DIRECT REGULATION OF HYPOTHALAMIC CORTICOTROPIN-RELEASING-HORMONE NEURONS BY ANGIOTENSIN-II

The possible role of angiotensin II (AII) in the control of the hypoth alamic-pituitary-adrenal (HPA) axis was studied in the rat by examinin g the regulation and cellular localization of AII receptors in the par aventricular nucleus (PVN) of the hypothalamus and the effect of AII o n corticotropin-releasing hormone (CRH) and vasopressin (VP) mRNA leve ls. In situ hybridization studies using cRNA S-35-labelled probes show ed that while type 1 AII receptor (AT(1)) mRNA levels were high in the periventricular and parvicellular pars of the PVN, only very low leve ls were present in the magnocellular pars. A similar distribution of A T(1) receptor binding in the periventricular, parvicellular and magnoc ellular divisions of the PVN was observed in autoradiographic studies in hypothalamic sections labelled with I-125[Sar(1),Ile(8)]AII. In add ition, AII receptor binding was clearly evident in nerve fibers adjace nt to the PVN. Double-labelling hybridization using digoxigenin-labell ed CRH, VP and oxytocin probes and S-35-labelled AT(1) receptor cRNA p robes showed AT(1) receptor mRNA in cells stained for CRH mRNA, but no t in VP or oxytocin cells. Four hours after a single intracerebroventr icular (i.c.v.) injection of 50 ng AII in conscious rats, CRH mRNA lev els in the PVN were increased by 43%, similar to the increases observe d following acute stress by intraperitoneal (i.p.) injection of 1.5 M NaCl (76%). On the other hand, while i.p. hypertonic saline injection increased VP mRNA levels by 29% in the PVN and by 32% in the supraopti c nucleus, i.c.v. AII injection had no significant effect. The data st rongly suggest that AII modulates CRH neurons directly through recepto rs in PVN perikarya, whereas regulation of magnocellular function is a t least partly indirect via receptors associated with afferent innerva tion to the PVN. The data support a direct role for AII in the regulat ion of PVN function.