Premium
Manganese stimulates luteinizing hormone releasing hormone secretion in prepubertal female rats: hypothalamic site and mechanism of action
Author(s) -
Lee Boyeon,
Hiney Jill K.,
Pine Michelle D.,
Srivastava Vinod K.,
Dees W. Les
Publication year - 2007
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2006.123083
Subject(s) - endocrinology , medicine , luteinizing hormone , hormone , secretion , mechanism of action , mechanism (biology) , hypothalamus , manganese , chemistry , biology , biochemistry , in vitro , physics , organic chemistry , quantum mechanics
We have shown recently that Mn 2+ stimulates gonadotropin secretion via an action at the hypothalamic level, and a diet supplemented with a low dose of the element is capable of advancing the time of female puberty. In this study, we used an in vitro approach to investigate the mechanism by which Mn 2+ induces luteinizing hormone‐releasing hormone (LHRH) secretion from prepubertal female rats. The medial basal hypothalamus from 30‐day‐old rats was incubated in Locke solution for 30 min to assess basal LHRH secretion, then incubated with buffer alone or buffer plus either a nitric oxide synthase (NOS) inhibitor ( N ‐monomethyl‐ l ‐arginine (NMMA); 300 or 500 μ m ) or a soluble guanylyl cyclase (sGC) inhibitor (1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ); 100 or 250 μ m ) for another 30 min. Finally, the incubation continued for a further 30 min, but in the presence of MnCl 2 (50 or 250 μ m ) to assess the effect of the blockers on stimulated LHRH secretion. Both 50 and 250 μ m MnCl 2 stimulated LHRH release ( P < 0.05 and P < 0.01, respectively). The addition of 300–500 μ m NMMA to the medium did not block Mn 2+ ‐stimulated release of LHRH, even with the higher dose of MnCl 2 . Furthermore, while 50, 100 and 250 μ m MnCl 2 all significantly induced LHRH release, the two lowest doses did not stimulate total nitrite released from the same tissue, an effect only observed with the highest dose. Taken together, these data suggest that Mn 2+ is not an effective stimulator of NO. Conversely, inhibiting sGC with ODQ blocked the Mn 2+ ‐stimulated secretion of LHRH in a dose‐dependent manner, indicating that GC is the site of action of Mn 2+ . Additionally, we showed that Mn 2+ stimulated cGMP and LHRH from the same tissues, and that downstream blocking of protein kinase G formation with KT5823 (10 μ m ) inhibited Mn 2+ ‐induced LHRH release. These data demonstrate that the principal action of Mn 2+ within the hypothalamus is to activate sGC directly and/or as a cofactor with available NO, hence generating cGMP and resulting in prepubertal LHRH release.