title: Taurocholate induces changes in rat cardiomyocyte contraction and calcium dynamics.
abstract: Obstetric cholestasis is characterized by raised bile acids, and can be complicated by intrauterine death. We have shown that the bile acid taurocholate causes loss of synchronous beating, bradycardia and cessation of contraction in cultured rat cardiomyocytes [Williamson, Gorelik, Eaton, Lab, de Swiet and Korchev (2001) Clin. Sci. 100, 363-369]. The aim of the present study was to investigate the effect of taurocholate on cardiomyocytes further. We demonstrated a reduced rate of contraction and proportion of beating cells when rat cardiomyocytes were exposed to increasing concentrations of taurocholate (0.1-3.0 mM); more marked at higher concentrations (P<0.001). Using scanning ion-conductance microscopy, we also demonstrated reduced amplitude of contraction and calcium transients with taurocholate. Our observations indicate that taurocholate affects calcium release from the sarcoplasmic reticulum and this parallels changes in contractile function. The relationship between the contraction amplitude and calcium transient is not linear, particularly at higher concentrations of taurocholate. We observed different effects in individual cultured neonatal cells; a reversible reduction in rate and amplitude of contraction in some, and irreversible oscillatory (fibrillatory) cessation of beating in others. The effects were more marked with higher concentrations. The contraction amplitude was also reduced in adult cardiomyocytes. The changes were reversible following removal of taurocholate in adult, but not in neonatal, cardiomyocytes exposed to higher concentrations (>0.3 mM) (P<0.001). In conclusion we have demonstrated that the bile acid taurocholate can cause different types of dysrhythmia in individual cardiomyocytes. These results provide further support for the hypothesis that obstetric cholestasis may produce cardiac-related sudden intrauterine death.
authors.affiliation: Division of Medicine, Imperial College School of Medicine, MRC Clinical Sciences Centre, Hammersmith Campus, Du Cane Road, London W12 0NN, U.K.
authors.forename: Julia
authors.initials: J
authors.lastname: Gorelik
authors.forename: Sian E
authors.initials: SE
authors.lastname: Harding
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Shevchuk
authors.forename: Duleepa
authors.initials: D
authors.lastname: Koralage
authors.forename: Max
authors.initials: M
authors.lastname: Lab
authors.forename: Michael
authors.initials: M
authors.lastname: de Swiet
authors.forename: Yuri
authors.initials: Y
authors.lastname: Korchev
authors.forename: Catherine
authors.initials: C
authors.lastname: Williamson
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D002779:Cholestasis / Q000378:metabolism; D005260:Female; D005313:Fetal Death / Q000209:etiology; D006801:Humans; D008297:Male; D023421:Models, Animal; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013656:Taurocholic Acid / Q000494:pharmacology*
chemical_list: D002756:Cholagogues and Choleretics; D013656:Taurocholic Acid; D002118:Calcium