Nitric oxide inhibits hypothalamic luteinizing hormone-releasing hormone release by releasing gamma amino butyric acid.

A. SEILICOVICH; B.H.DUVILANSKI,; D.PISERA,; S.THEAS,; M.GIMENO,; V.RETTORI,; S.M.MCCANN,

Proceedings of the National Academy of Sciences of the United States of America

NATL ACD SCIENCES

Año: 1995 vol. 92 p. 3421 - 3424

0027-8424

Nitric oxide synthase (NOS)-containing neurons, termed NOergic neurons, occur in various regions ofNOergic neurons, occur in various regions of the hypothalamus, including the median eminence-arcuate region, which plays an important role in controlling thean important role in controlling the release of luteinizing hormone-releasing hormone (LHRH). We examined the effect ofNO on release of y-aminobutyric acid (GABA) from medial basal hypothalamic (MBH) explants incubated in vitro. Sodium nitroprusside (NP) (300 ,uM), a spontaneousthe effect ofNO on release of y-aminobutyric acid (GABA) from medial basal hypothalamic (MBH) explants incubated in vitro. Sodium nitroprusside (NP) (300 ,uM), a spontaneousincubated in vitro. Sodium nitroprusside (NP) (300 ,uM), a spontaneousnitroprusside (NP) (300 ,uM), a spontaneous releaser of NO, doubled the release of GABA. This release was significantly reduced by incubation of the tissue with hemoglobin, a scavenger of NO, whereas hemoglobin alone hadNO, doubled the release of GABA. This release was significantly reduced by incubation of the tissue with hemoglobin, a scavenger of NO, whereas hemoglobin alone hadwas significantly reduced by incubation of the tissue with hemoglobin, a scavenger of NO, whereas hemoglobin alone hada scavenger of NO, whereas hemoglobin alone had no effect on the basal release of GABA. Elevation of the potassium concentration (40 mM) in the medium increased GABA release 15-fold; this release was further augmented by NP.effect on the basal release of GABA. Elevation of the potassium concentration (40 mM) in the medium increased GABA release 15-fold; this release was further augmented by NP.(40 mM) in the medium increased GABA release 15-fold; this release was further augmented by NP.15-fold; this release was further augmented by NP. Hemoglobin blocked the increase in GABA release induced by NPNP but had no effect on potassium-induced release, suggesting that the latter, is not related to NO. As in the case of hemoglobin,no effect on potassium-induced release, suggesting that the latter, is not related to NO. As in the case of hemoglobin,latter, is not related to NO. As in the case of hemoglobin, NG-monomethyl-L-arginine (NMMA), a competitive inhibitor of(NMMA), a competitive inhibitor of NOS, had no effect on basal release of GABA, which indicateshad no effect on basal release of GABA, which indicates again that NO is not significant to basal GABA release. However,that NO is not significant to basal GABA release. However, NMMA markedly inhibited the release ofGABA induced by highmarkedly inhibited the release ofGABA induced by high potassium, which indicates that NO plays a role in potassiuminduced release of GABA. In conditions in which the release of GABA was substantially augmented, there was a reduction inwhich indicates that NO plays a role in potassiuminduced release of GABA. In conditions in which the release of GABA was substantially augmented, there was a reduction inIn conditions in which the release of GABA was substantially augmented, there was a reduction inwas substantially augmented, there was a reduction in GABA tissue stores as well, suggesting that synthesis ofGABA in these conditions did not keep up with release of the amine. Although NO released GABA, there was no effect of the released GABA on NO production, for incubation ofMBH explants with GABA had no effect on NO release as measured by [14C]citrullinestores as well, suggesting that synthesis ofGABA in these conditions did not keep up with release of the amine. Although NO released GABA, there was no effect of the released GABA on NO production, for incubation ofMBH explants with GABA had no effect on NO release as measured by [14C]citrullinenot keep up with release of the amine. Although NO released GABA, there was no effect of the released GABA on NO production, for incubation ofMBH explants with GABA had no effect on NO release as measured by [14C]citrullineGABA, there was no effect of the released GABA on NO production, for incubation ofMBH explants with GABA had no effect on NO release as measured by [14C]citrullineon NO production, for incubation ofMBH explants with GABA had no effect on NO release as measured by [14C]citrullinehad no effect on NO release as measured by [14C]citrulline production. To determine whether GABA had any effect onTo determine whether GABA had any effect on the release of LHRH from these MBH explants, GABA waswas incubated with the tissue and the effect on LHRH release wason LHRH release was determined. GABA (10-5 or 10-6 M) induced a 70%o decrease in(10-5 or 10-6 M) induced a 70%o decrease in the release of LHRH, indicating that in the male rat GABA inhibits the release of this hypothalamic peptide. This inhibition in LHRH release induced by GABA was blocked by NMMA (300LHRH, indicating that in the male rat GABA inhibits the release of this hypothalamic peptide. This inhibition in LHRH release induced by GABA was blocked by NMMA (300the release of this hypothalamic peptide. This inhibition in LHRH release induced by GABA was blocked by NMMA (300LHRH release induced by GABA was blocked by NMMA (300 ,uM), which indicates that GABA converts the stimulatory effect of NO on LHRH release into an inhibitory one, presumably via GABA receptors, which activate chloride channels that hyperpolarizewhich indicates that GABA converts the stimulatory effect of NO on LHRH release into an inhibitory one, presumably via GABA receptors, which activate chloride channels that hyperpolarizeon LHRH release into an inhibitory one, presumably via GABA receptors, which activate chloride channels that hyperpolarizereceptors, which activate chloride channels that hyperpolarize the cell. Previous results have indicated that norepinephrinePrevious results have indicated that norepinephrine stimulates release of NO from the NOergic neurons,NOergic neurons, which then stimulates the release of LHRH. The current resultsthen stimulates the release of LHRH. The current results indicate that the NO released also induces release of GABA, which then inhibits further LHRH release. Thus, in vivo thereleased also induces release of GABA, which then inhibits further LHRH release. Thus, in vivo thethen inhibits further LHRH release. Thus, in vivo the norepinephrinergic-driven pulses of LHRH release may be terminated by GABA released from GABAergic neurons via NO.of LHRH release may be terminated by GABA released from GABAergic neurons via NO.GABAergic neurons via NO.