title: Vasodilating effect of norethisterone and its 5 alpha metabolites: a novel nongenomic action.
abstract: Estrogens are generally administered in hormone replacement therapy in combination with synthetic progestins. Studies of cardiovascular risk factors in postmenopausal women have shown a variety of responses according to the molecular structure of the progestin used in hormone replacement therapy schemes. The present study sets out to determine the vasoactive effects of norethisterone and its 5alpha-dihydro (5alpha-norethisterone) and -tetrahydro (3alpha,5alpha-norethisterone and 3beta,5alpha-norethisterone) metabolites in isolated precontracted rat thoracic aorta. The addition of norethisterone and 3alpha,5alpha-norethisterone in rat aorta exhibited a potent, concentration-response inhibition of noradrenaline-induced contraction, while 5alpha- and 3beta,5alpha-norethisterone had very little, if any, vasorelaxing effect. Relaxation to norethisterone and 3alpha,5alpha-norethisterone had very rapid time-courses and it was neither affected by the absence of endothelium nor by the inhibitor of nitric oxide synthase, Nomega-nitro-L-arginine methyl ester (L-NAME). The addition of specific anti-androgen, anti-progestin and anti-estrogen compounds and protein synthesis inhibitors did not preclude the vasorelaxing effect of norethisterone and its 3alpha,5alpha-reduced metabolite. The results strongly suggest that these effects are not mediated by nuclear sex steroid hormone receptors. The overall data document a novel nongenomic endothelium-independent vasorelaxing action of a 19-nor synthetic progestin and one of its A-ring-reduced derivatives.
authors.affiliation: Departamento de Biologi;a Celular y Fisiologi;a, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Apartado Postal 70-492, 04511, México, D.F., Mexico
authors.forename: Mercedes
authors.initials: M
authors.lastname: Perusquía
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Villalón
authors.forename: Erika
authors.initials: E
authors.lastname: Navarrete
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: García
authors.forename: Gregorio
authors.initials: G
authors.lastname: Pérez-Palacios
authors.forename: Ana E
authors.initials: AE
authors.lastname: Lemus
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009640:Norethindrone / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D014665:Vasodilator Agents; D009640:Norethindrone