Inhibition of Glucagon-Mediated Increases in Hepatic Cyclic Adenosine 3',5'-Monophosphate by Prostaglandin E1and E2

The effects of prostaglandin (PG) E1, E2>,A1 and F2α on glucagon-mediated increases in hepatic cyclic adenosine 3',5'-monophosphate (cAMP) were examined. In intact, anesthetized rats, intraportal injection of high doses of PGE, and E2, but not PGA, or F2α, modestly increased hepatic cAMP levels (by 60% at 1 min after injection). Upon their simultaneous intraportal administration with glucagon, both stimulatory and much lower, nonstimulatory, doses of PGE1, or E2 significantly suppressed glucagon-induced increases in hepatic cAMP, monitored at 15 sec or 1 min after injectionBy contrast, PGA1, PGF2αand insulin had no detectable effect on this rapid action of glucagon. In rat livers perfused in situ, PGE, also partially inhibited glucagon-mediated alterations in both hepatic cAMP and in glycogen synthetase activity. Studies directed toward identifying the mechanism by which PGE1, modulates the hepatic cAMP response to glucagon were inconclusive. In hepatic homogenates, maximal doses of PGE, enhanced basal adenylate cyclase (2-fold). This stimulation was not additive with that mediated by maximal doses of glucagon, a finding consistent with an action of both these agents upon the same hepatic adenylate cyclase activity. However, in contrast to its actions in intact liver, PGE, did not suppress the adenylate cyclase response of hepatic homogenates to either maximal or submaximal doses of glucagon. Further, PGE1, had no detectable influence on hepatic cyclic phosphodiesterase activity in vitro, implying that PGE1, was not acting to enhance the rate of cAMP catabolism.(Endocrinology95: 93, 1974)