Endothelins stimulate cyclic AMP accumulation in the isolated rat anterior pituitary gland: possible involvement of ETA receptor activation and prostaglandin E2 production.

Effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) on cyclic AMP (cAMP) levels were studied in the isolated rat anterior and intermediate-posterior pituitary slices. In the anterior pituitary, ET-1 increased cAMP levels in a concentration-dependent manner (10(-7)-10(-5) M). ET-3 also increased the levels at the same concentration range, but ET-1 was more potent than ET-3 at an approximate ED50, 10(-6) M. The stimulatory effects of ET-1 and ET-3 (10(-6) M) on cAMP levels were antagonized by the ETA receptor antagonist BQ 123, 2 x 10(-6) M, and the ETB receptor agonist IRL 1620 evoked only a weak increase in cAMP levels. Moreover, the effects of ET-1 and ET-3 were completely abolished by the cyclooxygenase inhibitor indomethacin, 2 x 10(-5) M. On the other hand, among prostaglandins, prostaglandin E2 (PGE2) increased cAMP levels in a concentration-dependent manner (10(-7)-10(-5) M), whereas prostaglandin D2 and prostaglandin I2 did not exhibit such effects. PGE2 levels were increased by application of ET-1 (10(-8)-10(-5) M). The ET-1-induced PGE2 accumulation was strongly inhibited by indomethacin and BQ 123, but not by treatment with pertussis toxin (100 ng/ml, 6 hr). Treatment with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also elevated the cAMP level by approximately 9-fold above the basal cAMP level. After 3-isobutyl-1-methylxanthine, ET-1 failed to increase PGE2 and cAMP levels. In the intermediate-posterior pituitary, ET-1 and ET-3 did not affect cAMP levels. The results suggest that endothelins increase cAMP levels via ETA receptor activation interacting with the pertussis toxin-insensitive G-protein, in which PGE2 production is involved in the rat anterior pituitary, whereas endothelins lack these effects in the intermediate-posterior pituitary.