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

Eur J Endocrinol. 2002 Oct;147(4):543-51. doi: 10.1530/eje.0.1470543.

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.

Design and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidines / pharmacology*
  • Animals
  • Benzylamines / pharmacology*
  • Blood Glucose
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetes Mellitus, Experimental / prevention & control
  • Enzyme Inhibitors / pharmacology*
  • In Vitro Techniques
  • Insulin / metabolism
  • Interleukin-1 / pharmacology*
  • Islets of Langerhans / cytology
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / enzymology
  • Nitrates / metabolism
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II
  • Proinsulin / biosynthesis
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Amidines
  • Benzylamines
  • Blood Glucose
  • Enzyme Inhibitors
  • Insulin
  • Interleukin-1
  • N-(3-(aminomethyl)benzyl)acetamidine
  • Nitrates
  • Proinsulin
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat