Comparison of inhibition of glucose-stimulated insulin secretion in rat islets of Langerhans by streptozotocin and methyl and ethyl nitrosoureas and methanesulphonates. Lack of correlation with nitric oxide-releasing or O6-alkylating ability.
We have studied inhibition of glucose-stimulated insulin secretion in islets of Langerhans isolated from adult Sprague-Dawley rats and treated with different alkylating agents. Streptozotocin (STZ), N-methyl-N-nitrosourea (MNU), and N-ethyl-N-nitrosourea (ENU) all released nitric oxide, as demonstrated by an increase in medium nitrite and cellular cyclic GMP. Methyl methanesulphonate (MMS) and ethyl methanesulphonate (EMS), which do not possess a nitroso group, did not show evidence of nitric oxide release. All five compounds, however, decreased glucose-stimulated insulin release, suggesting that nitric oxide release was not necessary for the inhibition of secretion. Lack of involvement of nitric oxide was further suggested by the failure of oxyhaemoglobin to reverse STZ and MNU inhibition of insulin secretion. Since ENU was at least as effective as MNU in inhibiting insulin secretion, it appears that alkylation of DNA at the O6 position of guanine may not be involved in this process.
Delaney
C A
CA
Department of Biochemistry, School of Biological Sciences, University of Sussex, Falmer, Brighton, U.K.
Dunger
A
A
Di Matteo
M
M
Cunningham
J M
JM
Green
M H
MH
Green
I C
IC
D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D006152:Cyclic GMP / Q000032:analysis; D005020:Ethyl Methanesulfonate / Q000494:pharmacology; D005038:Ethylnitrosourea / Q000494:pharmacology; D005947:Glucose / Q000037:antagonists & inhibitors*; D006147:Guanine / Q000031:analogs & derivatives / Q000032:analysis; D007328:Insulin / Q000032:analysis; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008741:Methyl Methanesulfonate / Q000494:pharmacology*; D008770:Methylnitrosourea / Q000494:pharmacology*; D009569:Nitric Oxide / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000477:Alkylating Agents; D007328:Insulin; D009569:Nitric Oxide; C007673:6-ethylguanine; D013311:Streptozocin; D006147:Guanine; D008770:Methylnitrosourea; C008449:O-(6)-methylguanine; D005020:Ethyl Methanesulfonate; D008741:Methyl Methanesulfonate; D006152:Cyclic GMP; D005947:Glucose; D005038:Ethylnitrosourea