Scott J M, Barclay P L, Shepperson N B
Department of Cardiovascular Biology, Pfizer Central Research, Sandwich, Kent, UK.
Eur J Pharmacol. 1993 Sep 21;242(1):91-7. doi: 10.1016/0014-2999(93)90014-9.
Candoxatrilat is a potent and selective inhibitor of neutral endopeptidase (EC 3.4.24.11), the enzyme responsible for the degradation of atrial natriuretic factor (ANF). In these studies, the renal effects of candoxatrilat were investigated in euvolemic and hypervolemic anaesthetised rats. In euvolemic rats, candoxatrilat (675 micrograms/kg per h) had no effect on urine output, sodium and potassium excretion or urinary cyclic GMP excretion. However, in hypervolemic rats, the natriuretic and diuretic responses to volume expansion were markedly potentiated by the candoxatrilat infusion, with a concomitant increase in urinary cyclic GMP. Acute volume expansion was characterised by natriuresis, diuresis and increased levels of plasma ANF and cyclic GMP (1.5-fold and 2-fold increases respectively, when compared to euvolemic rats). The results presented suggest that plasma ANF levels and volume status modulate responses to neutral endopeptidase inhibition. The development of the neutral endopeptidase inhibitor, candoxatrilat, provides the opportunity to exploit endogenous ANF effectively in disease states with elevated ANF.
坎多沙坦酯是一种强效、选择性的中性内肽酶（EC 3.4.24.11）抑制剂，该酶负责降解心房利钠因子（ANF）。在这些研究中，对血容量正常和血容量过多的麻醉大鼠进行了坎多沙坦酯的肾脏效应研究。在血容量正常的大鼠中，坎多沙坦酯（675微克/千克/小时）对尿量、钠和钾排泄或尿中环鸟苷酸排泄没有影响。然而，在血容量过多的大鼠中，坎多沙坦酯输注显著增强了对容量扩张的利钠和利尿反应，同时尿中环鸟苷酸增加。急性容量扩张的特征是利钠、利尿以及血浆ANF和环鸟苷酸水平升高（与血容量正常的大鼠相比，分别增加了1.5倍和2倍）。所呈现的结果表明，血浆ANF水平和容量状态调节对中性内肽酶抑制的反应。中性内肽酶抑制剂坎多沙坦酯的开发为在ANF升高的疾病状态下有效利用内源性ANF提供了机会。
