ENDOTHELIN-3 STIMULATES LUTEINIZING-HORMONE-RELEASING HORMONE (LHRH) SECRETION FROM LHRH NEURONS BY A PROSTAGLANDIN-DEPENDENT MECHANISM

Endothelin (ET) peptides have recently been recognized as putative regulators of the endocrine system. Particularly in the gonadal system, ET-3 stimulates LH secretion from anterior pituitary cells cultured in vitro. In these studies, we evaluate the actions of ET-3, the most abundant species of the ET family in the central nervous system, on LHRH release from arcuate nucleus-median eminence (AN-ME) fragments and an LHRH-secreting neuronal cell line (GT1 cells) in vitro. ET-3 exhibited a stimulatory effect on LHRH secretion from AN-ME fragments and GT1 cells incubated in a static system as well as in a dynamic perifusion paradigm. In all the systems used, the effects of ET-3 on LHRH secretion showed a dose dependency. The increase in LHRH secretion induced by ET-3 was accompanied by an increased secretion of prostaglandin E2 (PGE2), not only in the AN-ME incubations, but also in the GT1 incubation and perifusion systems. Blockade of arachidonic acid and/or PG synthesis significantly reduced the ET-3-induced LHRH and concomitant PGE2 release from both AN-ME fragments and GT1 cells incubated in vitro. In AN-ME incubations, ET-3 effects were enhanced by potassium-induced depolarization. This suggests that activation of other transmitter system(s) may be needed for obtaining a physiological activation of the LHRH neuronal system. In summary, in these studies we provide evidence for a direct action of ET-3 on the LHRH neuronal system. This action is exerted directly on LHRH neurons either at the level of the nerve terminals, the perikaryon, or both. In addition, the effects of ET-3 on LHRH release require a functional arachidonic acid metabolic pathway, particularly involving PG synthesis, in order to obtain stimulation, indicating that PGs are involved in the intracellular events leading to ET-3-evoked LHRH secretion.