The vasopressin-aquaporin 2 system plays a key role in urine concentration in dehydration. In contrast to the up-regulation of aquaporin 2, the down-regulation of vasopressin V2 receptor in dehydration is known. We investigated the mechanisms of this down-regulation in dehydration using reverse transcription-competitive polymerase chain reaction (RT-competitive PCR) and Western blot analysis. The incubation of microdissected inner medullary collecting ducts (IMCDs) in a hypertonic medium or with vasopressin stimulated V2 receptor mRNA and protein expression, showing that dehydration-induced hyperosmolality in renal medulla and increased plasma arginine vasopressin (AVP) concentration should up-regulate V2 receptor. The presence of inhibitory factors on V2 receptor in dehydration was suggested. Prostaglandin E2 is known to inhibit AVP-induced cyclic adenosine monophosphate (cAMP) production and to increase production in dehydration. Prostaglandin E2 slightly stimulated V2 receptor mRNA expression in IMCD in vitro. However, PGE2 inhibited V2 receptor mRNA expression in IMCD in the presence of 10^-9M vasopressin. The blockade of PGE2 synthesis by indomethacin in dehydrated rats increased V2 receptor protein expression after 24-48 hr with an early increase in V2 receptor mRNA expression. In summary, these data suggest that increased production of PGE2 in renal medulla plays a key role in the down-regulation of V2 receptor in dehydration.