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

The possible role of angiotensin II (AII) in the control of the hypothalamic-pituitary-adrenal (HPA) axis was studied in the rat by examining the regulation and cellular localization of AII receptors in the paraventricular nucleus (PVN) of the hypothalamus and the effect of AII on corticotropin-releasing hormone (CRH) and vasopressin (VP) mRNA levels. In situ hybridization studies using cRNA S-35-labelled probes showed that while type 1 AII receptor (AT(1)) mRNA levels were high in the periventricular and parvicellular pars of the PVN, only very low levels were present in the magnocellular pars. A similar distribution of AT(1) receptor binding in the periventricular, parvicellular and magnocellular divisions of the PVN was observed in autoradiographic studies in hypothalamic sections labelled with I-125[Sar(1),Ile(8)]AII. In addition, AII receptor binding was clearly evident in nerve fibers adjacent to the PVN. Double-labelling hybridization using digoxigenin-labelled CRH, VP and oxytocin probes and S-35-labelled AT(1) receptor cRNA probes showed AT(1) receptor mRNA in cells stained for CRH mRNA, but not in VP or oxytocin cells. Four hours after a single intracerebroventricular (i.c.v.) injection of 50 ng AII in conscious rats, CRH mRNA levels in the PVN were increased by 43%, similar to the increases observed 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 supraoptic nucleus, i.c.v. AII injection had no significant effect. The data strongly suggest that AII modulates CRH neurons directly through receptors in PVN perikarya, whereas regulation of magnocellular function is at least partly indirect via receptors associated with afferent innervation to the PVN. The data support a direct role for AII in the regulation of PVN function.