Abstract
Aim The effect of 8 weeks′ streptozotocin (STZ)- induced diabetes and aminoguanidine (AMNG), the inhibitor of advanced glycosylation reaction, treatment on arteriolar reactivity to vasoactive substances was investigated in vitro. Materials and Methods Studies were performed in untreated control rats (n = 10), STZ-induced (60 mg/kg i.v.) diabetic rats (n = 10), AMNG-treated (600 mg/l given in drinking water throughout 8 weeks) control rats (n = 10) and AMNG-treated (600 mg/l given in drinking water, beginning at 72h after STZ and throughout 8 weeks of diabetes) diabetic rats (n = 10). Results are expressed as the mean ±s.e. Relaxant responses are expressed as a percentage (%) relaxation of noradrenaline-induced tone. Statistical comparisons were made by one-way analysis of variance (ANOVA) followed by Tukey–Kramer multiple comparisons test. Results 1. The decreased body weights (205 ± 6 g) and increased blood glucose levels (583 ± 8 mg/dl) of diabetic rats were partially restored by treatment of aminoguanidine (253 ± 6 g, p < 0.05 and 480 ± 14 mg/dl, p < 0.001, respectively). 2. Diabetes caused a 71% deficit in maximal endothelium-dependent relaxation to acetylcholine for noradrenaline precontracted aortas (p < 0.001). AMNG treatment prevented the diabetes-induced impairment in endothelium dependent relaxation (58 ± 8%) to acetylcholine, maximum relaxation remaining in the non-diabetic range (78 ± 4%). 3. Neither diabetes nor treatment affected endothelium-independent relaxation (pD2 and max. Relax.) to sodium nitroprusside. 4. Vasoconstrictor responses (pD2 and Max. Contraction) to noradrenaline and KCl were not influenced by the diabetic state and treatment. Conclusion Our data suggest that 8 weeks of experimental diabetes is associated with a decreased endothelium-dependent vasodilatation. AMNG treatment may prevent diabetes-induced endothelial dysfunction. This may be mediated via the prevention of advanced glycosylation end product formation, the enhanced release of vasodilator substances such as prostacyclin, the increased elasticity of blood vessels, the antioxidant activity and inhibitor activity of enzyme aldose-reductase by AMNG.
Highlights
Hyperglycaemia is the primary cause of diabetic micro and macrovascular complications
Aminoguanidine is a small, hydrazine compound structurally identical to the amino-terminal group of arginine and several laboratories have reported beneficial effects of aminoguanidine in some diabetic complications. The mechanisms for these effects of AMNG were accompanied by reduction of advanced glycation end product (AGE) formation, the inhibition of an isoform of nitric oxide synthase and reactive oxygen species (ROS) formation, lipid peroxidation and oxidant-induced apoptosis
The body weights of diabetic rats (205 4- 7 g) were significantly lower than Normal Control (NC) (p < 0.001), AMNG-treated control group (AG-C) (p < 0.001) and AMNG treated-diabetic group (AG+D) (p < 0.05)
Summary
Hyperglycaemia is the primary cause of diabetic micro and macrovascular complications. I1"2J Several major mechanisms have been proposed for hyperglycaemia-induced tissue damage, including advanced glycation end product (AGE) formation, altered intracellular redox state, increased polyol pathway flux, apoptosis and increased de novo diacylglycerol synthesis with resultant activation of protein kinase C isoform. Aminoguanidine is a small, hydrazine compound structurally identical to the amino-terminal group of arginine and several laboratories have reported beneficial effects of aminoguanidine in some diabetic complications. The mechanisms for these effects of AMNG were accompanied by reduction of advanced glycation end product (AGE) formation, the inhibition of an isoform of nitric oxide synthase (iNOS) and reactive oxygen species (ROS) formation, lipid peroxidation and oxidant-induced apoptosis.
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