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Notes: Endothelin (ET), a peptide consisting of 21 amino-acid residues was recently isolated from the culture supernatant of porcine aortic endothelial cells. ET has been reported to be a more potent vasoconstrictor than angiotensin II. Other studies suggest that ET is involved in central control of the autonomie nervous system and body water regulation. Extracellular recordings were made from neurons in the anteroventral third ventricle (AV3V) and supraoptic nucleus (SON) in rat hypothalamic slice preparations. ET-3 was applied at concentrations of 10−10 M to 3x 10−7 M. Of 226 AV3V neurons tested, 48 (21%) were excited, 8 (4%) were inhibited, and 170 (75%) were unaffected by ET-3 at 10−7 M. The threshold concentration to evoke the responses was approximately 10−9 M. Of 144 SON neurons tested, 64 had a phasic firing pattern and 80 had a non-phasic firing pattern. Of 64 phasic neurons tested, 39 (61%) were inhibited by ET-3 at 10−7 M, 25 (39%) were non-responsive and none was excited. Of 80 non-phasic neurons tested, 14 (17.5%) were inhibited by ET-3 at 10−7 M, 66 (82.5%) were non-responsive and none was excited. The effects of ET-1 were compared with those of ET-3. The number of neurons responding to ET-1 and their responsiveness were almost the same as for ET-3. To investigate whether the ET responses are dependent on Ca2+ influx, a Ca2+ free medium and the Ca2+ antagonist, nicardipine, were used. The excitatory responses of AV3V neurons to ET were maintained in the Ca2+ free medium. Nicardipine at 10−5 M suppressed neither the excitatory responses of AV3V neurons nor the inhibitory responses of SON neurons to ET-3. After 8 to 12 h preincubation of slices with islet activating peptide (IAP: pertussis toxin) at 10−7 M, none of the 48 AV3V neurons tested was excited by either ET-3 or ET-1. On the other hand, inhibitory responses were still observed in 12 (52%) out of 23 phasic SON neurons tested after IAP treatment. These results suggest that ET has a direct action as a neuropeptide on hypothalamic neurons through the ETB receptor and that the mechanisms underlying the responses may be different in the AV3V and the SON.