Testosterone-induced relaxation of rat aorta is androgen structure specific and involves K+ channel activation

Recent studies have established that testosterone (Tes) produces acute (non genomic) vasorelaxation. This study examined the structural specificity of Tes-induced vasorelaxation and the role of vascular smooth muscle (VSM) Kchannels in rat thoracic aorta. Aortic rings from male Sprague-Dawley rats with (Endo+) and without endothelium (Endo-) were prepared for isometric te nsion recording. In Endo - aortas precontracted with phenylephrine, 5-300 m uM Tes produced dose-dependent relaxation from 10 muM (4 +/- 1%) to 300 muM (100 +/- 1%). In paired Endo+ and Endo- aortas, Tes-induced vasorelaxation was slightly but significantly greater in Endo+ aortas (at 5-150 muM Tes); sensitivity (EC50) of the aorta to Tes was reduced by nearly one-half in E ndo - vessels. Based on the sensitivity (EC50) of Endo- aortas, Tes, the ac tive metabolite 5 alpha -dihydrotestosterone, the major excretory metabolit es androsterone and etiocholanolone, the nonpolar esters Tes-enanthate and Tes-hemisuccinate (THS), and THS conjugates to BSA (THS-BSA) exhibited rela tive potencies for vasorelaxation dramatically different from androgen rece ptor-mediated effects observed in reproductive tissues, with a rank order o f THS-BSA > Tes > androsterone = THS = etiocholanolone > dihydrotestosteron e >> Tes-enanthate. Pretreatment of aortas with 5 mM 4-aminopyridine attenu ated Tes-induced vasorelaxation by an average of 44 +/- 2% (25-300 muM Tes) . In contrast, pretreatment of aortas with other K+ channel inhibitors had no effect. These data reveal that Tes-induced vasorelaxation is a structura lly specific effect of the androgen molecule, which is enhanced in more pol ar analogs that have a lower permeability to the VSM cell membrane, and tha t the effect of Tes involves activation of K+ efflux through K+ channels in VSM, perhaps via the voltage-dependent (delayed-rectifier) K+ channel.