On the protective mechanisms of nitric oxide in acute pancreatitis.
BACKGROUND
Ectopic protease activation, microcirculatory changes, and leucocyte activation are the main events in the pathogenesis of acute pancreatitis. Nitric oxide (NO) is known to be a key mediator in the normal and inflamed pancreas.


OBJECTIVE
To investigate the targets on which NO exerts its effect in caerulein induced pancreatitis.


METHODS
Acute pancreatitis was induced in rats which additionally received either the NO synthase substrate, L-arginine; the NO donor, sodium nitroprusside; or the NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME). At six hours, pancreatic injury (oedema, leucocyte content, ectopic trypsinogen activation) was analysed and pancreatic oxygenation and perfusion were determined. A direct influence of NO on amylase secretion and trypsinogen activation was evaluated separately in vitro.


RESULTS
Both NO donors reduced the grade of inflammation. L-NAME increased the severity of inflammation, while decreasing pancreatic tissue oxygenation. Although neither amylase secretion nor intracellular trypsinogen activation in caerulein stimulated pancreatic acini was influenced by either NO donors or inhibitors, both NO donors decreased intrapancreatic trypsinogen activation peptide (TAP) and pancreatic oedema in vivo, and L-NAME increased TAP.


CONCLUSIONS
NO protects against injury caused by pancreatitis in the intact animal but has no discernible effect on isolated acini. It is likely that in pancreatitis NO acts indirectly via microcirculatory changes, including inhibition of leucocyte activation and preservation of capillary perfusion.
Werner
J
J
Department of Surgery, Massachusetts General Hospital, Boston 02114, USA.
Fernández-del Castillo
C
C
Rivera
J A
JA
Kollias
N
N
Lewandrowski
K B
KB
Rattner
D W
DW
Warshaw
A L
AL
D000208:Acute Disease; D000818:Animals; D001120:Arginine / Q000627:therapeutic use; D002478:Cells, Cultured; D002108:Ceruletide; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000627:therapeutic use; D009842:Oligopeptides / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009842:Oligopeptides; D014665:Vasodilator Agents; C080396:trypsinogen activation peptide; D009599:Nitroprusside; D009569:Nitric Oxide; D002108:Ceruletide; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester