BACKGROUND: Disturbances in the function of sphincter of Oddi (SO) may prevent normal bile flow and thus enhance the probability of common bile duct stone (CBDS) formation. Previously, we have shown increased prevalence of hypothyroidism in CBDS patients. METHODS: In animal (pig) experiments, thyroxine (T4) and triiodothyronine have a specific inhibitory effect on SO contractility, which raises the possibility that the lack of this prorelaxing effect in hypothyroidism could, at least in part, explain the increased prevalence of CBDS. The aims of the present study were to investigate, whether human SO reacts similarly to T4, and to study the mechanisms of the T4 prorelaxing effect. RESULTS: We found that T4 had similar inhibitory effects on both human and pig SO contractions. The T4 effect was dose-dependent, and maximum was observed in 30 min. The maximal prorelaxing effect was achieved with 0.1 nM T4 concentration, the effect of the physiological T4 concentration (0.01 nM) being about half of the maximal effect. Addition of alpha-adrenoceptor antagonist phentolamine, beta-adrenoceptor antagonist propranolol, nitric oxide (NO)-synthesis inhibitor L-NAME, nerve conductance blocker tetrodotoxin, or cyclooxygenase inhibitor diclofenac did not affect the T4-induced inhibition of contraction. Addition of transcription inhibitor actinomycin D or translation inhibitor cyclophosphamide partially reversed the T4-induced inhibition of contraction. Addition of K+ channel blocker glibenclamide totally reversed the T4-induced inhibition of contraction. In Western blotting, the thyroid hormone receptor (TR) antibody recognized 53 kDa and 58 kDa proteins, corresponding to beta1 and beta2 isoforms of TR, in the human SO tissue. CONCLUSIONS: We conclude that T4 has a direct prorelaxing effect on human SO that expresses TR beta1 and beta2. This effect is mediated through a transcriptional mechanism that requires new mRNA and protein synthesis and subsequently leads to the activation of K+ channels.
BACKGROUND: Disturbances in the function of sphincter of Oddi (SO) may prevent normal bile flow and thus enhance the probability of common bile duct stone (CBDS) formation. Previously, we have shown increased prevalence of hypothyroidism in CBDS patients. METHODS: In animal (pig) experiments, thyroxine (T4) and triiodothyronine have a specific inhibitory effect on SO contractility, which raises the possibility that the lack of this prorelaxing effect in hypothyroidism could, at least in part, explain the increased prevalence of CBDS. The aims of the present study were to investigate, whether human SO reacts similarly to T4, and to study the mechanisms of the T4 prorelaxing effect. RESULTS: We found that T4 had similar inhibitory effects on both human and pig SO contractions. The T4 effect was dose-dependent, and maximum was observed in 30 min. The maximal prorelaxing effect was achieved with 0.1 nM T4 concentration, the effect of the physiological T4 concentration (0.01 nM) being about half of the maximal effect. Addition of alpha-adrenoceptor antagonist phentolamine, beta-adrenoceptor antagonist propranolol, nitric oxide (NO)-synthesis inhibitor L-NAME, nerve conductance blocker tetrodotoxin, or cyclooxygenase inhibitor diclofenac did not affect the T4-induced inhibition of contraction. Addition of transcription inhibitor actinomycin D or translation inhibitor cyclophosphamide partially reversed the T4-induced inhibition of contraction. Addition of K+ channel blocker glibenclamide totally reversed the T4-induced inhibition of contraction. In Western blotting, the thyroid hormone receptor (TR) antibody recognized 53 kDa and 58 kDa proteins, corresponding to beta1 and beta2 isoforms of TR, in the human SO tissue. CONCLUSIONS: We conclude that T4 has a direct prorelaxing effect on human SO that expresses TR beta1 and beta2. This effect is mediated through a transcriptional mechanism that requires new mRNA and protein synthesis and subsequently leads to the activation of K+ channels.