The effects of repeated doses of the
endopeptidase inhibitor candoxatrilat (150 mg i.v.) were examined over a 24-hour period in patients with severe chronic
heart failure (New York Heart Association class III-IV). Plasma alpha-hANF(99-126) was elevated at baseline (235 +/- 59 pg/ml), increased 2.5-fold at 2 hours after the first dose, and remained significantly elevated throughout the 24-hour protocol. In contrast, pro-hANF(31-67) decreased from 3,151 +/- 616 to 2,072 +/- 362 pg/ml (p less than 0.05). Cardiac index (CI) increased only transiently after the first dose of
candoxatrilat (CI, 2.11 +/- 0.2 to 2.67 +/- 0.28 l/min/m2, p less than 0.05).
Sodium excretion increased sixfold (p less than 0.05) 2 hours after the first dose of
candoxatrilat and remained significantly elevated throughout the protocol. Degree of natriuresis and diuresis in response to
candoxatrilat was closely related to baseline cardiac output. Glomerular filtration rate and volume excretion did not change significantly. Pulmonary capillary wedge pressure fell from 23 +/- 3 to 18 +/- 3 mm Hg (p less than 0.05) and remained below baseline throughout the 24 hours. Arterial pressure, heart rate, and total peripheral resistance did not change significantly during the 24-hour period. Urinary cGMP excretion increased fivefold (p less than 0.05), whereas urinary
ANF immunoreactivity and plasma cGMP levels remained unchanged. Excretion of
prostacyclin metabolite 6-keto-PGF-1 alpha increased 3.3-fold (p less than 0.05). Plasma
norepinephrine and
epinephrine levels decreased significantly after
candoxatrilat and remained suppressed over the 24-hour period. There was also a transient reduction in plasma
vasopressin,
aldosterone levels, and plasma
renin activity. Hematocrit, total
protein content, and
plasma albumin concentrations did not change, indicating that no fluid shift into the extravascular space had occurred.
CONCLUSIONS: 1) The inhibition of
ANF degradation causes sustained drop in left and right atrial pressures that appears to be mediated by an inhibition of neurohumoral activity; 2) concomitant inhibition of
bradykinin breakdown (which in turn stimulates renal
prostacyclin synthesis) contributes to natriuresis; 3) the close correlation between renal response and baseline cardiac index indicates that an inadequate renal perfusion secondary to
low cardiac output diminishes the efficacy of this treatment modality. This spectrum of action would be advantageous for a first-line
diuretic agent early in the course of disease rather than in patients with advanced chronic
heart failure.