Jiménez W, Gal C S, Ros J, Cano C, Cejudo P, Morales-Ruiz M, Arroyo V, Pascal M, Rivera F, Maffrand J P, Rodés J
Hormonal Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic Universitari, University of Barcelona and Instituto Reina Sofia de Investigaciones Nefrológicas, Barcelona, Spain.
J Pharmacol Exp Ther. 2000 Oct;295(1):83-90.
Water retention in experimental cirrhosis can be reversed by blocking V(2)-vasopressin (AVP) receptors with the nonpeptide antagonist OPC-31260 or by using the kappa-opioid receptor agonist niravoline, a compound inhibiting central AVP release. However, reluctance to use these drugs in human beings has emerged because the former loses aquaretic efficacy in rats after 2 days of treatment and the latter may have adverse effects in humans. Recently, a new potent and selective nonpeptide V(2)-AVP receptor antagonist, SR121463, has been developed that could be useful for the treatment of dilutional hyponatremia in human cirrhosis. The current study assessed the aquaretic efficacy of 10-day chronic oral administration of SR121463 (0.5 mg/kg/day) in cirrhotic rats with ascites and impaired water excretion after a water load (minimum urinary osmolality >160 mOsm/kg and percentage of water load excreted <60%). Urine volume (UV), osmolality (U(Osm)V), and sodium excretion (U(Na)V) were measured daily. At the end of the 10-day treatment, mean arterial pressure also was measured. In basal conditions cirrhotic rats showed ascites, sodium retention, and impaired water excretion. UV, U(Osm)V, and U(Na)V did not change throughout the study in cirrhotic rats receiving the vehicle. In contrast, SR121463 increased UV and reduced U(Osm)V during the 10-day treatment. This resulted in a greater renal ability to excrete a water load and normalization in serum sodium and osmolality. During the first 6 days of treatment, SR121463 also increased U(Na)V without affecting mean arterial pressure. These data suggest that SR121463 could be of therapeutical value for chronic management of human cirrhosis.
实验性肝硬化中的水潴留可通过用非肽拮抗剂OPC - 31260阻断V(2)-血管加压素（AVP）受体或使用κ-阿片受体激动剂尼拉沃林（一种抑制中枢AVP释放的化合物）来逆转。然而，由于前者在治疗2天后在大鼠中失去利水作用，而后者可能对人类有不良反应，因此人们对在人类中使用这些药物有所顾虑。最近，一种新型强效选择性非肽V(2)-AVP受体拮抗剂SR121463已被研发出来，它可能对治疗人类肝硬化中的稀释性低钠血症有用。当前研究评估了对有腹水且水负荷后排水受损（最低尿渗透压>160 mOsm/kg且排出的水负荷百分比<60%）的肝硬化大鼠进行为期10天的慢性口服给予SR121463（0.5 mg/kg/天）的利水效果。每天测量尿量（UV）、渗透压（U(Osm)V）和钠排泄量（U(Na)V）。在为期10天的治疗结束时，还测量了平均动脉压。在基础状态下，肝硬化大鼠表现出腹水、钠潴留和排水受损。接受赋形剂的肝硬化大鼠在整个研究过程中UV、U(Osm)V和U(Na)V均未改变。相比之下，在为期10天的治疗期间，SR121463增加了UV并降低了U(Osm)V。这导致肾脏排出水负荷的能力增强，血清钠和渗透压恢复正常。在治疗的前6天，SR121463还增加了U(Na)V，而不影响平均动脉压。这些数据表明，SR121463可能对人类肝硬化的慢性管理具有治疗价值。
