The susceptibility of Lewis (LEW/N) rats to severe inflammatory disease has been causally associated with subnormal responsiveness of their hypothalamic CRH-secreting neurons and, consequently, their hypothalamic-pituitary-adrenal axis to several stimulatory neurotransmitters and inflammatory cytokines. In the present study we investigated in this strain the secretory dynamics of another major activator of pituitary ACTH secretion, arginine vasopressin (AVP). To accomplish this, we evaluated the circadian plasma concentrations and circadian and glucocorticoid-induced changes in hypothalamic content and in vitro release of AVP in 8- to 10-week-old female LEW/N rats and compared these measurements to those obtained in parallel from age- and sex-matched histocompatible, inflammatory disease-resistant Fischer (F344/N) rats. Plasma concentrations and hypothalamic content and in vitro release of AVP were significantly elevated in LEW/N compared to F344/N rats in both the morning and evening. These indices of higher AVP secretion in LEW/N than in F344/N rats were also present after chronic dexamethasone treatment. These findings suggest increased AVP production and release in LEW/N rats, perhaps representing an adaptive compensation for insufficient CRH and glucocorticoid secretion. The high levels of circulating AVP might contribute to the excessive inflammatory responses of these animals.