Renal response to candoxatrilat in patients with heart failure.
OBJECTIVE
Our primary objective was to compare the effects of three different doses of candoxatrilat with the effects of placebo on urinary volume in patients with moderately severe heart failure. The effects of candoxatrilat on urinary composition, neuroendocrine indexes and renal hemodynamic function were also studied.


BACKGROUND
Candoxatrilat, a neutral endopeptidase inhibitor, reduces degradation of atrial natriuretic peptide and provokes diuresis in patients with mild heart failure, but the renal effects have not been studied in patients with moderately severe heart failure in a placebo-controlled study.


METHODS
In a double-blind crossover trial, the effects of intravenous boluses of saline vehicle (placebo) and 50, 100 and 200 mg of candoxatrilat were compared on separate days in 12 patients with heart failure. Urinary output and composition were measured for 8 h. Renal blood flow and glomerular filtration rate were determined by radionuclide techniques. Blood was withdrawn for the measurement of hormones before and 3 h after dosing.


RESULTS
All doses of candoxatrilat increased urinary volume (e.g., [mean +/- SEM] 263 +/- 53 to 490 +/- 82 ml for saline solution and the 200-mg dose, respectively, p < 0.01) and sodium content (14 +/- 4 to 37 +/- 11 mmol, p < 0.001) in the 1st 4 h after dosing. Plasma atrial natriuretic peptide increased (140 +/- 26 to 279 +/- 37 pg/ml, p < 0.01), whereas aldosterone decreased (178 +/- 41 to 125 +/- 35 pg/ml, p < 0.01), and renin activity was unchanged (10 +/- 2 to 12 +/- 3 ng/ml per h).


CONCLUSIONS
Candoxatrilat given acutely causes diuresis, even in patients with moderately severe heart failure.
Good
J M
JM
Department of Medicine (Cardiology), Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.
Peters
M
M
Wilkins
M
M
Jackson
N
N
Oakley
C M
CM
Cleland
J G
JG
D000368:Aged; D000450:Aldosterone / Q000097:blood; D009320:Atrial Natriuretic Factor / Q000097:blood; D018592:Cross-Over Studies; D006152:Cyclic GMP / Q000652:urine; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage*; D004231:Diuresis / Q000187:drug effects; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004573:Electrolytes / Q000652:urine; D006333:Heart Failure / Q000188:drug therapy* / Q000652:urine; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D012079:Renal Circulation / Q000187:drug effects*; D012964:Sodium / Q000652:urine; D014556:Urine; D014660:Vasoactive Intestinal Peptide / Q000097:blood
D003509:Cyclohexanecarboxylic Acids; D004573:Electrolytes; D014660:Vasoactive Intestinal Peptide; D000450:Aldosterone; C060942:candoxatrilat; D009320:Atrial Natriuretic Factor; D012964:Sodium; D015260:Neprilysin; D006152:Cyclic GMP