Reducing extracellular pH sensitizes the acinar cell to secretagogue-induced pancreatitis responses in rats.
OBJECTIVE
Protease activation within the pancreatic acinar cell is a key early event in acute pancreatitis and may require low pH intracellular compartments. Clinical studies suggest that acidosis may affect the risk for developing pancreatitis. We hypothesized that exposure to an acid load might sensitize the acinar cell to secretagogue-induced pancreatitis.


METHODS
Secretagogues (cerulein, carbachol, and bombesin) can induce protease activation in acinar cells at high (100 nmol/L, 1 mmol/L, and 10 micromol/L, respectively) but not at physiologically relevant concentrations. The effects of decreasing extracellular pH (pHe) in early secretagogue-induced pancreatitis (zymogen activation and injury) were examined in rats (1) in vitro with isolated acini and (2) in vivo with an acid challenge.


RESULTS
In acini, lowering pHe from 7.6 to 6.8 enhanced secretagogue-induced zymogen activation and injury, but did not affect secretion. For cerulein, this sensitization was seen over a range of concentrations (0.01-100.00 nmol/L). However, reduced pHe alone had no effect on zymogen activation, amylase secretion, or cell injury. We have reported that zymogen activation is mediated by the vacuolar ATPase (vATPase), a proton transporter. vATPase inhibition, using concanamycin (100 nmol/L), blocked the low pHe effects on zymogen activation. An acute acid load given in vivo enhanced cerulein-induced (50 microg/kg) trypsinogen activation and pancreatic edema.


CONCLUSIONS
These studies suggest that acid challenge sensitizes the pancreatic acinar cell to secretagogue-induced zymogen activation and injury and may increase the risk for the development and severity of acute pancreatitis.
Bhoomagoud
Madhavi
M
Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Jung
Thomas
T
Atladottir
Jorunn
J
Kolodecik
Thomas R
TR
Shugrue
Christine
C
Chaudhuri
Anamika
A
Thrower
Edwin C
EC
Gorelick
Fred S
FS
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000681:Amylases / Q000378:metabolism; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002108:Ceruletide / Q000494:pharmacology; D002918:Chymotrypsin / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000378:metabolism; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D010179:Pancreas / Q000473:pathology*; D010195:Pancreatitis / Q000378:metabolism* / Q000473:pathology; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014357:Trypsin / Q000378:metabolism
D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D018942:Macrolides; D011422:Propionates; D019344:Lactic Acid; C036978:concanamycin A; D002108:Ceruletide; D002217:Carbachol; C514135:sodium propionate; D000681:Amylases; D002918:Chymotrypsin; D014357:Trypsin; D000251:Adenosine Triphosphatases