Testosterone-induced relaxation of coronary arteries: Activation of Bk ca channels via the cGMP-dependent protein kinase

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Androgens are reported to have both beneficial and detrimental effects on human cardiovascular health. The aim of this study was to characterize nongenomic signaling mechanisms in coronary artery smooth muscle (CASM) and define the ionic basis of testosterone (TES) action. TES-induced relaxation of endothelium-denuded porcine coronary arteries was nearly abolished by 20 nM iberiotoxin, a highly specific inhibitor of large-conductance, calcium-activated potassium (BKCa) channels. Molecular patch-clamp studies confirmed that nanomolar concentrations of TES stimulated BKCa channel activity by ~ 100-fold and that inhibition of nitric oxide synthase (NOS) activity by N G-monomethyl-L-arginine nearly abolished this effect. Inhibition of nitric oxide (NO) synthesis or guanylyl cyclase activity also attenuated TES-induced coronary artery relaxation but did not alter relaxation due to 8-bromo-cGMP. Furthermore, we detected TES-stimu-lated NO production in porcine coronary arteries and in human CASM cells via stimulation of the type 1 neuronal NOS isoform. Inhibition of the cGMP-dependent protein kinase (PKG) attenuated TES-stimu-lated BKCa channel activity, and direct assay determined that TES increased activity of PKG in a concentration-dependent fashion. Last, the stimulatory effect of TES on BK Ca channel activity was mimicked by addition of purified PKG to the cytoplasmic surface of a cell-free membrane patch from CASM myocytes (~ 100-fold increase). These findings indicate that TES-induced relaxation of endothelium-denuded coronary arteries is mediated, at least in part, by enhanced NO production, leading to cGMP synthesis and PKG activation, which, in turn, opens BK Ca channels. These findings provide a molecular mechanism that could help explain why androgens have been reported to relax coronary arteries and relieve angina pectoris.

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American Journal of Physiology - Heart and Circulatory Physiology





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This article was published in American Journal of Physiology - Heart and Circulatory Physiology, Volume 302, Issue 1, Pages H115-H123.

The published version is available at http://dx.doi.org/10.1152/ajpheart.00046.2011.

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