Androgens are bronchoactive drugs that act by relaxing airway smooth muscle and preventing bronchospasm.
Changes in the androgen levels in asthmatic men may be associated with the severity of asthma. Androgens induce a nongenomic relaxation in airway smooth muscle, but the underlying mechanisms remain unclear. The aim of this study was to investigate the potential bronchorelaxing action of testosterone (TES) and its metabolites (5α- and 5β-dihydrotestosterone (DHT). A preventive effect on ovalbumin (OVA)-induced bronchospasm was observed in sensitized guinea pigs for each androgen. Androgens were studied in response to bronchoconstrictors: carbachol (CCh) and KCl in isolated trachea rings with and without epithelium from non-sensitized and sensitized animals as well as on OVA-induced contraction. Androgens concentration-dependently abolished the contraction in response to CCh, KCl, and OVA. There were significant differences in the sensitivity to the relaxation induced by each androgen. 5β-DHT was more potent for relaxing KCl-induced contraction, while TES and 5α-DHT were more potent for CCh- and OVA-induced contraction. No differences were found in preparations with and without epithelium or in the presence of a nitric oxide (NO) synthase inhibitor or an inhibitor of K(+) channels. These data indicate the absence of involvement of the epithelium-, NO- and K(+) channels-dependent pathway in androgen-induced relaxation. However, in dissociated tracheal myocytes loaded with the calcium-binding fluorescent dye Fura -2, physiological concentrations of androgens decreased the KCl-induced [Ca(2+)]i increment. 5β-DHT was the most potent at decreasing KCl-induced [Ca(2+)]i increment and preventing bronchospasm. We suggest that androgen-induced brochorelaxation was mediated via decreased Ca(2+) influx through L-type Ca(2+)channels but additional Ca(2+) entry blockade may be involved. Molecular changes in androgen structure may determine its preferential site of action.
Departamento de Biología Celular y FisiologíaInstituto de Investigaciones BiomédicasDepartamento de FarmacologíaFacultad de Medicina, Universidad Nacional Autónoma de México, Mexico, Distrito Federal 04510, MexicoDepartamento de Investigación en Hiperreactividad BronquialInstituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico, Distrito Federal, Mexico.
Luis M
LM
Montaño
Departamento de Biología Celular y FisiologíaInstituto de Investigaciones BiomédicasDepartamento de FarmacologíaFacultad de Medicina, Universidad Nacional Autónoma de México, Mexico, Distrito Federal 04510, MexicoDepartamento de Investigación en Hiperreactividad BronquialInstituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico, Distrito Federal, Mexico.
Julia
J
Espinoza
Departamento de Biología Celular y FisiologíaInstituto de Investigaciones BiomédicasDepartamento de FarmacologíaFacultad de Medicina, Universidad Nacional Autónoma de México, Mexico, Distrito Federal 04510, MexicoDepartamento de Investigación en Hiperreactividad BronquialInstituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico, Distrito Federal, Mexico.
Edgar
E
Flores-Soto
Departamento de Biología Celular y FisiologíaInstituto de Investigaciones BiomédicasDepartamento de FarmacologíaFacultad de Medicina, Universidad Nacional Autónoma de México, Mexico, Distrito Federal 04510, MexicoDepartamento de Investigación en Hiperreactividad BronquialInstituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico, Distrito Federal, Mexico.
Jaime
J
Chávez
Departamento de Biología Celular y FisiologíaInstituto de Investigaciones BiomédicasDepartamento de FarmacologíaFacultad de Medicina, Universidad Nacional Autónoma de México, Mexico, Distrito Federal 04510, MexicoDepartamento de Investigación en Hiperreactividad BronquialInstituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico, Distrito Federal, Mexico perusqui@unam.mx.
Mercedes
M
Perusquía
D000728:Androgens / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001986:Bronchial Spasm / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control*; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology*; D010047:Ovalbumin / Q000009:adverse effects / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000503:physiopathology*
D000728:Androgens; D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D011189:Potassium Chloride; D002217:Carbachol; D010047:Ovalbumin; D002118:Calcium
5α-dihydrotestosterone; 5β-dihydrotestosterone; airway smooth muscle; asthma; bronchoactive steroids; testosterone