Dantrolene mitigates caerulein-induced pancreatitis in vivo in mice.
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 Ca(2+) within the pancreatic acinar cell. This Ca(2+) release is modulated by the intracellular Ca(2+) 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 Ca(2+) signals and particularly RYR-Ca(2+) may be useful as prophylactic treatment for this disease in high-risk settings for pancreatitis.
Orabi
Abrahim I
AI
Department of Pediatrics, 333 Cedar St., New Haven, CT 06520, USA.
Shah
Ahsan U
AU
Ahmad
Mahwish U
MU
Choo-Wing
Rayman
R
Parness
Jerome
J
Jain
Dhanpat
D
Bhandari
Vineet
V
Husain
Sohail Z
SZ
D000681:Amylases / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects*; D002108:Ceruletide; D019610:Cytoprotection; D003620:Dantrolene / Q000494:pharmacology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D013997:Time Factors; D014357:Trypsin / Q000378:metabolism
D002121:Calcium Channel Blockers; D019837:Ryanodine Receptor Calcium Release Channel; D002108:Ceruletide; D000681:Amylases; D014357:Trypsin; D003620:Dantrolene
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