Behavioural, autonomic and endocrine responses associated with C-fos expression in the forebrain and brainstem after intracerebroventricular infusions of endothelins.

Endothelins are a range of peptides (endothelin-1, endothelin-2, and endothelin-3) well known to act peripherally as powerful cardiovascular-regulating agents. Recently, they have been shown to be localized in CSN, where they may act as central neurotransmitters. A variety of putative roles has been ascribed to them in the CNS. To identify those regions of the brain capable of responding to these peptides, the expression of c-fos (an immediate-early gene), has been used to map patterns of activation following intracerebroventricular (i.c.v.) infusions of endothelins in Lister-hooded rats. This has been correlated with changes in heart rate, core temperature and plasma corticosterone levels. Endothelin-3 i.c.v. (50 pmol) decreased both heart rate and core temperature (both recorded by telemetry). This effect lasted for about 30-45 min. Endothelin-1 (10 pmol) or endothelin-3 (50 pmol) i.c.v. induced c-fos expression in the specific regions in the forebrain and brainstem. Strong expression was found in the septum, bed nucleus of the stria terminalis, parvicellular paraventricular nucleus, the central nucleus of the amygdala, dorsal motor nucleus of the vagus and solitary nucleus. There was less marked c-fos expression in other areas of the basal forebrain, such as the organum vasculosum of the lamina terminals, median preoptic nucleus, supraoptic nucleus and the magnocellular. There are two classes of endothelin receptor (A and B). An endothelin-A receptor antagonist, BQ-123, abolished c-fos expression in all structures in the forebrain and brainstem following endothelin-1 infusions. However, an endothelin-B agonist (TetraAla endothelin-1) did not induce discernible c-fos expression in the forebrain or brainstem. These results suggest that the endothelin-A receptor is responsible for endothelin-dependent c-fos induction in the brain. Interactions between endothelins and angiotensin II were also studied. The pattern of c-fos induced by endothelin-3 and angiotensin II was different (particularly in the anteroventral region of the third ventricle). Furthermore, prior infusions of endothelin-3 interfered with the expression of c-fos induced by subsequent angiotensin II, and also suppressed the latter's dipsogenic effect. These results show that endothelin-3 and angiotensin II interact at both behavioural and cellular levels, and that endothelins may play significant roles in the central control of fluid balance and autonomic activity.