Ryanodine receptors contribute to bile acid-induced pathological calcium signaling and pancreatitis in mice
| Autor: | Dong Wang, Syeda Maham Mahmood, Yuhuan Luo, Kamaldeen A. Muili, Rayman Choo-Wing, Vijay P. Singh, Abrahim I. Orabi, Jerome Parness, Sheharyar Sarwar, George Perides, Vineet Bhandari, Sohail Z. Husain, Meena Ananthanaravanan |
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| Rok vydání: | 2012 |
| Předmět: |
Male
medicine.medical_specialty Physiology medicine.drug_class Acinar Cells Dantrolene Bile Acids and Salts Mice chemistry.chemical_compound Physiology (medical) Internal medicine medicine Acinar cell Animals Calcium Signaling Pancreas Calcium signaling Hepatology Bile acid Ryanodine Ryanodine receptor Gastroenterology Ryanodine Receptor Calcium Release Channel medicine.disease Endocrinology Pancreatitis chemistry Acute pancreatitis Taurolithocholic acid Taurolithocholic Acid medicine.drug |
| Zdroj: | American Journal of Physiology-Gastrointestinal and Liver Physiology. 302:G1423-G1433 |
| ISSN: | 1522-1547 0193-1857 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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