Differential effects of a steroidal antiestrogen, EM-139, on prostaglandin and cyclic adenosine 3',5'-monophosphate production in the circular and longitudinal layers of bovine myometrium.

Abstract

The regulation of prostaglandin (PG) production and cAMP generation was studied in vitro in cultured smooth muscle cells isolated specifically from the circular or longitudinal layers of the bovine myometrium. We found that prostacyclin (PGI2) was the principal PG produced by the myometrium, especially in the longitudinal layer, followed closely by PGE2 and marginally by PGF2 alpha. The PG production (fg/ml, mean +/- SD) in the circular and longitudinal layers was, respectively, PGE2 (424.4 +/- 162.0) > PGI2 (189.5 +/- 19.0) > PGF2 alpha (9.5 +/- 3.0) versus PGI2 (751 +/- 36) > PGE2 (515.7 +/- 94.0) > PGF2 alpha (16.3 +/- 3.0); production was stimulated up to 15-fold 24 h after addition of phorbol 12-myristate (PMA; 100 nM). Hormonal control of PG production was assessed by use of a steroidal antiestrogen, EM-139. PG production was inhibited in a concentration-dependent manner by EM-139 in both circular and longitudinal layers, with maximal inhibition at 1 microM. In parallel studies, chronic treatment with EM-139 resulted in significant increases in isoproterenol-induced cAMP production in both muscle layers, but more especially in the circular layer. This antiestrogenic effect was reversed by addition of 17 beta-estradiol. These results indicate that the two smooth muscle layers of the bovine myometrium have distinct patterns of PG production and that the adenylate cyclase/cAMP response of the circular layer is more sensitive to estrogen modulation. Our findings with a cell culture model of separated myometrial layers provide strategic information for a better understanding of the regulation of uterine contractility during pregnancy.