RT Journal Article
SR Electronic
T1 Prostacyclin as an Endogenous Modulator of Adenosine Cyclic 3',5'-Monophosphate Levels in Rat Myometrium and Endometrium
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 823
OP 840
VO 16
IS 3
A1 MARIE-FRANÇAISE VESIN
A1 LIEN DO KHAC
A1 SIMONE HARBON
YR 1979
UL http://molpharm.aspetjournals.org/content/16/3/823.abstract
AB Our previous study (Vesin et al., 1978, Mol. Pharmacol. 14: 24-37) showed that arachidonic acid, a precursor of prostaglandins, can elicit contractions of the estrogen-treated rat myometrium and stimulate cAMP accumulation in myometrium and endometrium. The present investigation characterizes the nature of the prostaglandin material(s) involved in the arachidonic acid responses. All prostaglandins tested were active contractile agents (PGF2a > PG2 > PGI2 > 6-keto-PGF1α). Only PGE2 and PGI2, but not 6-keto-PGF1a could induce, marked increases in intracellular cAMP in both tissues. PGI2 was more active than PGE2, although maximal responses were similar in magnitude for both compounds. Prior treatment of the uterine tissues with prostacyclin synthesis inhibitors viz. tranylcypromine and 15-hydroperoxy arachidonic acid (HP-AA), antagonized cAMP elevations caused by arachidonic acid, suggesting that PGI2 might be involved. In contrast, tranylcypromine did not affect the arachidonic acid-induced contractions. Further experiments demonstrate that arachidonic acid treatment also stimulates the concomitant release from the myometrium and endometrium of a platelet antiaggregatory material that could be identified as PGI2 by the following criteria: a) it shared the chemical lability of authentic PGI2, b) its generation was abolished by prior treatment of the tissue with indomethacin, tranylcypromine or HP-AA and c) 6-keto-PGF1α, the end product of PGI2 was the major prostaglandin generated from [14C]arachidonic acid in myometrial and endometrial homogenates. No PGE2 or PGD2 could be detected. Basal values of PGI2 released were similar for both uterine tissues (about 60 pmol/g tissue) and were increased with arachidonic acid to 130 pmol PGI2/g tissue. Such local PGI2 concentrations were sufficient to account for the twofold increment in tissue cAMP, which was similarly induced by corresponding concentrations of authentic PGI2. Quantitative correlations, PGI2 versus cAMP, could also be demonstrated under conditions of enhanced PGI2 generation from endogenous arachidonic acid (e.g., during isolation and stripping of the myometrium). These data indicate that locally generated PGI2 could not be implicated in the contractile effect of arachidonic acid. They do offer strong suggestive evidence that endogenous PGI2 largely contribute to the modulation of intracellular cAMP levels in the myometrium and endometrium. ACKNOWLEDGMENTS We are indebted to Drs. J. E. Pike and G. L. Bundy for their generous gifts of prostaglandins and analogues. We wish to thank Mrs. J. Robichon and G. Thomas for their excellent technical assistance. A special acknowledgment is extended to Mrs. J. Jalicot for typing the manuscript.