Involvement of 5-lipoxygenase pathway in norepinephrine stimulation of rat pineal melatonin synthesis.
The effect of lipoxygenase inhibition, leukotriene agonists and antagonists, and 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) was examined in the rat pineal gland in organ culture. To study melatonin secretion pineal explants were incubated for 6 h in tissue culture medium 199 with the different drugs. Melatonin concentration in the pineal gland and the medium was measured by RIA. Exposure of explants to norepinephrine (NE) brought about a 2- to 5-fold increase in both parameters, an effect that was reduced but not abolished, by the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA; 10(-5) M). Lilly 171883 (10(-5) M) or FPL 55712 (10(-5) M; both antagonists of leukotrienes) reduced NE-induced melatonin production. Neither NDGA nor Lilly 171883 affected melatonin production in the absence of NE. Leukotrienes C4 and D4 increased melatonin release to the media at all concentrations tested (1-1,000 nM) with a maximum effect at 1 nM (leukotriene C4) and 10 nM (leukotriene D4). Significantly higher tissue melatonin concentrations as compared to controls were observed after exposure of pineal explants to 1 and 100 nM of leukotriene C4, or 100 nM of leukotriene D4. Another 5-lipoxygenase metabolite, 5-HETE, increased pineal melatonin content at concentrations of 1, 10 and 100 nM whereas only 1,000 nM stimulated melatonin release. These results suggest that the 5-lipoxygenase pathway plays a significant role in NE-stimulated melatonin production by the rat pineal gland.
Centro de Estudios Farmacológicos y de Principios Naturales, Buenos Aires, Argentina.
M I
MI
Vacas
M I
MI
Keller-Sarmiento
G S
GS
Etchegoyen
E N
EN
Pereyra
M F
MF
Gimeno
D P
DP
Cardinali
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D001091:Arachidonate Lipoxygenases / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D008550:Melatonin / Q000096:biosynthesis*; D009638:Norepinephrine / Q000494:pharmacology*; D009924:Organ Culture Techniques; D010870:Pineal Gland / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology
D000098:Acetophenones; D002867:Chromones; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D013189:SRS-A; D013777:Tetrazoles; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D009637:Masoprocol; C044660:LY 171883; C006312:FPL 55712; D001091:Arachidonate Lipoxygenases; D001094:Arachidonate 5-Lipoxygenase; D008550:Melatonin; D009638:Norepinephrine