Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction.
Increased blood flow and vascular leakage of proteins preferentially affect tissues that are sites of diabetic complications in humans and animals. These vascular changes in diabetic rats are largely prevented by aminoguanidine. Glucose-induced vascular changes in nondiabetic rats are also prevented by aminoguanidine and by NG-monomethyl-L-arginine (NMMA), an established inhibitor of nitric oxide (NO.) formation from L-arginine. Aminoguanidine and NMMA are equipotent inhibitors of interleukin-1 beta-induced 1) nitrite formation (an oxidation product of NO.) and cGMP accumulation by the rat beta-cell insulinoma cell line RINm5F, and 2) inhibition of glucose-stimulated insulin secretion and formation of iron-nitrosyl complexes by islets of Langerhans. In contrast, NMMA is approximately 40 times more potent than aminoquanidine in elevating blood pressure in nondiabetic rats. These results demonstrate that aminoguanidine inhibits NO. production and suggest a role for NO. in the pathogenesis of diabetic vascular complications.
Corbett
J A
JA
Department of Pathology, Washington University School of Medicine, St Louis, Missouri 63110.
Tilton
R G
RG
Chang
K
K
Hasan
K S
KS
Ido
Y
Y
Wang
J L
JL
Sweetland
M A
MA
Lancaster
J R
JR
Williamson
J R
JR
McDaniel
M L
ML
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects; D002478:Cells, Cultured; D003925:Diabetic Angiopathies / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019001:Nitric Oxide Synthase; D051381:Rats; D011919:Rats, Inbred Strains; D012039:Regional Blood Flow / Q000187:drug effects; D019323:omega-N-Methylarginine
D006146:Guanidines; D007328:Insulin; D007375:Interleukin-1; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D005947:Glucose; C004479:pimagedine