Highly selective inhibition of inducible nitric oxide synthase ameliorates experimental acute pancreatitis.
OBJECTIVE
Inducible nitric oxide synthase (iNOS) activity is increased in experimental acute pancreatitis. The aim of this study was to evaluate treatment with the selective iNOS inhibitors AR-C (AR-C102222AA) and L-NIL (L-N6-(1-iminoethyl)-lysine) in experimental acute pancreatitis.


METHODS
Acute pancreatitis was induced in anesthetized Australian possums by topical administration of carbachol on the sphincter of Oddi. AR-C treatment was 2 intravenous infusions (2.5 micromol/kg over 15 minutes) at 2 and 4 hours after acute pancreatitis induction. L-NIL treatment was an intraarterial infusion (1 mg/kg/h) from 2 hours after acute pancreatitis induction. At 8 hours, pancreatic tissue was harvested and inflammation assessed (histologic score). Blood samples were collected for plasma amylase, lipase, and amino acid levels. Blood pressure, central venous pressure, supplementary fluids, and urine output were monitored.


RESULTS
Treatment with AR-C or L-NIL reduced the plasma levels of amylase and the volume of supplementary fluids and improved the histological score (all P < 0.05). In animals with acute pancreatitis, plasma arginine levels were reduced (P < 0.05), while citrulline and ornithine levels increased (P < 0.05), consistent with increased nitric oxide production. Treatment with AR-C ameliorated the reduced arginine level.


CONCLUSIONS
Treatment with AR-C or L-NIL, commencing 2 hours after the induction of acute pancreatitis, has significant and beneficial effects in experimental acute pancreatitis in Australian possums.
Sandstrom
Per
P
Department of Biomedicine and Surgery, University Hospital of Linkoping, Linkoping, Sweden. per.sandstrom@lio.se
Brooke-Smith
Mark E
ME
Thomas
Anthony C
AC
Grivell
Marlene B
MB
Saccone
Gino T P
GT
Toouli
James
J
Svanvik
Joar
J
D000208:Acute Disease; D000596:Amino Acids / Q000097:blood; D000681:Amylases / Q000097:blood; D000818:Animals; D002496:Central Venous Pressure; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006400:Hematocrit; D008049:Lipase / Q000097:blood; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010195:Pancreatitis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology*; D048330:Trichosurus; D014882:Water-Electrolyte Balance
C489944:AR C102222AA; D000596:Amino Acids; D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D011799:Quinazolines; D052247:Nitric Oxide Synthase Type II; D008049:Lipase; D000681:Amylases; D008239:Lysine