Molecular Pharmacology, Vol 16, 823-840, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Prostacyclin as an Endogenous Modulator of Adenosine Cyclic 3',5'-Monophosphate Levels in Rat Myometrium and Endometrium

¹ Laboratoire d’Endocrinologie et Regulations Cellulaires, LA 272, Institut de Biochimie, Université Paris-Sud, 91405 ORSAY CEDEX (France)

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 (PGF_2a > PG₂ > PGI₂ > 6-keto-PGF₁). Only PGE₂ and PGI₂, but not 6-keto-PGF_1a 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-PGF₁, 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.

Note:
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.

This article has been cited by other articles:

				I. Boulven, B. Palmier, P. Robin, M. Vacher, S. Harbon, and D. Leiber Platelet-Derived Growth Factor Stimulates Phospholipase C-{gamma}1, Extracellular Signal-Regulated Kinase, and Arachidonic Acid Release in Rat Myometrial Cells: Contribution to Cyclic 3',5'-Adenosine Monophosphate Production and Effect on Cell Proliferation Biol Reprod, August 1, 2001; 65(2): 496 - 506. [Abstract] [Full Text] [PDF]

				H. Le Stunff, L. Dokhac, and S. Harbon The Roles of Protein Kinase C and Tyrosine Kinases in Mediating Endothelin-1-Stimulated Phospholipase D Activity in Rat Myometrium: Differential Inhibition by Ceramides and Cyclic AMP J. Pharmacol. Exp. Ther., February 1, 2000; 292(2): 629 - 637. [Abstract] [Full Text]