In earlier studies we have provided data to include endothelins, a new family of peptides originally discovered in endothelial cells, in the control of LHRH release. Several lines of evidence indicate that endothelins participate in the control of reproduction. The effects of the peptides are exhibited at the level of the hypothalamus by modulating the release of LHRH and, also, at the pituitary level by enhancing the secretion of LH. Our studies, utilizing hypothalamic explants and a neuronal cell line which releases LHRH (GT1 cells), have shown that endothelin-3 (ET-3) stimulates LHRH secretion and that prostaglandin E2 is a possible intracellular mediator in these effects. Many peptidergic and aminergic systems appear to regulate the release of LHRH. However, only a few seem to be active endogenously in the control of physiologically occurring events such as puberty and the preovulatory surge of gonadotropins. In order to assign a physiologically important role for ET-3 in reproductive events, one must demonstrate that the endogenous substance is involved in specific physiological phenomena. During the past year, we have devoted our efforts to developing a specific sheep anti-ET-3 serum so that, using a passive immunization paradigm, we could evaluate the relative participation of endogenous endothelins in reproduction. During the last year, we have obtained two high titer anti-ET-3 sera which could be used in passive immunization studies. Ongoing experiments are evaluating the pharmacodynamics of these antibodies after intravenous injection to assess their suitability for blocking the activity of endogenous ET-3.
