title: The progestin levonorgestrel induces endothelium-independent relaxation of rabbit jugular vein via inhibition of calcium entry and protein kinase C: role of cyclic AMP.
abstract: The progestin and oestrogen component of oral contraceptives have been involved in the development of venous thromboembolic events in women. In the present study we determined the vasoactive effects of sex steroids used in oral contraceptives in isolated preconstricted rabbit jugular veins in the presence of diclofenac and examined the underlying mechanisms. The natural hormone progesterone, the synthetic progestins levonorgestrel, 3-keto-desogestrel, gestodene and chlormadinone acetate, and the synthetic estrogen 17 alpha-ethinyloestradiol induced concentration-dependent relaxations of endothelium-intact veins constricted with U46619. Levonorgestrel also inhibited constrictions evoked by either a high potassium (K(+)) solution or phorbol myristate acetate (PMA) in the absence and presence of extracellular calcium (Ca(2+)). In addition, levonorgestrel depressed contractions evoked by Ca(2+) and reduced (45)Ca(2+) influx in depolarized veins. Relaxations to levonorgestrel in U46619-constricted veins were neither affected by the presence of the endothelium nor by the inhibitor of soluble guanylyl cyclase, NS2028, but were significantly improved either by the selective cyclic AMP phosphodiesterase inhibitor rolipram or in the absence of diclofenac, and decreased by the protein kinase A inhibitor, Rp-8-CPT-cAMPS. Rolipram also potentiated relaxations to levonorgestrel in PMA-constricted veins in the presence, but not in the absence of extracellular Ca(2+). Levonorgestrel increased levels of cyclic AMP and inhibited PMA-induced activation of protein kinase C in veins. These findings indicate that levonorgestrel caused endothelium-independent relaxations of jugular veins via inhibition of Ca(2+) entry and of protein kinase C activation. In addition, the cyclic AMP effector pathway contributes to the levonorgestrel-induced relaxation possibly by depressing Ca(2+) entry.
authors.affiliation: Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Herkert
authors.forename: H
authors.initials: H
authors.lastname: Kuhl
authors.forename: R
authors.initials: R
authors.lastname: Busse
authors.forename: V B
authors.initials: VB
authors.lastname: Schini-Kerth
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002122:Calcium Chloride / Q000494:pharmacology; D002715:Chlormadinone Acetate / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D017135:Desogestrel / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology*; D004997:Ethinyl Estradiol / Q000494:pharmacology; D066298:In Vitro Techniques; D007601:Jugular Veins / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D016912:Levonorgestrel / Q000494:pharmacology*; D008297:Male; D009652:Norpregnenes / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D045167:Progesterone Congeners / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011817:Rabbits; D020889:Rolipram / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; D009652:Norpregnenes; D045167:Progesterone Congeners; D013873:Thionucleotides; D002715:Chlormadinone Acetate; C033273:Gestodene; C044815:etonogestrel; D004997:Ethinyl Estradiol; D016912:Levonorgestrel; D011189:Potassium Chloride; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D017135:Desogestrel; D000242:Cyclic AMP; D011493:Protein Kinase C; D006152:Cyclic GMP; D020889:Rolipram; D002122:Calcium Chloride; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium