title: Nongenomic bronchodilating action elicited by dehydroepiandrosterone (DHEA) in a guinea pig asthma model.
abstract: Primates secrete large amounts of the precursor steroid dehydroepiandrosterone (DHEA); in humans, its levels are low during childhood and start declining after the fourth decade. It has been postulated that the progressive decline in DHEA levels may be related with the severity of asthma associated with age. To determine whether DHEA may regulate the airway smooth muscle (ASM) activity, isolated tracheal rings with and without epithelium from male guinea pigs were isometrically recorded to characterize the response of ASM to DHEA at different concentrations on KCl- and carbachol (CCh)-induced contraction as well as on ovalbumin (OVA)-induced contraction in sensitized guinea pigs. Additionally, we used barometric plethysmography in sensitized guinea pigs in order to compare changes of the lung resistance increased by the antigen challenge to OVA in the absence and presence of different doses of DHEA. DHEA concentration-dependently abolished the contraction to KCl, CCh and OVA, and no differences were found in preparations with and without epithelium. DHEA-induced relaxation was not modified by the suppression of protein synthesis or transcription, pharmacological inhibition of nitric oxide (NO) synthase, nor by antagonist of β2-adrenergic receptors or an inhibitor of the 3β-HSD enzyme. Likewise, Ca(2+)-induced contraction in Ca(2+)-free depolarized tissues was antagonized by DHEA, and the contraction to the L-type voltage-dependent calcium channel activator (Bay K 8644) was inhibited by DHEA. Furthermore, DHEA prevented OVA-induced increases in lung resistance. These results indicate that DHEA-induced relaxation in ASM is a nongenomic (membrane) action and is not produced after its bioconversion. The data suggest that DHEA-induced relaxation is an epithelium- and NO-independent mechanism that involves a blockade of voltage-dependent calcium channels and possible non-selective cation channels.
authors.affiliation: Universidad Nacional Autónoma de México, Instituto de Investigaciones Biomédicas, Departamento de Biología Celular y Fisiología, México, D.F. 04510, Mexico.
authors.forename: Julia
authors.initials: J
authors.lastname: Espinoza
authors.forename: Luis M
authors.initials: LM
authors.lastname: Montaño
authors.forename: Mercedes
authors.initials: M
authors.lastname: Perusquía
mesh_terms: D000818:Animals; D001249:Asthma; D001986:Bronchial Spasm / Q000517:prevention & control; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D014132:Trachea / Q000187:drug effects / Q000502:physiology
chemical_list: D003687:Dehydroepiandrosterone
keywords: ASM; Adrenal steroid; Airway smooth muscle; Asthma; BK; Bronchorelaxation; CCh; DHEA; DHEA-S; DMSO; Dehydroepiandrosterone; E(max); EAR; IC(50); KCl; KCl–Ca(2+)-free solution; KCl–Ca(2+)∅; KHS; Krebs–Henseleit bicarbonate solution; LAR; N(ω)-nitro-l-arginine methyl ester; NO; OVA; R(L); ROCC; SOCE; VDCC; airway smooth muscle; bradykinin; carbachol; dehydroepiandrosterone; dehydroepiandrosterone sulfate; dimethylsulfoxide; early asthmatic response; inhibitory concentration 50; l-NAME; late asthmatic response; lung resistance; maximal effect; nitric oxide; ovalbumin; potassium chloride; receptor-operated Ca(2+) channel; store-operated Ca(2+) entry; voltage-dependent Ca(2+) channels