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

DI NUNZIO A; JAUREGUIBERRY MS; RODANO V; BIANCIOTTI LG; VATTA MS

AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY, INTEGRATIVE AND COMPARATIVE PHYSIOLOGY

AMER PHYSIOLOGICAL SOC

Año: 2002 vol. 283 p. 615 - 622

0363-6119

Theexistence of endothelin binding sites on the catecholaminergicneurons of the hypothalamus suggests that endothelins(ETs) participate in the regulation of noradrenergictransmission modulating various hypothalamic-controlledprocesses such as blood pressure, cardiovascular activity,etc. The effects of ET-1 and ET-3 on the neuronal release ofnorepinephrine (NE) as well as the receptors and intracellularpathway involved were studied in the rat anteriorhypothalamus. ET-1 (10 nM) and ET-3 (10 nM) diminishedneuronal NE release and the effect blocked by the selectiveET type B receptor antagonist BQ-788 (100 nM). N-nitro-L-arginine methyl ester (10 M), methylene blue (10 M),and KT5823 (2 M), inhibitors of nitric oxide synthaseactivity, guanylate cyclase, and protein kinase G, respectively,prevented the inhibitory effects of both ETs onneuronal NE release. In addition, both ETs increased nitricoxide synthase activity. Furthermore, 100 M picrotoxin,a GABAA-receptor antagonist, inhibited ET-1 andET-3 response. Our results show that ET-1 as well as ET-3has an inhibitory neuromodulatory effect on NE release inthe anterior hypothalamus mediated by the ET type Breceptor and the involvement of a nitric oxide-dependentpathway and GABAA receptors. ET-1 and ET-3 may thusdiminish available NE in the synaptic gap leading todecreased noradrenergic activity.