The progestin levonorgestrel induces endothelium-independent relaxation ofrabbit jugular vein via inhibition of calcium entry and protein kinase C: role of cyclic AMP

1 The progestin and oestrogen component of oral contraceptives have been in volved 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. 2 The natural hormone progesterone, the synthetic progestins levonorgestrel , 3-keto-desogestrel, gestodene and chlormadinone acetate, and the syntheti c estrogen 17 alpha-ethinyloestradiol induced concentration-dependent relax ations of endothelium-intact Veins constricted with U46619. Levonorgestrel also inhibited constrictions evoked by either a high potassium (K+) solutio n or phorbol myristate acetate (PMA) in the absence and presence of extrace llular calcium (Ca2+). In addition, levonorgestrel depressed contractions e voked by Ca2+ and reduced Ca-45(2+) influx in depolarized veins. 3 Relaxations to levonorgestrel in U46619-constricted veins were neither af fected by the presence of the endothelium nor by the inhibitor of soluble g uanylyl cyclase, NS2028, but were significantly improved either by the sele ctive 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-constricte d veins in the presence, but not in the absence of extracellular Ca2+. Levo norgestrel increased levels of cyclic AMP and inhibited PMA-induced activat ion of protein kinase C in veins. 4 These findings indicate that levonorgestrel caused endothelium-independen t relaxations of jugular veins via inhibition of Ca2+ entry and of protein kinase C activation. In addition, the cyclic AMP effector pathway contribut es to the levonorgestrel-induced relaxation possibly by depressing Ca2+ ent ry.