Biochemical evidence for nitric oxide formation from streptozotocin in isolated pancreatic islets.
Streptozotocin (STZ) is selectively toxic to insulin-secreting beta-cells of pancreatic islets and induces impairment of islet glucose oxidation and of glucose-induced insulin secretion. Similar effects are induced by Interleukin-1 (IL-1), and the deleterious effects of IL-1 on islets appear to be mediated by nitric oxide (NO). STZ contains a nitroso moiety and may liberate NO by processes analogous to those for the NO-releasing drug nitroprusside. NO is rapidly transformed to nitrite in aqueous solution, and NO activates heme-containing enzymes such as guanylyl cyclase and inhibits iron-sulfur enzymes such as mitochondrial aconitase. Data presented here indicate that incubation of rat islets with STZ at concentrations that impair insulin secretion results in generation of nitrite, stimulation of islet guanylyl cyclase and accumulation of cGMP, and inhibition of islet mitochondrial aconitase activity to a degree similar to that achieved by IL-1. Effects of STZ on beta-cells may be mediated by local liberation of NO from STZ within islets.
Turk
J
J
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
Corbett
J A
JA
Ramanadham
S
S
Bohrer
A
A
McDaniel
M L
ML
D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D013311:Streptozocin / Q000378:metabolism* / Q000494:pharmacology*
D007328:Insulin; D007375:Interleukin-1; D009573:Nitrites; D011994:Recombinant Proteins; D009599:Nitroprusside; D009569:Nitric Oxide; D013311:Streptozocin; D000154:Aconitate Hydratase; D006162:Guanylate Cyclase; D006152:Cyclic GMP