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1 Groton Laboratories, Pfizer Global Research and Development, Pfizer Pharmaceuticals, Inc., Groton, Connecticut 06340 - 5146; and 2 Michael E. DeBakey Institute For Comparative Cardiovascular Sciences and Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843 - 4466
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 µM Tes produced dose-dependent relaxation from 10 µM
(4 ± 1%) to 300 µM (100 ± 1%). In paired Endo+ and Endo aortas, Tes-induced vasorelaxation was slightly but
significantly greater in Endo+ aortas (at 5-150 µM Tes);
sensitivity (EC50) of the aorta to Tes was reduced by
nearly one-half in Endo vessels. Based on the sensitivity
(EC50) of Endo aortas, Tes, the active metabolite
5
-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 µM 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.
endothelium; endothelium-dependent vasodilation; endothelium-independent vasodilation; vasorelaxation; vasodilation
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