Vasoactive effects of bile salts in cirrhotic rats: In vivo and in vitro studies,

Abstract

To clarify a possible pathogenic role for bile salts in the hyperdynamic circulation of cirrhosis, we studied the vasoactive effects of three different bile salts-tauroursodeoxycholic acid, taurochenodeoxycholic acid and taurodeoxycholic acid-in cirrhotic rats. Cirrhosis was induced with bile duct ligation; controls underwent sham surgery. In vivo, the bile salts were intravenously infused at one of three doses (1.2 x 10(-7), 1.2 x 10(-6) and 6.0 x 10(-5) mol x 100 gm-1 x min-1) for 5 min. Taurochenodeoxycholic acid and taurodeoxycholic acid infusions increased mesenteric arterial blood flow and conductance and induced systemic arterial hypotension, whereas tauroursodeoxycholic acid had no significant effect. At similar plasma levels of bile salts, the responses in cirrhotic rats were attenuated compared with those of controls. In vitro, isolated rings of superior mesenteric and carotid arteries and portal vein were precontracted with phenylephrine; then dilatory responses to cumulative doses of bile salts (10(-6) to 10(-3) mol/L) were measured. In all three vessels, taurodeoxycholic acid produced stronger dilatory effects than did taurochenodeoxycholic acid, whereas tauroursodeoxycholic acid showed no significant effect. Vessels from cirrhotic and control rats did not differ in degree of response. These results indicate that bile salts are directly vasoactive and can induce splanchnic vasodilation at the pathophysiological plasma levels seen in cirrhosis. Bile salts may be involved in the pathogenesis of splanchnic hyperemia and hyperdynamic circulation in cirrhosis.

Structural determinants of monohydroxylated bile acids to activate β1 subunit-containing BK channels

“…Vasodilation caused by an increase in bile acid levels in systemic circulation is a major determinant of the systemic hypotension associated with porto-systemic shunting that may occur in hepatobiliary disease (32). In hepatobiliary disease, not only overall increase in systemic bile acid levels but also changes in composition may occur, with drastic increase in LC levels (11).…”

G Protein–Coupled Bile Acid Receptor 1 Stimulation Mediates Arterial Vasodilation through a KCa1.1 (BKCa)–Dependent Mechanism

“…In brief, BAs have the capacity to signal via nuclear and G protein-coupled receptors, including G protein-coupled bile acid receptor 1 (GPBAR1), as well as, large conductance Ca 21 activated potassium channel K Ca 1.1 (BK Ca ) (Dopico et al, 2002) and muscarinic receptors (Sheikh Abdul Kadir et al, 2010) in which myriad effects on cardiovascular function have been demonstrated, including changes in myocyte contraction and synchronization (Bogin et al, 1983;Gorelik et al, 2002;Sheikh Abdul Kadir et al, 2010), vasodilation in a number of ex vivo isolated vascular models (Pak and Lee, 1993;Pak et al, 1994;Dopico et al, 2002;Bukiya et al, 2007;Sheikh Abdul Kadir et al, 2010), and bradycardia in vivo (Joubert, 1978a,b). In addition, BA dx.doi.org/10.1124/jpet.113.210005. s This article has supplemental material available at jpet.aspetjournals.org.…”

β1 (KCNMB1) Subunits Mediate Lithocholate Activation of Large-Conductance Ca2+-Activated K+ Channels and Dilation in Small, Resistance-Size Arteries

“…Bile acids (cholane-derived steroids) attenuate vascular reactivity in vitro and reduce systemic blood pressure in vivo (Pak and Lee, 1993;Bomzon and Ljubuncic, 1995). Furthermore, a spillover of bile acids from the portal to the systemic circulation is responsible for the systemic hypotension observed in patients with liver damage and/or significant portosystemic circulatory shunt.…”