Early and intermediate Amadori glycosylation adducts, oxidative stress, and endothelial dysfunction in the streptozotocin-induced diabetic rats vasculature.
OBJECTIVE
In a model of streptozotocin-induced Type 1 diabetes mellitus in rats of 9 weeks duration, we analysed time associations between the development of hyperglycaemia, early and intermediate glycosylation Amadori adducts, or AGE compared with enhancement of oxidative stress and endothelial dysfunction.


METHODS
Endothelial function was tested at several stages of streptozotocin-induced diabetes and after treatment with insulin, resulting in different concentrations of blood glucose, glycosylated haemoglobin (an Amadori adduct), and AGE. Other animals were studied antagonising the formation of AGE with aminoguanidine.


RESULTS
Relaxation in response to acetylcholine (1 nmol/l to 10 micro mol/l) was tested in isolated segments from aorta or mesenteric microvessels. Impairment of endothelium-dependent relaxations occurred after 2 weeks of untreated diabetes. Preincubation of vessels affected with 100 U/ml superoxide dismutase improved the relaxations to acetylcholine, along the time-course of the endothelial impairment. This indicates the participation of reactive oxygen species on diabetic endothelial dysfunction. The impairment of endothelium-dependent relaxations was recovered after 3 more weeks of insulin treatment. Aminoguanidine treatment did not modify this pattern of development. The time course of the rise and disappearance of endothelial dysfunction showed a higher correlation with glycosylated haemoglobin concentrations than with blood glucose or serum AGE.


CONCLUSIONS
Enhancement of early and intermediate Amadori adducts of protein glycosylation was the factor showing a better relation with the development of endothelium impairment. These results are consistent with a role for these products in the development of diabetic vasculopathy.
Rodríguez-Mañas
L
L
Research Unit and Service of Geriatrics, University Hospital of Getafe, Madrid, Spain.
Angulo
J
J
Vallejo
S
S
Peiró
C
C
Sánchez-Ferrer
A
A
Cercas
E
E
López-Dóriga
P
P
Sánchez-Ferrer
C F
CF
D000109:Acetylcholine / Q000493:pharmacokinetics; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002352:Carrier Proteins; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D006442:Glycated Hemoglobin / Q000737:chemistry / Q000187:drug effects; D006146:Guanidines / Q000008:administration & dosage / Q000493:pharmacokinetics; D007328:Insulin / Q000008:administration & dosage / Q000493:pharmacokinetics; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000187:drug effects*; D009638:Norepinephrine / Q000008:administration & dosage / Q000493:pharmacokinetics; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D013482:Superoxide Dismutase / Q000187:drug effects; D013997:Time Factors
D000109:Acetylcholine; D001786:Blood Glucose; D002352:Carrier Proteins; D006442:Glycated Hemoglobin; D006146:Guanidines; D007328:Insulin; D009638:Norepinephrine; D013311:Streptozocin; D013482:Superoxide Dismutase; C004479:pimagedine