Inter-relationships between endothelin and prostaglandin F-2 alpha in corpus luteum function

In cattle and other species, the corpus luteum plays a central role in the regulation of cyclicity and maintenance of pregnancy. In the absence of fer tilization and implantation, the corpus luteum undergoes functional and mor phological regression or luteolysis. Luteal regression is initiated in dome stic ruminants by surges of prostaglandin F-2 alpha (PGF(2 alpha)) from the uterus. Despite intensive investigation, the mechanisms by which PGF(2 alp ha) causes luteal regression remain undetermined. Recent studies from sever al laboratories have demonstrated that endothelial cells and their product, endothelin 1, are required for the manifestation of the luteolytic effects of PGF(2 alpha). Experimental evidence strongly supports the concept that luteal endothelin 1 inhibits luteal steroidogenesis and mediates the effect s of PGF(2 alpha). Endothelin 1 caused a dose-dependent reduction in both b asal and luteinizing hormone-stimulated biosynthesis of progesterone and pr ostacyclin, and an increase in PGF(2 alpha) by ovine and bovine luteal cell s. Specific receptors for endothelin 1 were identified on large and small b ovine luteal cells, and the addition of specific endothelin receptor antago nists abolished the inhibitory effects of endothelin 1. Luteal endothelin 1 content increased as the cyclic corpus luteum aged, and the highest concen trations were observed during luteolysis. The amount of mRNA encoding endot helin 1 was greatly increased during the period of luteolysis. Gene express ion for endothelin 1 was increased, in a time-dependent manner, in corpora lutea collected from heifers and ewes after exogenous administration of PGF (2 alpha). In heifers, exogenous PGF(2 alpha) resulted in increased luteal output of endothelin 1. In ewes, the luteolytic effects of PGF(2 alpha) wer e mitigated by pretreatment with a specific endothelin receptor antagonist. Administration of endothelin 1 or a sub-luteolytic dose of PGF(2 alpha) to ewes reduced concentrations of jugular venous progesterone but did not sho rten luteal lifespan. However, a combination of endothelin 1 and PGF(2 alph a) acted synergistically to bring about complete luteolysis and reduced lif espan of the corpus luteum. In summary, endothelin 1 appears to have a dire ct effect on luteal cells in cattle and sheep, and it plays an essential ro le in mediating the luteolytic effects of PGF(2 alpha).