IN-VIVO AND IN-VITRO EFFECTS OF ARGININE-VASOPRESSIN RECEPTOR ANTAGONISTS ON THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS IN THE RAT

Arginine-vasopressin (AVP) is regarded as a potent stimulator of pituitary adrenocorticotropin (ACTH) secretion and participates therefore in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis function in concert with the physiological activator of the axis, hypothalamic corticotropin-releasing hormone (CRH). We examined the effects of AVP and/or three synthetic V-1b receptor antagonists on the activity of the HPA axis in vivo and in vitro in the rat. AVP was injected intravenously to Sprague-Dawley rats (1 mu g/rat) through an indwelling jugular catheter. AVP stimulated ACTH release, with maximal effect 10 min after injection. Intravenous injection of three V-1b antagonists, [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-O-ethyltryrosine,4-valine] arginine vasopressin (d(CH2)(5)[Tyr(Et(2))]VAVP (WK 1- 1), 9-desglycine[1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid),2-O-ethyltyrosine,4-valine] arginine vasopressin desGly(9)d(CH2)(5)[Tyr(Et(2))]-VAVP (WK 3-6), and 9-desglycine[1-(beta-mercapto-beta,beta-cyclopentamethylenpropionic acid),2-D-(O-ethyl)tyrosine,4-valine] arginine vasopressin des Gly(9)d(CH2)(5)[D-Tyr(Et(2))]VAVP (AO 3-21), prevented AVP-stimulated ACTH secretion. Explanted rat hypothalami incubated in vitro with graded concentrations of AVP (10(-14)-10(-5) M) secreted immunoreactive CRH (iCRH) in a concentration-dependent fashion. Maximal stimulatory effect occurred at the concentration of 10(-6) M. Incubation of hypothalami with WK 1- 1, WK 3-6, or AO 3-21 (10(-6) M) prevented AVP-stimulated iCRH secretion. Results suggest that AVP plays a relevant, multiple role in the activation of the HPA axis in the rat. In fact, interactions between AVP and the pituitary corticotroph may not be solely due to a direct effect of AVP on ACTH secretion, but also to activation of the hypothalamic CRH neuron. These effects of AVP appear to be mediated by the V-1b receptor subtype.