title: Up-regulation of renal adenylate cyclase-coupled vasopressin receptors after chronic administration of vasopressin antagonists to rats.
abstract: Chronic administration of vasopressin [antidiuretic hormone (ADH)] antagonists has been shown to produce a paradoxical antidiuresis in both ADH-replete and ADH-deplete (diabetes insipidus) rats. The antidiuretic effect is progressive, reaching maximal levels in 4 to 5 days, and sustained, persisting for at least 24 hr after cessation of treatment. The antidiuretic profiles associated with these antagonists do not coincide with the profiles of potent ADH agonists, arginine vasopressin and 1-deamino-8-D-arginine vasopressin. To investigate the mechanism of the antidiuretic effect of ADH antagonists, male diabetes insipidus rats were administered antagonists selective for the renal [adenylate cyclase-coupled (V2)] or pressor (phosphytidyl inositol-coupled) vasopressin receptor and urine output (volume and osmolality) and renal vasopressin receptor properties (concentration and affinity) were determined and compared to rats treated with arginine vasopressin or 1-deamino-8-D-arginine vasopressin. After acute administration, only the V2-acting antagonists were antidiuretic, but were 3 orders of magnitude less potent than 1-deamino-8-D-arginine vasopressin. Following chronic administration, all of the antagonists were antidiuretic, but the level of antidiuresis achieved with the phosphytidyl inositol-coupled vasopressin receptor-selective antagonist was 2- to 3-fold lower than for analogs with V2 activity. Maximal antidiuretic effects were realized in 5 days and were apparent at 24 hr after cessation of treatment. The antidiuretic activities and potencies of the ADH antagonists appeared to be increased following chronic antagonist administration. Finally, renal vasopressin receptor concentration was significantly elevated 24 hr after cessation of antagonist treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Investigative Toxicology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
authors.forename: S
authors.initials: S
authors.lastname: Caltabiano
authors.forename: L B
authors.initials: LB
authors.lastname: Kinter
mesh_terms: D000262:Adenylyl Cyclases / Q000187:drug effects / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051381:Rats; D011910:Rats, Brattleboro; D011945:Receptors, Angiotensin / Q000378:metabolism / Q000502:physiology*; D017483:Receptors, Vasopressin; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology; D014563:Urodynamics / Q000187:drug effects; D014667:Vasopressins / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D057911:Angiotensin Receptor Antagonists; D011945:Receptors, Angiotensin; D017483:Receptors, Vasopressin; D014667:Vasopressins; D001127:Arginine Vasopressin; D000262:Adenylyl Cyclases