esch
G
G
D000450:Aldosterone / Q000097:blood; D009320:Atrial Natriuretic Factor / Q000097:blood; D000242:Cyclic AMP / Q000032:analysis; D004311:Double-Blind Method; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use*; D008875:Middle Aged; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011422:Propionates / Q000494:pharmacology / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000627:therapeutic use*
D007189:Indans; D011422:Propionates; D011480:Protease Inhibitors; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; C062766:candoxatril; D000242:Cyclic AMP; D015260:Neprilysin