Elevated calcium and activation of trypsinogen in rat pancreatic acini.
BACKGROUND
Acute pancreatitis associated with hypercalcaemia has been described in humans and experimental animals. It has been demonstrated that calcium dose dependently accelerates trypsinogen activation, and it is generally believed that ectopic activation of digestive enzymes is an early event in the pathophysiology of acute pancreatitis.


OBJECTIVE
Trypsinogen activation peptide (TAP) was measured in isolated rat pancreatic acini exposed to elevated extracellular calcium in order to investigate the association between calcium and trypsinogen activation in living cells. TAP was determined in the culture medium either before (extracellular compartment) or after (intracellular compartment) cell homogenisation.


RESULTS
Neither secretory stimulation nor elevated calcium alone caused an increase in TAP levels. Maximal cerulein or carbachol stimulation superimposed on high medium calcium, however, significantly increased intracellular trypsinogen activation twofold. This increase was inhibited by either NG-monomethyl-L-arginine (L-NMMA) or verapamil. Acinar cell morphology and function remained intact as demonstrated by electron microscopy and secretagogue dose-response studies.


CONCLUSIONS
These results support the hypothesis that increased intracellular trypsinogen activation is an early step in the pathogenesis of hypercalcaemia induced pancreatitis. The model may have a bearing on other types of pancreatitis as elevated cytosolic calcium is thought to be an early event in the pathogenesis of acute pancreatitis in general.
Frick
T W
TW
Department of Surgery, Massachusetts General Hospital, Boston, USA.
Fernández-del Castillo
C
C
Bimmler
D
D
Warshaw
A L
AL
D000208:Acute Disease; D000818:Animals; D002118:Calcium / Q000097:blood*; D002217:Carbachol / Q000494:pharmacology; D002108:Ceruletide / Q000494:pharmacology; D046508:Culture Techniques; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005765:Gastrointestinal Agents / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000032:analysis*; D010179:Pancreas / Q000201:enzymology* / Q000648:ultrastructure; D010195:Pancreatitis / Q000097:blood / Q000201:enzymology / Q000209:etiology*; D051381:Rats; D017208:Rats, Wistar; D014362:Trypsinogen / Q000378:metabolism*
D005765:Gastrointestinal Agents; D009842:Oligopeptides; C080396:trypsinogen activation peptide; D002108:Ceruletide; D002217:Carbachol; D014362:Trypsinogen; D002118:Calcium