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

Sohail Z. Husain, Abrahim I. Orabi, Kamaldeen A. Muili, Yuhuan Luo, Sheharyar Sarwar, Syeda Maham Mahmood, Dong Wang, Rayman Choo-Wing, Vijay P. Singh, Jerome Parness, Meena Ananthanaravanan, Vineet Bhandari, George Perides

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

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 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.

Original languageEnglish (US)
Pages (from-to)G1423-G1433
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume302
Issue number12
DOIs
StatePublished - Jun 15 2012

Keywords

  • Acinar cell injury
  • Calcium channels
  • Dantrolene
  • Ryanodine
  • Tauro-lithocholic acid-3-sulfate

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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    Husain, S. Z., Orabi, A. I., Muili, K. A., Luo, Y., Sarwar, S., Mahmood, S. M., Wang, D., Choo-Wing, R., Singh, V. P., Parness, J., Ananthanaravanan, M., Bhandari, V., & Perides, G. (2012). Ryanodine receptors contribute to bile acid-induced pathological calcium signaling and pancreatitis in Mice. American Journal of Physiology - Gastrointestinal and Liver Physiology, 302(12), G1423-G1433. https://doi.org/10.1152/ajpgi.00546.2011