Article: PDF OnlyDiscovery and Therapeutic Utility of Vasopressin Antagonists in RatsKinter, Lewis B.; Dytko, George; Ashton, Daryl; McDonald, Jeanne; Huffman, William; Stassen, Frans Author Information Departments of Pharmacology, Molecular Pharmacology, and Peptide Chemistry, Smith Kline & French Laboratories, Swedeland, Pennsylvania, U.S.A. Journal of Cardiovascular Pharmacology: Volume 8 - Issue - p S36-S43 Free Abstract 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. © Lippincott-Raven Publishers.
