Further in vivo evidence for antagonist-to-antidiuretic action of arginine vasopressin

The effect of a new arginine vasopressin (AVP) analogue, [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid), 2-O-ethyltyrosine, 4-valine]AVP or d(CH2)5Tyr(Et)VAVP, was examined on exogenous and endogenous AVP in the conscious rat. An intravenous injection of 8 micrograms/kg body wt of the AVP analogue completely blocked the antidiuretic effect of exogenous AVP (4 ng/kg body wt iv). Similarly, 8 micrograms/kg of the AVP analogue totally abolished the antidiuretic effect of infused AVP (0.1 mU X kg-1 X min-1) in the homozygous Brattleboro rats with central diabetes insipidus. The antagonism of this antidiuretic effect of exogenous AVP occurred in the absence of changes in urinary solute excretion, glomerular filtration rate (GFR), and mean arterial pressure. Intraperitoneal administration of the AVP analogue (30 micrograms/kg body wt) decreased the mean urinary osmolality in rats after 24 h of fluid deprivation from 3,098 +/- 140 to 797 +/- 155 mosmol/kg H2O (P less than 0.001). The duration of the antagonism of endogenous AVP was approximately 4.5 h. The antagonism of AVP was not dependent on the vascular properties of AVP, since the AVP analogue also blocked the antidiuretic effect of exogenous 1-deamino-8-D-AVP (DDAVP), an AVP analogue with negligible vascular properties. These in vivo results therefore indicate that d(CH2)5Tyr(Et)VAVP is a specific antagonist of the hydrosmotic effect of exogenous and endogenous AVP. In contrast to some previous analogues, this effect of the AVP analogue occurred in the absence of any known diuretic factors including an increase in GFR, solute excretion, and blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)