Dantrolene mitigates caerulein-induced pancreatitis in vivo in mice

Orabi AI, Shah AU, Ahmad MU, Choo-Wing R, Parness J, Jain D, Bhandari V, Husain SZ. Dantrolene mitigates caerulein-induced pancreatitis in vivo in mice. Am J Physiol Gastrointest Liver Physiol 299: G196-G204, 2010. First published May 6, 2010; doi:10.1152/ajpgi.00498.2009.-Acute pancreatitis is a painful, inflammatory disorder for which adequate treatments are lacking. An early, critical step in its development is the aberrant signaling of Ca2+ within the pancreatic acinar cell. This Ca2+ release is modulated by the intracellular Ca2+ channel the ryanodine receptor (RYR). We have previously shown that RYR inhibition reduces pathological intra-acinar protease activation, an early marker of pancreatitis. In this study, we examined whether pretreatment with the RYR inhibitor dantrolene attenuates the severity of caerulein-induced pancreatitis in mice. Immunofluorescent labeling for RYR from mouse pancreatic sections showed localization to the basolateral region of the acinar cell. After 1 h of caerulein hyperstimulation in vivo, dantrolene 1) reduced pancreatic trypsin activity by 59% (P < 0.05) and 2) mitigated early ultrastructural derangements within the acinar cell. Eight hours after pancreatitis induction, dantrolene reduced pancreatic trypsin activity and serum amylase by 61 and 32%, respectively (P < 0.05). At this later time point, overall histological severity of pancreatitis was reduced by 63% with dantrolene pretreatment (P < 0.05). TUNEL-positive cells were reduced by 58% (P < 0.05). These data suggest that the RYR plays an important role in mediating early acinar cell events during in vivo pancreatitis and contributes to disease severity. Blockade of Ca2+ signals and particularly RYR-Ca2+ may be useful as prophylactic treatment for this disease in high-risk settings for pancreatitis.