The relaxant effect of sex steroids in rat myometrium is independent of the gamma-amino butyric acid system.

The mechanism of action on the uterine-relaxant effect of sex steroids has been suggested to involve an interaction with gamma-amino butyric acid (GABA) receptors. However, other lines of evidence do not seem to support this suggestion. In view of this controversy, this study was designed to investigate the potential relaxant effect of GABA, muscimol (a GABA(A) receptor agonist), testosterone, progesterone and their 5-reduced metabolites in rat uterus at different endocrine stages (pregnant, nonpregnant and estrogenized), with particular emphasis on verifying if the relaxant effect of steroids involves an interaction with GABA(A) receptors. Contractions from uterine rings were recorded by isometric method, the sequential addition of either GABA (at different concentrations) on the spontaneous and KCl-induced contraction or muscimol (also at different concentrations) on the contraction induced by KCl was devoid of any significant effect. In contrast, the sequential addition of progesterone relaxed the tonic KCl-induced contraction in a concentration-dependent manner. This effect of progesterone was mimicked by its 5-reduced metabolites. The 5(beta)-configured isomers were more potent than progesterone and the 5(alpha)-configured ones. Interestingly, the relaxation produced by the above steroids was not blocked by the GABA(A) receptor antagonists, picrotoxin or bicuculline, but was reversed by calcium. Taken together, the above findings suggest that the relaxant action of the sex steroids analyzed in this study is not mediated by an interaction with GABA(A) receptors, instead a blockade of calcium influx appears to be responsible.