Endothelin-1 and -3 diminish neuronal NE release through an NO mechanism in rat anterior hypothalamus

Abstract

The existence of endothelin binding sites on the catecholaminergic neurons of the hypothalamus suggests that endothelins (ETs) participate in the regulation of noradrenergic transmission modulating various hypothalamic-controlled processes such as blood pressure, cardiovascular activity, etc. The effects of ET-1 and ET-3 on the neuronal release of norepinephrine (NE) as well as the receptors and intracellular pathway involved were studied in the rat anterior hypothalamus. ET-1 (10 nM) and ET-3 (10 nM) diminished neuronal NE release and the effect blocked by the selective ET type B receptor antagonist BQ-788 (100 nM). N(omega)-nitro-L-arginine methyl ester (10 microM), methylene blue (10 microM), and KT5823 (2 microM), inhibitors of nitric oxide synthase activity, guanylate cyclase, and protein kinase G, respectively, prevented the inhibitory effects of both ETs on neuronal NE release. In addition, both ETs increased nitric oxide synthase activity. Furthermore, 100 microM picrotoxin, a GABA(A)-receptor antagonist, inhibited ET-1 and ET-3 response. Our results show that ET-1 as well as ET-3 has an inhibitory neuromodulatory effect on NE release in the anterior hypothalamus mediated by the ET type B receptor and the involvement of a nitric oxide-dependent pathway and GABA(A) receptors. ET-1 and ET-3 may thus diminish available NE in the synaptic gap leading to decreased noradrenergic activity.

Long-term modulation of tyrosine hydroxylase activity and expression by endothelin-1 and -3 in the rat anterior and posterior hypothalamus

“…Our results support that ET-1 and ET-3 regulate catecholaminergic transmission in the hypothalamus by controlling the synthesis (11,12), uptake (unpublished observations), and release of NE (33,41). These findings suggest that ETs modulate NE turnover.…”

“…Various reports support that the NO pathway is coupled to ET B receptor activation (9,40). In this sense, we reported that in the AHR, both ETs decrease NE release and participate in the short-term regulation of TH activity through the activation of ET B receptors coupled to the NO pathway (11,33). Present findings show that in the AHR, ET B receptors also mediated the long-term effect of ETs on TH activity since the reduction was abolished by a selective antagonist (BQ-788) and mimicked by an agonist (IRL-1620).…”

“…It was shown that ET-1 increases dopamine release in the rat striatum, whereas ET-3 augments catecholamine output in cortical, as well as striatal brain slices (27,52). We previously reported that both ETs modulate NE release, as well as the short-term modulation of TH activity and expression of the phosphorylated forms of the enzyme in the AHR and PHR (11,12,33,41).…”

Short-term Effects of Endothelins on Tyrosine Hydroxylase Activity and Expression in the Olfactory Bulb of Normotensive Rats

“…ETs behave as neurotransmitters and/or neuromodulators within the central nervous system. In this sense we reported that ETs modulate noradrenergic neurotransmission in the anterior and posterior hypothalamus of normotensive rats [11,12,15,17,18].…”

“…We previously observed that 10 nM is the concentration of ETs that modifies hypothalamic catecholaminergic activity in vitro [11,12,15,17,18]. Endogenous ETs levels have been determined in cerebrospinal fluid and different regions of CNS, but not in the OB [16].…”