Discovery and Therapeutic Utility of Vasopressin Antagonists in Rats
Discovery and Therapeutic Utility of Vasopressin Antagonists in Rats
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大鼠加压素拮抗剂的发现及其治疗用途
DOI：
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发表时间：
1986
影响因子：
3
通讯作者：
F. Stassen
中科院分区：
文献类型：
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作者：
L. Kinter;G. Dytko;D. Ashton;J. McDonald;W. Huffman;F. Stassen
加压素是调节哺乳动物肾水重吸收的主要生理因子。加压素刺激水重吸收的抑制剂以前已被用作实验动物和人类的利尿剂。本研究描述并表征了强效加压素拮抗剂 desGly d(CH2)5D-Tyr(Et)VAVP (SK&F 101926) 及相关类似物对清醒大鼠肾水和溶质排泄的药理作用。 SK&F 101926 的给药与清醒缺水大鼠肾水排泄的剂量依赖性增加相关。在这些测试中，选择性加压素升压药 (V1) 拮抗剂 (SK&F 100273) 作为利尿剂无效。 SK&F 101926 以竞争性方式拮抗清醒的含水大鼠中外源性加压素刺激的抗利尿作用。当施用 SK&F 101926 时，仅观察到 Na+、K+ 和尿素的肾脏排泄略有增加。内源性肌酐排泄的变化与 SK&F 101926 的给药无关，表明该药物不会影响肾小球滤过率。 SK&F 101926 替代给药途径的生物等效性排序为腹膜内 = 静脉内 = 肌内 = 皮下 > 鼻内 > 直肠、眼部和口服。 SK&F 101926（20 μg/kg/天）可有效阻止抗利尿激素不当综合征 (SIADH) 大鼠模型中低钠血症的发生。 SK&F 100273 (100 μg/kg) 会加速大鼠内毒素相关性休克的发生。我们得出结论，SK&F 101926 对大鼠来说是一种有效的水利尿剂。作用机制很可能是血管加压素对肾上皮 (V2) 受体的拮抗作用。 SK&F 101926 和其他加压素拮抗剂预示着一类新的强效防水剂，可能可用于治疗以体内水分过多和/或加压素分泌不当为特征的临床病症和病理。表明了加压素 V1 受体激活在感染性休克发病机制中的作用。
Vasopressin is the primary physiological factor regulating renal water reabsorption in mammals. Inhibitors of vasopressin-stimulated water reabsorption have previously been used as water diuretic agents in both experimental animals and man. The present studies describe and characterize the pharmacological effects of the potent vasopressin antagonist desGly d(CH2)5D-Tyr(Et)VAVP (SK&F 101926) and related analogs on renal water and solute excretion in conscious rats. Administration of SK&F 101926 was associated with dose-dependent increases in renal water excretion in conscious hydropenic rats. A selective vasopressin pressor (V1) antagonist (SK&F 100273) was inactive as a diuretic agent in these tests. SK&F 101926 antagonized, in a competitive fashion, exogenous vasopressin-stimulated antidiuresis in conscious water-loaded rats. Only modest increases in renal excretion of Na+, K+, and urea were observed when SK&F 101926 was administered. No changes in endogenous creatinine excretion were associated with the administration of SK&F 101926, suggesting that this drug does not affect glomerular filtration rate. The rank order of bioequivalency of alternative routes of administration of SK&F 101926 was intraperitoneal = intravenous = intramuscular = subcutaneous > intranasal ≫ rectal, ocular, and oral. SK&F 101926 (20 μg/kg/day) was effective in blocking the development of hyponatremia in a rat model of the syndrome of inappropriate antidiuretic hormone (SIADH). SK&F 100273 (100 μg/kg) hastened the onset of endotoxin-associated shock in rats. We conclude that SK&F 101926 is a potent water diuretic (aquaretic) agent in rats. The mechanism of action is most probably antagonism of vasopressin at renal epithelial (V2) receptors. SK&F 101926 and other vasopressin antagonists herald a new class of potent aquaretic agents potentially useful for the treatment of clinical conditions and pathologies characterized by excessive body water and/or inappropriate secretion of vasopressin. A role for vasopressin V1 -receptor activation in the pathogenesis of septic shock is indicated.