Sexual dimorphism in airway responsiveness to sex hormones in rabbits

Abstract

TO THE EDITOR: Recently, Massaro and Massaro (4) demonstrated a sexual dimorphism of alveolar size in male and female adult rats and mice and that estrogen receptor (ER)-␣ and ER-␤ are required for this sexual dimorphism.Our group recently showed that a similar phenomenon of sexual dimorphism presents in airway responsiveness to sex hormones in rabbits. We studied the direct effect of sex hormones (testosterone and 17␤-estradiol) on airway smooth muscle (ASM) at rest and precontracted with acetylcholine or carbachol. Testosterone induced a concentration-dependent (10 Ϫ12 M to 10 Ϫ4 M) contraction of ASM at rest and a concentration-dependent (10 Ϫ12 M to 10 Ϫ4 M) relaxation of ASM precontracted with 10 Ϫ5 M acetylcholine or carbachol (3). This action of testosterone was observed only in male rabbits, whereas testosterone had no effect in female rabbits. Mechanical removal of the airway epithelium abolished significantly (P Ͻ 0.05) the relaxing effect of testosterone (10 Ϫ7 M to 10 Ϫ4 M). In contrast to testosterone, 17␤-estradiol had an epithelium-independent relaxing effect on ASM from male rabbits precontracted with acetylcholine, only in the concentration of 10 Ϫ6 M (P ϭ 0.005). Similar results have been obtained in a previous study demonstrating that in male rabbits, ␤-estradiol caused an epithelial-independent relaxation of tracheal muscle strips precontracted with either acetylcholine or KCl (5). Indirect immunofluorescence with an anti-human androgen receptor (AR) monoclonal antibody revealed that ASM cells express AR. However, in culture of epitheliumintact ASM, the presence of testosterone (10 Ϫ8 M or 10 Ϫ4 M) for 24 or 48 h did not alter their responsiveness to acetylcholine. Besides, the testosterone effect was not influenced by the presence of the specific AR antagonist flutamide or the inhibitor of DNA transcription actinomycin D in the perfusing medium.Nevertheless, there are not many studies in airways. There are studies on vessels suggesting this phenomenon of sexual dimorphism. Many clinical and epidemiological studies show a bigger frequency of cardiovascular diseases in men than in pre-menopause women (1), whereas studies in rabbits demonstrated a different effect of testosterone in male and female animals in the development of athiromatic plaque (2).The results above suggest that in our experiments, sexual dimorphism was not due to classic steroid receptors. It remains to be investigated whether the action of testosterone on rabbit trachea is mediated by nonclassic membrane receptors that also exist in tracheal smooth muscle cells. REFERENCES 1. Barrett-Connor E. Sex differences in coronary heart diseases. Why are women so superior? The 1995 Ancel Keys Lecture. Circulation 95: 252-264, 1997. 2. Hanke H, Lenz C, Hess B, Spindler KD, Weidemann W. Effect of testosterone on plaque development and androgen receptor expression in the arterial vessel wall. Circulation 103: 1382-1385, 2001. 3. Kouloumenta V, Hatziefthimiou A, Paraskeva E, Gourgoulianis K, Molyvdas PA. Non-genomic effect of testosterone...

Physiological Parameters Affecting the Modulatory Role of Airway Epithelium on Airway Smooth Muscle Responsiveness

“…In rabbit trachea testosterone relaxes precontracted ASM in an epithelium-dependent way 41 Gender differences in the incidence of asthma Testosterone serum levels are depressed in patients with respiratory failure, 76 cystic fibrosis, 77 hypoxic pulmonary fibrosis 78 and COPD 79…”

“…Immunohistochemistry studies show that ASM obtained from male rabbits express classical androgen 41 and estrogens receptors. 42 Similarly, immunofluorescence experiments performed in our laboratory revealed that rabbit ASM cells express Androgen Receptors (ARs).…”

“…Namely, in rabbit trachea 17β-estradiol relaxes precontracted airways in an epithelium independent way. 41,50 On the other hand, testosterone may increase vagal activity and thus contract rab- bit 41 or guinea pig airways. 51 This effect of testosterone depends on animal gender as it is present only in male animals.…”

Παράγοντες Που Επηρεάζουν Την Απελευθέρωση Του Μονοξειδίου Του Αζώτου (NO) Στους Αεραγωγούς

“…Μελέτες που έγιναν σε ΛΜΙ τραχείας ενήλικων άρρενων κουνελιών φάνηκε ότι η τεστοστερόνη επιδρά άμεσα στην ανταποκρισιμότητα των ΛΜΙ των αεραγωγών με τρόπο εξαρτώμενο από το επιθήλιο και την παραγωγή ΝΟ [81,82] . Συγκεκριμένα προκαλεί δοσοεξαρτώμενη σύσπαση σε ημικρίκια τραχείας ενήλικων άρρενων κουνελιών και δοσοεξαρτώμενη χάλαση όταν σε αυτά έχουμε προτύτερα επιδράσει με ACh και καρβαχόλη (CCh) ενώ δεν έχει καμμία επίδραση σε ιστό θηλυκών κουνελιών.…”

“…Η μηχανική αφαίρεση του επιθηλίου εξουδετερώνει σημαντικά την δράση της χάλασης της ορμόνης. Αντίθετα η δράση χάλασης σε προσυσπασμένα ημικρίκια τραχείας ενήλικων άρρενων κουνελιών της 17β-οιστραδιόλης είναι ανεξάρτητη της παρουσίας επιθηλίου [82,83] .…”