Ursodeoxycholic acid and in vitro vasoactivity of hydrophobic bile acids.
Lipophilic bile acids, such as deoxycholic acid (DCA), are nonspecific endothelium-independent vasorelaxants whose underlying basis is complex, involving membrane calcium channels blockade and receptor antagonism. The vasorelaxant action of these acids has also been linked to the generation of reactive oxygen species and an increased extent of lipid peroxidation. Ursodeoxycholic acid (UDCA) is a naturally occurring tertiary dihydroxy hydrophilic acid whose mechanism of action has been attributed to minimizing the effects of lipophilic bile acids. Hence, we considered UDCA might be a useful pharmacological tool to delineate the role of enhanced lipid peroxidation in lipophilic bile acid-induced vasorelaxation. UDCA abrogates in vitro DCA-induced vasorelaxation in rat aortic rings and can suppress DCA-initiated lipid peroxidation in vascular smooth muscle microsomal membrane fractions prepared from the rat aortae. Three different studies were performed. In study 1, the ability of UDCA to restore the DCA-blunted contractile response to the alpha1-adrenoceptor, phenylephrine in rat aortic rings, was evaluated. In study 2, the ability of UDCA to restore DCA-induced vasorelaxation in precontracted rat aortic rings was assessed. In study 3, the ability of UDCA to suppress the increased extent of lipid peroxidation effected by DCA in vascular smooth muscle microsomal membrane fractions prepared from rat aortae was measured using the thiobarbituric acid reactive substance (TBARS) assay. UDCA, at a concentration equivalent to that seen in the plasma of patients with cholestatic liver disease treated with the bile acid, partially restored DCA-induced impaired contractility, prevented DCA-induced vasorelaxation, and abolished DCA-induced increases in the extent of lipid peroxidation. In conclusion, these data suggest that DCA-induced vasorelaxation is mediated by increasing the extent of lipid peroxidation in vascular tissue.
Bomzon
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A
Department of Pharmacology, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa.
Ljubuncic
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P
D000818:Animals; D001012:Aorta, Abdominal / Q000502:physiology; D001647:Bile Acids and Salts / Q000502:physiology*; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000502:physiology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid