Document Detail

Evaluation of the long-term pancreatic effects of constitutive nitric oxide synthase inhibition in dogs.
MedLine Citation:
PMID:  15035777     Owner:  NLM     Status:  MEDLINE    
Constitutive and inducible isoforms of nitric oxide synthase (NOS) catalyze the synthesis of nitric oxide (NO) from L-arginine in various tissues and in different pathophysiologic states. Short-term treatment with NOS inhibitors has been associated with pancreatic enzyme elevations and pancreatic acinar cell degeneration; however, long-term pancreatic effects of NOS inhibition are not known. The purpose of this study was to evaluate the subchronic pancreatic effects of L-nitro-arginine (LNA), a compound that preferentially inhibits constitutive NOS isoforms. LNA was administered orally at doses of 10 and 30 mg/kg per day to 6 female dogs/group for 4 weeks. To differentiate whether the pancreatic effects of LNA may be related to its arginine structure, an additional group was given L-arginine (L-Arg) at plasma concentrations similar to the high dose of LNA (30 mg/kg per day). Pancreatic effects were monitored by changes in serum levels of pancreatic enzymes at regular intervals and by microscopic examinations at the end of the study. Both LNA and L-Arg were systematically available throughout the 4-week study period. LNA produced dose-related elevations (1.3-10-fold above concurrent control) in serum levels of pancreatic enzymes (amylase, lipase and trypsin-like immunoreactivity) during the 4-week treatment period with peak elevations occurring during the first week. Histologic assessments of the pancreas conducted at the end of the 4-week dosing period were unremarkable. Additionally, LNA treatment resulted in reduction in heart rate (40%), gastric distension and gastric mucosal erosion and ulceration. No pancreatic, cardiac, or gastric effects were seen with L-Arg, indicating that above effects were likely due to NOS inhibition. Results of this study confirmed previous observations of acute pancreatic alterations following the inhibition of constitutive NOS isoforms. However, these pancreatic alterations appear to be only transient effects as elevations in serum enzymes declined over time and no structural acinar cell damage was seen after continuous treatment with LNA for 4 weeks, suggesting an adaptation to NOS inhibition over time.
K L Kolaja; R R Bell; D Janssen; P T Manning; M J Schlosser; K N M Khan
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Inflammopharmacology     Volume:  12     ISSN:  0925-4692     ISO Abbreviation:  Inflammopharmacology     Publication Date:  2004  
Date Detail:
Created Date:  2004-03-23     Completed Date:  2004-05-27     Revised Date:  2005-11-17    
Medline Journal Info:
Nlm Unique ID:  9112626     Medline TA:  Inflammopharmacology     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  33-45     Citation Subset:  IM    
Pfizer Corporation, Skokie, IL, USA.
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MeSH Terms
Amylases / blood
Arginine / pharmacology
Enzyme Inhibitors / pharmacology*
Heart Rate / drug effects
Lipase / blood
Nitric Oxide Synthase / antagonists & inhibitors*
Nitroarginine / pharmacology
Pancreas / drug effects*,  physiology
Trypsin / blood
Reg. No./Substance:
0/Enzyme Inhibitors; 2149-70-4/Nitroarginine; 74-79-3/Arginine; EC Oxide Synthase; EC; EC 3.2.1.-/Amylases; EC

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