Characterization of leukotriene-induced contraction of the guinea-pig gallbladder in vitro

Abstract

Metabolites of arachidonic acid like prostaglandins have an established role in the pathogenesis of gallstone formation and cholecystitis, but any contribution by leukotrienes is less clear. Leukotrienes might contribute to the disease process by contracting the inflamed and (or) obstructed gallbladder, resulting in further inflammatory damage and biliary pain. To better define the role of leukotrienes, we assessed their effects on gallbladder contractility in vitro. Both leukotriene C4 (LTC4) and D4 (LTD4) had a concentration-dependent excitatory effect on guinea-pig gallbladder smooth muscle. The LTD4-receptor antagonist MK-571 (1 microM) competitively depressed the contractile response, to both LTD4 and LTC4. The source of calcium was defined using ryanodine to deplete intracellular calcium stores and nifedinine to block extracellular entry. Ryanodine (10 microM) antagonized gallbladder contraction at low concentrations of LTD4 (10(-10) and 10(-9) M). Nifedipine (1 microM) had a greater inhibitory effect on the contractile response at high concentrations of LTD4 (10(-8)-10(-6) M). LTD4-induced contractions were unaffected in tissues pretreated with the neural blocker tetrodotoxin or the muscarinic antagonist atropine. Thus, leukotrienes act directly on the gallbladder smooth muscle, causing contraction at concentrations found in models of cholecystitis, suggesting that these inflammatory mediators contribute to the symptoms and morbidity associated with gallbladder disease.

Gallbladder wall inflammatory cells in pediatric patients with biliary dyskinesia and cholelithiasis: a pilot study

“…Gallbladder mast cells would have the potential to contribute to pain generation by at least 2 mechanisms: sensitivity to distension as seen with mast cell degranulation in the gastrointestinal tract and through the generation of gallbladder spasms induced by mast cell products. For example, both histamine and cysteinyl leukotrienes increase the excitability of gallbladder smooth muscle and lead to contraction [22][23][24][25].…”

Leukotriene-induced contraction is mediated by cysteinyl leukotriene receptor CysLT1 in guinea pig fundus but by CysLT1 and CysLT2 in antrum

“…More studies using potent, selective CysLT 2 receptor antagonists are needed to clarify the CysLT subtype mediating antral contraction. If confirmed, the leukotrieneinduced contraction in the antrum mediated by both CysLT 1 and CysLT 2 is different to the esophagus, lower esophageal sphincter and gallbladder, in which CysLT 1 mediating leukotriene-induced contraction (Falcone and Krell, 1992;Freedman et al, 1993;Chang et al, 2008;Huang, 2009), and different from ileum, in which CysLT 2 mediating contraction (Bäck et al, 1996;Bäck, 2002). The effects of LTD 4 were not affected by atropine or tetrodotoxin.…”

“…This indicates that the cysteinyl leukotriene action is not neurally mediated and suggests a direct effect of cysteinyl leukotrienes on the gastric muscle. Direct effects have also been described on the cysteinyl leukotriene-induced contraction in the gallbladder, esophagus and lower esophageal sphincter (Freedman et al, 1993;Chang et al, 2008;Huang, 2009). …”

“…CysLT 1 receptors are expressed in the small intestine, colon and liver, whereas CysLT 2 receptors are found in the stomach, small intestine, colon, liver and pancreas (Brink et al, 2003;Kanaoka and Boyce, 2004;Capra et al, 2007;Bäck, 2002;Heise et al, 2000). Previous studies demonstrated that cysteinyl leukotrienes cause contraction of the esophagus (Chang et al, 2008;Kim et al, 1998), lower esophageal sphincter (Huang, 2009;Kim et al, 1998), stomach (Goldenberg and Subers, 1983;Miura et al, 1992;Miyata et al, 1995), ileum (Bäck et al, 1996), colon (Ieiri et al, 2001) and gallbladder (Falcone and Krell, 1992;Life Sciences 88 (2011) Freedman et al, 1993) as well as relaxation in the internal anal sphincter (de Godoy et al, 2009). The cysteinyl leukotriene-induced contractions are mediated by CysLT 1 receptors in the esophagus, lower esophageal sphincter and gallbladder (Falcone and Krell, 1992;Freedman et al, 1993;Chang et al, 2008;Huang, 2009).…”

“…Previous studies demonstrated that cysteinyl leukotrienes cause contraction of the esophagus (Chang et al, 2008;Kim et al, 1998), lower esophageal sphincter (Huang, 2009;Kim et al, 1998), stomach (Goldenberg and Subers, 1983;Miura et al, 1992;Miyata et al, 1995), ileum (Bäck et al, 1996), colon (Ieiri et al, 2001) and gallbladder (Falcone and Krell, 1992;Life Sciences 88 (2011) Freedman et al, 1993) as well as relaxation in the internal anal sphincter (de Godoy et al, 2009). The cysteinyl leukotriene-induced contractions are mediated by CysLT 1 receptors in the esophagus, lower esophageal sphincter and gallbladder (Falcone and Krell, 1992;Freedman et al, 1993;Chang et al, 2008;Huang, 2009). On the other hand, the cysteinyl leukotriene-induced contraction is mediated by CysLT 2 receptors in the ileum (Bäck et al, 1996).…”