Endothelium-dependent dilatory effects of 3α-OH-tibolone in gracilis muscle arterioles of the female Wistar rat

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Abstract
Tibolone is a synthetic steroid used for the treatment of the symptoms of menopause that, once metabolized, has estrogenic, progestogenic, and androgenic properties. We investigated the direct vasodilatory effects of the major active tibolone metabolite 3α-OH-tibolone and its sulfated form on female rat skeletal muscle arterioles, which play an important role in the control of blood pressure. In isolated, pressurized spontaneously constricted arterioles (mean passive diameter 83 ± 3 μm), we investigated the vasodilatory effect of 3α-OH-tibolone and its sulfated form. To study the role of the endothelium and in particular that of nitric oxide, we repeated the experiments with 3α-OH-tibolone after removal of the endothelium and on vessels pretreated with the nitric oxide synthesis inhibitor, Nω-nitro-L-arginine (L-Na). Finally we compared the vasodilatory effect of 3α-OH-tibolone with 17β-estradiol. A dose-dependent dilatation to 3α-OH-tibolone was observed starting at a concentration of 10−10 M. With the sulfated form of 3α-OH-tibolone, dilatation was only present at the highest concentration (10−4 M). In the denuded vessels, the vasodilatory effect was absent at concentrations from 10−10 to 10−7 M. The dilatation induced by 3α-OH-tibolone was not significantly reduced by L-Na. The vasodilatory effect of 3α-OH-tibolone did not differ from that of 17β-estradiol. 3α-OH-tibolone has a dose-dependent vasodilatory effect on isolated skeletal muscle arterioles from the rat. The sulfated form has no vasodilatory effect in this setup. This finding suggests that during this short incubation time there was no conversion of the sulfated metabolite into its active form by the vascular endothelium. The vasodilatory effect of 3α-OH-tibolone is endothelium dependent at physiologic concentrations and comparable to that of 17β-estradiol.