title: Endothelium-dependent dilatory effects of 3alpha-OH-tibolone in gracilis muscle arterioles of the female Wistar rat.
abstract: OBJECTIVE
  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 3alpha-OH-tibolone and its sulfated form on female rat skeletal muscle arterioles, which play an important role in the control of blood pressure.
  
  
  METHODS
  In isolated, pressurized spontaneously constricted arterioles (mean passive diameter 83 +/- 3 microm), we investigated the vasodilatory effect of 3alpha-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 3alpha-OH-tibolone after removal of the endothelium and on vessels pretreated with the nitric oxide synthesis inhibitor, Nomega-nitro-L-arginine (L-Na). Finally we compared the vasodilatory effect of 3alpha-OH-tibolone with 17beta-estradiol.
  
  
  RESULTS
  A dose-dependent dilatation to 3alpha-OH-tibolone was observed starting at a concentration of 10 M. With the sulfated form of 3alpha-OH-tibolone, dilatation was only present at the highest concentration (10 M). In the denuded vessels, the vasodilatory effect was absent at concentrations from 10 to 10 M. The dilatation induced by 3alpha-OH-tibolone was not significantly reduced by L-Na. The vasodilatory effect of 3alpha-OH-tibolone did not differ from that of 17beta-estradiol.
  
  
  CONCLUSIONS
  3alpha-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 3alpha-OH-tibolone is endothelium dependent at physiologic concentrations and comparable to that of 17beta-estradiol.
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Iolente J M
authors.initials: IJ
authors.lastname: Korstjens
authors.forename: Raimond G V
authors.initials: RG
authors.lastname: Smolders
authors.forename: Marius J
authors.initials: MJ
authors.lastname: van der Mooren
authors.forename: Helenius J
authors.initials: HJ
authors.lastname: Kloosterboer
authors.forename: Peter
authors.initials: P
authors.lastname: Kenemans
authors.forename: Pieter
authors.initials: P
authors.lastname: Sipkema
mesh_terms: D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D018482:Muscle, Skeletal / Q000098:blood supply*; D009213:Myography; D009652:Norpregnenes / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects*
chemical_list: C485705:3-hydroxytibolone; D009652:Norpregnenes; D004958:Estradiol