Testosterone-induced vasorelaxation in the rat mesenteric arterial bed is mediated predominantly via potassium channels

1 We have investigated the involvement of nitric oxide and K+ channels in the vasorelaxant responses to physiologically-relevant concentrations of testosterone in the rat isolated mesenteric arterial bed. 2 Testosterone (100 pM - 10 muM) elicited concentration-dependent relaxations in the isolated mesenteric arterial bed (pEC(50) = 9.47 (9.22 - 9.73, 95% CI), maximal relaxation, R-max = 62.8 +/- 2.0%, n = 6). A nitric oxide synthase (NOS) inhibitor, N-G-nitro-L-arginine methyl ester (L-NAME, 300 pm) or removal of the endothelium significantly inhibited maximal relaxations to testosterone (L-NAME: R-max = 51.4 +/- 1.1%, P < 0.01, n = 6; endothelium-denuded: R-max = 46.9 +/- 2.8%, P < 0.001, n = 5). 3 Raising the extracellular K+ concentration to 30 and 60 mM, or pre-treatment with 300 muM tetrabutylammonium chloride (TBA), a calcium-activated K+ channel inhibitor, abolished vasorelaxations induced by testosterone. A selective inhibitor of ATP-sensitive K+ (K-ATP) channels, glibenclamide (10 muM) and an inhibitor of voltage-sensitive K+ (K-V) channels, 4-aminopyridine (4-AP, I mm) did not affect testosterone-induced responses. Vasorelaxation to I muM testosterone was significantly (P < 0.05) inhibited by 100 nM charybdotoxin (ChTx), an inhibitor of large conductance calcium-activated K+ (BKCa) channels (control: 63.3 +/- 9.9%, n 6; ChTx: 11.9 +/- 12.7%, n = 3). 4 Neither the testosterone receptor antagonist, flutamide (10 muM) nor an aromatase inhibitor, aminoglutethimide (10 muM) inhibited testosterone-induced responses. 5 In conclusion, the present findings demonstrate, in the rat isolated mesenteric arterial bed, that testosterone causes acute vasorelaxations at physiologically relevant concentrations which are, in part, mediated via NO- and endothelium-dependent pathways, However, the activation of BKCa channels plays a substantial role in testosterone-induced vasorelaxation.