Adenylate-Cyclase-Dependent Pituitary Adrenocorticotropin Secretion Is Defective in the Inflammatory-Disease-Susceptible Lewis Rat

Abstract

Susceptibility to arthritis in the Lewis rat is associated with a defect of the hypothalamic-pituitary-adrenal axis. We examined the pituitary corticotropes of both intact and dexamethasone-treated male and female inflammatory-disease-susceptible Lewis and inflammatory-disease-resistant Fischer rats. We determined adrenocorticotropin levels in the media from primary cultures of anterior pituitary cells of both strains. In other experiments we have measured intracellular cyclic adenosine monophosphate and inositol monophosphate accumulation. Cells were incubated with corticotropin-releasing hormone, arginine vasopressin, forskolin, phorbol myristate acetate, or thyrotropin-releasing hormone. Corticotropin-releasing hormone stimulated adrenocorticotropin secretion from both male and female Lewis rat pituitary cells in a concentration-dependent manner. Basal and stimulated adrenocorticotropin levels in cells from Lewis rats were lower than those measured in the incubation media of Fischer rat dispersed pituitary cells. Arginine vasopressin, as well as forskolin and phorbol myristate acetate, induced a significant release of adrenocorticotropin from pituitary cells of both strains. Incubation with corticotropin-releasing hormone did not produce a significant accumulation of intracellular cyclic adenosine monophosphate in Lewis rat dispersed pituicytes of both sexes. On the other hand, forskolin induced a significant increase of intracellular cyclic adenosine monophosphate in the same cultures. Finally, inositol monophosphate accumulation was comparable in pituitary cells from both Lewis and Fischer rats of both sexes incubated with thyrotropin-releasing hormone. Adrenocorticotropin secretion from pituitary cells of male Lewis rats treated in vivo with dexamethasone was either reduced or abolished following incubation with different secretagogues. A defect in pituitary adrenocorticotropin secretion could be among the causes of the hyporesponsiveness of the hypothalamic-pituitary-adrenal axis in the Lewis rat. Such a defect appears to be associated with dysfunction of receptor-coupled events related to adenylate cyclase.

Chronic Daily Ethanol and Withdrawal: 1. Long‐Term Changes in the Hypothalamo‐Pituitary‐Adrenal Axis

“…This hypothesis is consistent with evidence that Lewis rats, which exhibit low plasma corticosterone levels and are prone to alcohol consumption (Suzuki et al, 1988), are characterized by a hyporesponsive hypothalamic CRF system Sternberg et al, 1992), defective pituitary adenylate cyclase-dependent ACTH secretion (Bernardini et al, 1996), and increased gene expression for glucocorticoid and mineralocorticoid receptors (Oitzel et al, 1995;Smith et al, 1994) that mediate corticosterone negative feedback on the HPA axis. Likewise, atypical depression in humans has been reported to be characterized by decreased plasma cortisol (Chrousos, 1995) and low csf CRF levels (Geracioti et al, 1997).…”

Ion Channels and Signaling in the Pituitary Gland

“…Forskolin, an activator of AC, and cell-permeable cAMP stimulate GH (531), PRL (218), LH (532,533), and ACTH release (534). In single lactotrophs, cAMP-induced facilitation of exocytosis, measured by changes in the plasma membrane capacitance, was also detected (430).…”

Endocrine Perturbation Increases Susceptibility of Mice to Anthrax Lethal Toxin

“…Hyper-HPA axis and GC responsiveness have been associated with resistance to inflammatory disease, while a blunted HPA axis and GC response are associated with greater susceptibility to some autoimmune/ inflammatory diseases (8,40,41,59). BALB/c mice and Fischer rats are hyper-GC responsive and resistant to inflammatory disease compared to hypo-HPA-responsive C57BL/6 mice or Lewis rats (2,3,8,37,38,40,41,59). Interruption of the GC response by adrenalectomy (ADX) or with a GR antagonist (RU486) enhances the inflammatory responses through inhibition of GR-mediated cytokine gene repression and increases mortality in otherwise inflammation-resistant hosts.…”