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 greater than intranasal much greater than rectal, ocular, and oral.
SK&F 101926 (20 micrograms/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 micrograms/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.(ABSTRACT TRUNCATED AT 250 WORDS)