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.
Domae
M
M
Department of Pharmacology, School of Medicine, Fukuoka University, Japan.
Yamada
K
K
Inoue
T
T
Satoh
M
M
Furukawa
T
T
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis*; D004347:Drug Interactions; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D008297:Male; D008969:Molecular Sequence Data; D010903:Pituitary Gland, Anterior / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D010904:Pituitary Gland, Posterior / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000187:drug effects* / Q000502:physiology*; D013268:Stimulation, Chemical; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D017466:Receptors, Endothelin; D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP; D015232:Dinoprostone; D015056:1-Methyl-3-isobutylxanthine