title: Testosterone-induced relaxation of rat aorta is androgen structure specific and involves K+ channel activation.
abstract: Recent studies have established that testosterone (Tes) produces acute (nongenomic) vasorelaxation. This study examined the structural specificity of Tes-induced vasorelaxation and the role of vascular smooth muscle (VSM) K+ channels in rat thoracic aorta. Aortic rings from male Sprague-Dawley rats with (Endo+) and without endothelium (Endo-) were prepared for isometric tension recording. In Endo- aortas precontracted with phenylephrine, 5-300 microM Tes produced dose-dependent relaxation from 10 microM (4 +/- 1%) to 300 microM (100 +/- 1%). In paired Endo+ and Endo- aortas, Tes-induced vasorelaxation was slightly but significantly greater in Endo+ aortas (at 5-150 microM Tes); sensitivity (EC(50)) of the aorta to Tes was reduced by nearly one-half in Endo- vessels. Based on the sensitivity (EC(50)) of Endo- aortas, Tes, the active metabolite 5alpha-dihydrotestosterone, the major excretory metabolites androsterone and etiocholanolone, the nonpolar esters Tes-enanthate and Tes-hemisuccinate (THS), and THS conjugates to BSA (THS-BSA) exhibited relative potencies for vasorelaxation dramatically different from androgen receptor-mediated effects observed in reproductive tissues, with a rank order of THS-BSA > Tes > androsterone = THS = etiocholanolone > dihydrotestosterone >> Tes-enanthate. Pretreatment of aortas with 5 mM 4-aminopyridine attenuated Tes-induced vasorelaxation by an average of 44 +/- 2% (25-300 microM Tes). In contrast, pretreatment of aortas with other K+ channel inhibitors had no effect. These data reveal that Tes-induced vasorelaxation is a structurally specific effect of the androgen molecule, which is enhanced in more polar analogs that have a lower permeability to the VSM cell membrane, and that the effect of Tes involves activation of K+ efflux through K+ channels in VSM, perhaps via the voltage-dependent (delayed-rectifier) K+ channel.
authors.affiliation: Groton Laboratories, Pfizer Global Research and Development, Pfizer Pharmaceuticals, Inc., Groton, CT 06340-5146, USA.
authors.forename: A Q
authors.initials: AQ
authors.lastname: Ding
authors.forename: J N
authors.initials: JN
authors.lastname: Stallone
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects*; D004247:DNA / Q000378:metabolism; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D016678:Genome; D012739:Gonadal Steroid Hormones / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012669:Seminal Vesicles / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000728:Androgens; D012739:Gonadal Steroid Hormones; D015221:Potassium Channels; D014665:Vasodilator Agents; D013196:Dihydrotestosterone; C049564:dihydrotestosterone heptanoate; D013739:Testosterone; C029763:testosterone-17-succinate; D004247:DNA