Ryanodine receptors contribute to bile acid-induced pathological calcium signaling and pancreatitis in mice

Husain SZ, Orabi AI, Muili KA, Luo Y, Sarwar S, Mahmood SM, Wang D, Choo-Wing R, Singh VP, Parness J, Ananthanaravanan M, Bhandari V, Perides G. Ryanodine receptors contribute to bile acid-induced pathological calcium signaling and pancreatitis in mice. Am J Physiol Gastrointest Liver Physiol 302: G1423-G1433, 2012. First published April 19, 2012; doi: 10.1152/ajpgi.00546.2011.-Biliary pancreatitis is the most common etiology for acute pancreatitis, yet its pathophysiological mechanism remains unclear. Ca2+ signals generated within the pancreatic acinar cell initiate the early phase of pancreatitis, and bile acids can elicit anomalous acinar cell intracellular Ca2+ release. We previously demonstrated that Ca2+ released via the intracellular Ca2+ channel, the ryanodine receptor (RyR), contributes to the aberrant Ca2+ signal. In this study, we examined whether RyR inhibition protects against pathological Ca2+ signals, acinar cell injury, and pancreatitis from bile acid exposure. The bile acid tauro-lithocholic acid-3-sulfate (TLCS) induced intracellular Ca2+ oscillations at 50 mu M and a peak-plateau signal at 500 mu M, 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.