Effect of manganese on luteinizing hormone-releasing hormone secretion in adult male rats.
Recently studies have demonstrated that low doses of (Mn(+2)) in the form of manganese chloride can stimulate specific puberty-related hormones and advance signs of pubertal development in immature female and male rats. In the present study, we used an in vitro system to evaluate the ability of 0, 50, 250, and 500 microM doses of Mn(+2) to stimulate luteinizing hormone-releasing hormone (LHRH) secretion and to assess the hypothalamic mechanism of this action in adult male Sprague-Dawley rats. We demonstrated that Mn(+2) at 500 microM, but not the lower doses, increased LHRH release, nitric oxide (NO) synthase (NOS) activity, and the content of cyclic cGMP in the medial basal hypothalamus. Inhibition of NOS with a competitive inhibitor (Nomega-nitro-L-arginine methyl ester hydrochloride) prevented the Mn-induced increase in LHRH release. Additionally, methylene blue and KT5823, specific inhibitors of guanylyl cyclase and protein kinase G (PKG), respectively, also blocked the stimulatory effect of Mn(+2) on LHRH release. These in vitro studies demonstrated that the hypothalamic mechanism of Mn(+2) action in adult males is by activation of the NOS/NO system, resulting in increases in cGMP and PKG and thus the secretion of LHRH from the nerve terminals. These results indicate Mn(+2) can cause LHRH release in adult males, and this action is discussed in relation to age, gender, as well as mechanistic and functional differences between adult and immature animals.
Prestifilippo
Juan Pablo
JP
Facultad de Medicina, Centro de Estudios Farmacológicos y Botánicos, CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina. jprestifilippo@yahoo.com.ar
Fernández-Solari
Javier
J
Mohn
Claudia
C
De Laurentiis
Andrea
A
McCann
Samuel M
SM
Dees
Wl
W
Rettori
Valeria
V
D000367:Age Factors; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D002712:Chlorides / Q000633:toxicity*; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D017895:Manganese Compounds; D008751:Methylene Blue / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects*
D002227:Carbazoles; D002712:Chlorides; D006454:Hemoglobins; D007211:Indoles; D017895:Manganese Compounds; D047428:Protein Kinase Inhibitors; C073601:KT 5823; D009569:Nitric Oxide; D007987:Gonadotropin-Releasing Hormone; D019001:Nitric Oxide Synthase; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; C025340:manganese chloride; D008751:Methylene Blue; D019331:NG-Nitroarginine Methyl Ester