Herkert O, Kuhl H, Busse R, Schini-Kerth V B
Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
Br J Pharmacol. 2000 Aug;130(8):1911-8. doi: 10.1038/sj.bjp.0703524.
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.
口服避孕药中的孕激素和雌激素成分与女性静脉血栓栓塞事件的发生有关。在本研究中，我们在双氯芬酸存在的情况下，测定了口服避孕药中使用的性激素对离体预收缩兔颈静脉的血管活性作用，并研究了其潜在机制。天然激素孕酮、合成孕激素左炔诺孕酮、3-酮去氧孕烯、孕二烯酮和醋酸氯地孕酮，以及合成雌激素17α-乙炔雌二醇，均可诱导U46619收缩的内皮完整静脉出现浓度依赖性舒张。在有无细胞外钙（Ca2+）的情况下，左炔诺孕酮还可抑制高钾（K+）溶液或佛波醇肉豆蔻酸酯乙酸酯（PMA）引起的收缩。此外，左炔诺孕酮可抑制Ca2+引起的收缩，并减少去极化静脉中（45）Ca2+的内流。U46619收缩静脉对左炔诺孕酮的舒张作用既不受内皮存在与否的影响，也不受可溶性鸟苷酸环化酶抑制剂NS2028的影响，但选择性环磷酸腺苷磷酸二酯酶抑制剂咯利普兰或在无双氯芬酸的情况下可显著增强其舒张作用，而蛋白激酶A抑制剂Rp-8-CPT-cAMPS则可减弱其舒张作用。咯利普兰在有细胞外Ca2+存在但无细胞外Ca2+不存在时，也可增强PMA收缩静脉对左炔诺孕酮的舒张作用。左炔诺孕酮可增加静脉中环磷酸腺苷水平，并抑制PMA诱导的蛋白激酶C活化。这些发现表明，左炔诺孕酮通过抑制Ca2+内流和蛋白激酶C活化，引起颈静脉内皮非依赖性舒张。此外，环磷酸腺苷效应途径可能通过抑制Ca2+内流，促进左炔诺孕酮诱导的舒张。
