title: Ryanodine receptors contribute to bile acid-induced pathological calcium signaling and pancreatitis in mice.
abstract: Biliary pancreatitis is the most common etiology for acute pancreatitis, yet its pathophysiological mechanism remains unclear. Ca(2+) signals generated within the pancreatic acinar cell initiate the early phase of pancreatitis, and bile acids can elicit anomalous acinar cell intracellular Ca(2+) release. We previously demonstrated that Ca(2+) released via the intracellular Ca(2+) channel, the ryanodine receptor (RyR), contributes to the aberrant Ca(2+) signal. In this study, we examined whether RyR inhibition protects against pathological Ca(2+) signals, acinar cell injury, and pancreatitis from bile acid exposure. The bile acid tauro-lithocholic acid-3-sulfate (TLCS) induced intracellular Ca(2+) oscillations at 50 μM and a peak-plateau signal at 500 μM, and only the latter induced acinar cell injury, as determined by lactate dehydrogenase (LDH) leakage. Pretreatment with the RyR inhibitors dantrolene or ryanodine converted the peak-plateau signal to a mostly oscillatory pattern (P < 0.05). They also reduced acinar cell LDH leakage, basolateral blebbing, and propidium iodide uptake (P < 0.05). In vivo, a single dose of dantrolene (5 mg/kg), given either 1 h before or 2 h after intraductal TLCS infusion, reduced the severity of pancreatitis down to the level of the control (P < 0.05). These results suggest that the severity of biliary pancreatitis may be ameliorated by the clinical use of RyR inhibitors.
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA. sohail.husain@chp.edu
authors.forename: Sohail Z
authors.initials: SZ
authors.lastname: Husain
authors.forename: Abrahim I
authors.initials: AI
authors.lastname: Orabi
authors.forename: Kamaldeen A
authors.initials: KA
authors.lastname: Muili
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Luo
authors.forename: Sheharyar
authors.initials: S
authors.lastname: Sarwar
authors.forename: Syeda Maham
authors.initials: SM
authors.lastname: Mahmood
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.forename: Rayman
authors.initials: R
authors.lastname: Choo-Wing
authors.forename: Vijay P
authors.initials: VP
authors.lastname: Singh
authors.forename: Jerome
authors.initials: J
authors.lastname: Parness
authors.forename: Meena
authors.initials: M
authors.lastname: Ananthanaravanan
authors.forename: Vineet
authors.initials: V
authors.lastname: Bhandari
authors.forename: George
authors.initials: G
authors.lastname: Perides
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D003620:Dantrolene / Q000494:pharmacology; D008297:Male; D051379:Mice; D010195:Pancreatitis / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D013658:Taurolithocholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D001647:Bile Acids and Salts; D019837:Ryanodine Receptor Calcium Release Channel; C066776:taurolithocholic acid 3-sulfate; D012433:Ryanodine; D013658:Taurolithocholic Acid; D003620:Dantrolene