title: Efficacy of 1400 W, a novel inhibitor of inducible nitric oxide synthase, in preventing interleukin-1beta-induced suppression of pancreatic islet function in vitro and multiple low-dose streptozotocin-induced diabetes in vivo.
abstract: OBJECTIVE
  Nitric oxide (NO), generated by inducible nitric oxide synthase (iNOS), has been implicated in beta-cell destruction in type 1 diabetes. In the present study, we tested a highly selective iNOS inhibitor, 1400 W, against interleukin-1beta (IL-1beta) induced suppression of rat pancreatic islets, and investigated whether 1400 W could prevent multiple low-dose streptozotocin (MLDS) induced diabetes in mice. Furthermore, we studied if 1400 W affected lipopolysaccharide (LPS) induced increase in plasma nitrite+nitrate (NO(x)) in mice.
  
  
  METHODS
  Precultured rat pancreatic islets were exposed for 48 h to 0, 1, 10 or 50 micromol/l 1400 W in the presence or absence of 25 U/ml IL-1beta, whereupon islet functions were analyzed. MLDS-treated mice were given 5.9 mg/kg body weight of 1400 W intraperitoneally daily or 14 mg/kg body weight twice a day. Blood glucose was monitored and degree of pancreatic mononuclear infiltration was determined. Mice previously injected intraperitoneally with LPS (500 microg) were given 1400 W (14 mg/kg body weight) intraperitoneally and plasma NO(x) was determined after 3, 6 and 10 h.
  
  
  RESULTS
  The inhibitor alone did not affect islet functions. 1400 W (50 micromol/l) fully counteracted both the suppression of glucose oxidation rate, (pro)insulin biosynthesis and nitrite accumulation caused by IL-1beta. Cytokine-induced decrease in medium insulin accumulation and glucose-stimulated insulin release was partly counteracted by 1400 W, suggesting that inhibition of insulin release was partially NO independent. LPS-induced increase in plasma NO(x) was markedly inhibited for up to 10 h after 1400 W administration. Irrespective of 1400 W treatment, animals treated with MLDS developed hyperglycemia and pancreatic insulitis.
  
  
  CONCLUSIONS
  1400 W counteracted IL-1beta-induced suppression of rat islets in vitro and LPS induction of NO(x) in vivo, however, it failed to protect against MLDS diabetes in vivo. The latter might be due to a failure by 1400 W in vivo to inhibit NO formation at the level of the pancreatic islet.
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden. Tobias.Rydgren@medcellbiol.uu.se
authors.forename: Tobias
authors.initials: T
authors.lastname: Rydgren
authors.forename: Stellan
authors.initials: S
authors.lastname: Sandler
mesh_terms: D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D001786:Blood Glucose; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D011384:Proinsulin / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000578:Amidines; D001596:Benzylamines; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007328:Insulin; D007375:Interleukin-1; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009566:Nitrates; D011384:Proinsulin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat