Tibolone and its metabolites acutely relax rabbit coronary arteries in vitro

Abstract

Objectives: To compare the acute effects of estradiol, tibolone and its metabolites on coronary arteries in vitro and to investigate possible vascular mechanisms. Methods: Coronary artery ring segments from female rabbits were mounted in myographs for isometric tension recordings. Concentration–response curves to tibolone, 3α-OH-tibolone, 3β-OH-tibolone, Δ4-isomer and 17β-estradiol were obtained after precontraction with potassium 30 mmol/l and after addition of N ω -nitro- l-arginine methyl ester 10 −4 mol/l ( l-NAME, an inhibitor of endothelial nitric oxide (NO) synthase) or tetraethylammonium chloride 10 −2 mol/l (TEA, an unspecific inhibitor of potassium channels). The effects of the different substances to calcium concentration–response curves were evaluated. Responses are expressed as maximal contraction ( E max), concentration giving half maximal contraction (log EC 50) or area under curve (AUC). Results: Tibolone and its metabolites induced a concentration-dependent vasodilatation comparable to that of 17β-estradiol with the rank of potency: 3β-OH-tibolone ≅ tibolone > 3α-OH-tibolone > Δ4-isomer (ANOVA). l-NAME partly inhibited the relaxation to all substances. TEA induced a slight rightward shift of the relaxation to 3α-OH-tibolone (log EC 50: −5.05 versus −5.20; P<0.05; Student’s t-test), but not to the other substances. Calcium concentration-dependent contraction curves were inhibited by all substances compared to controls (AUC, P<0.05, ANOVA). Conclusions: Our data indicate that the acute relaxation induced by tibolone and its metabolites in coronary arteries in vitro are probably mediated by endothelium independent inhibition of calcium channels but may also involve an endothelium-dependent mechanism via nitric oxide. The effect of tibolone is comparable to that of 17β-estradiol in this set-up.