Comp. Biochem. Physiol. Vol. 118C, No. 1, pp. 5–10, 1997 ISSN 0742-8413/97/$17.00 Copyright  1997 Elsevier Science Inc. All rights reserved. PII S0742-8413(97)00029-7 Inhibitory Effect of Sex Steroids on Guinea-Pig Airway Smooth Muscle Contractions Mercedes Perusquı ´a, Ricardo Herna ´ndez, Luis M. Montan ˜o,* , † Carlos M. Villalo ´n,‡ and Marı ´a G. Campos§ Depto. de Biologı ´a Celular, Instituto de Investigaciones Biome ´dicas, Universidad Nacional Auto ´ noma de Me ´xico, Apdo. Postal 70-492, 04511 Mexico City, Mexico;*Depto. de Farmacologı ´a, Fac. de Medicina and † Instituto Nacional de Enfermedades Respiratorias, Tlapan 4502, 14080 Mexico City, Mexico; ‡ Terape ´utica Experimental, CINVESTAV., IPN., Apdo. Postal 22026, 14000 Mexico City, Mexico; and §UIM-Farmacologı ´a, Centro Me ´dico Nacional Siglo XXI, Apdo. Postal 73032, 03020 Mexico City, Mexico ABSTRACT. We assessed the possible inhibition of airway smooth muscle contraction by progesterone and pregnanolones (5α and 5β-reduced). Progesterone and 5β-pregnanolone prevented histamine- or carbachol- induced contraction in isolated guinea-pig trachea and potency was related to their respective chemical structure; progesterone was the most potent inhibitor in a concentration-dependent manner. The steroids also exhibited calcium antagonist activities in this tissue as assessed by their action on calcium entry in depolarized preparations; this event involved the immediate blockade of the extracellular calcium influx in the muscle cell membrane, indicating a nongenomic action. Classical GABA A antagonists did not block the progesterone response, implying no involvement of the GABA A -receptor complex. Our results suggest a bronchodilating effect induced by sex steroids, and probably by other related compounds, before the genomic mechanisms take place. This nongenomic action of steroids could have potential therapeutic usefulness in the treatment of asthma. comp biochem physiol 118C;1:5–10, 1997.  1997 Elsevier Science Inc. KEY WORDS. Airway smooth muscle, bronchodilating effect, guinea-pig, nongenomic actions, pregnanolone, progesterone, progesterone metabolites, relaxation, steroid action, steroids, trachea INTRODUCTION onstrated a direct inhibitory effect of steroids and, conse- quently, their mechanism of action, on the contractile re- Steroid hormones regulate a large number of critical biologi- sponse of airway smooth muscle. It is noteworthy, that cal functions. Regarding the modulation of smooth muscle corticosteroids reduce bronchial hyperresponsiveness and contractility, different classes of steroid hormones (e.g., pro- asthma symptoms; although their precise mode of action gestins, androgens, estrogens, and corticosteroids) have is far from clear, it is likely that they suppress the allergic been reported to induce a rapid relaxant effect of reproduc- inflammatory response (3) and increase the effect of bron- tive smooth muscle, i.e., pregnant (18) and nonpregnant chodilator medications (17,39). Obviously, the elucidation (20,22,30,32) uterus, epidydymis, and seminal vesicles (19). of a presumed bronchodilator effect by steroids could reveal Likewise, steroids can induce relaxation in nonreproductive a physiological significance of these hormones on bronchial smooth muscles, such as those from urinary tract (4), gastro- hyperresponsiveness in asthmatic subjects. intestinal tissues (5,21,23), and blood vessels (31,36,37). Therefore, we set out to analyze, as a first approach, the With respect to airway smooth muscle, glucocorticoids potential inhibitory effect of 5-reduced progestins (either potentiate the bronchodilator activity of isoprenaline produced by the ovary or metabolized peripherally from pro- (15,35) in the guinea-pig trachea, whereas 17β-estradiol gesterone) on tracheal smooth muscle. For this purpose, we and some related estrogenic steroids, as well as progesterone, evaluated the direct effects of progesterone, 3β-hydroxy-5α- corticosterone, and cortisol, potentiated the isoprenaline- pregnan-20-one and 3β-hydroxy-5β-pregnan-20-one on the induced relaxation of pig bronchus more than 4-fold (9). histamine- or carbachol-induced tracheal smooth muscle However, to the best of our knowledge, no study has dem- contraction in guinea-pigs. To further analyze the effects of these steroids on extracellular calcium dependent processes, Address reprint requests to: Mercedes Perusquı ´a, Ph.D., Instituto de Investi- gaciones Biome ´dicas, UNAM., Apartado Postal 70-492, Mexico City, C.P. the steroids were evaluated on the calcium-induced con- 04511, Mexico; Tel. (525) 622 38 29; Fax (525) 679 78 03; E-mail: traction in depolarized tissues. In addition, since sex steroid perusqui@servidor.unam.mx. activity in neuronal functions has mainly been focused on Received 12 October 1996; revised 7 March 1997; accepted 13 March 1997. the GABA A receptor (13,26,38,40), we also assayed the ef-