Desensitization of the adrenocorticotrophin responses to arginine vasopressin and corticotrophin-releasing hormone in ovine anterior pituitary cells

Abstract

Following repeated or prolonged exposure to either corticotrophin-releasing hormone (CRH) or arginine vasopressin (AVP), pituitary adrenocorticotrophin (ACTH) responsiveness is reduced. This study compared the characteristics of desensitization to CRH and AVP in perifused ovine anterior pituitary cells. Desensitization to AVP occurred at relatively low AVP concentrations and was both rapid and readily reversible. Treatment for 25 min with AVP at concentrations greater than 2 nM caused significant reductions in the response to a subsequent 5 min 100 nM AVP pulse (IC 50 =6·54 nM). Significant desensitization was observed following pretreatment with 5 nM AVP for as briefly as 5 min. Desensitization was greater following a 10 min pretreatment, but longer exposures caused no further increase. Resensitization was complete within 40 min following 15 min treatment with 10 nM AVP. Continuous perifusion with 0·01 nM CRH had no effect on AVP-induced desensitization. Treatment with 0·1 nM CRH for either 25 or 50 min caused no reduction in the response to a subsequent 5 min stimulation with 10 nM CRH. When the pretreatment concentration was increased to 1 nM significant desensitization was observed, with a greater reduction in response occurring after 50 min treatment. Recovery of responsiveness was progressive following 50 min treatment with 1 nM CRH and was complete after 100 min. Our data show that in the sheep AVP desensitization can occur at concentrations and durations of AVP exposure within the endogenous ranges. This suggests that desensitization may play a key role in regulating ACTH secretion in vivo. If, as has been suggested, CRH acts to set corticotroph gain while AVP is the main dynamic regulator, any change in responsiveness to CRH may significantly influence the overall control of ACTH secretion.

Stress Responsiveness of the Hypothalamic–Pituitary–Adrenal Axis: Age-Related Features of the Vasopressinergic Regulation

“…For example, in humans (DeBold et al, 1984; Favrod-Coune et al, 1993), non-human primates (Goncharova, 2009a), rats (Vale et al, 1983; Antoni, 1993; Serradeil-Le Gal et al, 2005), and horses (Evans et al, 1993), CRH is a much more potent secretagogue than AVP. At the same time, some groups have reported that in the sheep AVP is the more potent secretagogue (Familari et al, 1989; Hassan et al, 2003). In all cases, a marked synergism between CRH and AVP has been observed (Antoni, 1993; Favrod-Coune et al, 1993; Aguilera et al, 1994; Aguilera, 1998; Serradeil-Le Gal et al, 2005).…”

“…The ability of both neuropeptides CRH and AVP to stimulate the secretion of ACTH has been demonstrated in humans (DeBold et al, 1984; Salata et al, 1988; Favrod-Coune et al, 1993) and various other species, including non-human primates (Goncharova and Lapin, 2002; Goncharova, 2009a), rats (Vale et al, 1983; Antoni, 1993), mice (Muller et al, 2000; Lolait et al, 2007), horses (Evans et al, 1993), and sheep (McFarlane et al, 1995; Hassan et al, 2003). The relative importance of each seems to vary depending on the species.…”

Mechanisms of desensitization of the adrenocorticotropin response to arginine vasopressin in ovine anterior pituitary cells

“…If PKC was involved in the desensitization process, pretreatment with DiC 8 would be expected to reduce the response to a subsequent stimulation with AVP. The experimental design was similar to that which we have previously used to investigate desensitization of the ACTH response to AVP (Hassan et al 2003): perifused cells were stimulated with 5-min pulses of AVP after 100, 180 and 260 min of perifusion, resulting in three peaks of ACTH secretion (Fig. 1a).…”

“…The experimental protocol employed was based on that which we have previously used to investigate resensitization of the ACTH response to AVP (Hassan et al 2003). Perifused cells were stimulated with a single, 5-min pulse of 100 nM AVP after 160 min of perifusion, resulting in a characteristic peak of ACTH secretion.…”

“…The effects of AVP on corticotroph cells of the anterior pituitary are mediated by activation of the V1b (also known as V3) vasopressin receptor, a phospholipase C (PLC)-coupled member of the G protein-coupled receptor (GPCR) superfamily (De Keyzer et al 1994). Recently, we have shown that treatment of perifused ovine anterior pituitary cells with AVP can cause desensitization of the ACTH response to a subsequent stimulation with AVP (Hassan et al 2003). This desensitization occurred at concentrations and durations of AVP treatment that were within the ranges of AVP pulses measured in the sheep portal circulation, suggesting that the desensitization process might play an important physiologic role in the regulation of ACTH secretion.…”