The effects of bile acids on beta-adrenoceptors, fluidity, and the extent of lipid peroxidation in rat cardiac membranes

Bile acids have been proposed as a causative factor for the cardiomyopathy of cholestatic liver disease, since they cause negative inotropism and chro notropism and attenuate cardiac responsiveness to sympathetic stimulation. Bile acids can also modify membrane fluidity and generate reactive oxygen s pecies (ROS). The effects of 10(-6)-10(-3) M deoxycholic acid (DCA) and che nodeoxycholic acid (CDCA) and their taurine conjugates, TDCA and TCDCA, on (1) the binding characteristics of beta-adrenoceptors, (2) membrane fluidit y, and (3) the extent of lipid peroxidation in rat cardiac membranes were a ssessed. The results were compared to the effects of the oxidant, 10(-4)-10 (-3) M hydrogen peroxide (H2O2), and the membrane-fluidizing compound, 5 x 10(-5) M 2-(2-methoxyethoxy)ethyl 8-(cis-2-n-octylcyclopropyl)octanoate (A( 2)C). Cardiac beta-adrenoceptor density alone was reduced at 10(-4) M bile acid concentration while, at 10(-3) M bile acids, reductions in both recept or density and affinity were seen. At 10(-4) M H2O2, receptor number and af finity were reduced, whereas A(2)C increased receptor affinity without affe cting receptor density. Bile acids (10(-3) M) and 10(-4) M H2O2 reduced mem brane fluidity. H2O2 caused a concentration-depenclent increase in the exte nt of lipid peroxidation, whereas the bile acids and A(2)C had no effect. B ile acids (10(-4) M) reduced beta-adrenoceptor density in the absence of va riations in membrane fluidity and in the extent of membrane lipid peroxidat ion. This result suggests that bile acids, at concentrations equivalent to the plasma/serum total or estimated free bile acid concentration may have a possible role in the etiology of cardiomyopathy of cholestatic liver disea se. At 10(-3) M bile acid concentration, beta-adrenoceptor number and affin ity were adversely affected, accompanied by a decrease in membrane fluidity but without any significant increase in the extent of membrane lipid perox idation. Although cardiac beta-adrenoceptor density and affinity and membra ne fluidity were adversely affected by bile acids, the relevance of these f indings tu our understanding of the etiological basis of hepatic cardiomyop athy is questionable, since such concentrations exceeded the highest concen trations seen in the plasma and/or tissues of patients with cholestatic liv er disease. (C) 2000 Elsevier Science Inc.