Endothelin and free radicals modulate microvascular responses in streptozotocin-induced diabetic rats

The quantitative contribution of endothelin and free radicals in modulating peripheral endothelial and smooth muscle-dependent vascular responses in 4 weeks streptozotocin-induced diabetic rats was investigated. Skin blood flow was monitored in base of blisters raised on the hind footpad. Smooth muscle-dependent vasodilation was tested using sodium nitroprusside (SNP). Endothelial-mediated inflammatory responses were induced via either electrical stimulation (ES) of the sciatic nerve or substance P (SP) perfusion over the blister base. Role of endothelin and free radicals was examined using ET-A or ET-B receptor antagonists (BQ-123 or BQ-788) and superoxide anions or hydroxyl radicals scavengers (superoxide dismutase (SOD) or N-acetyl cysteine (NAC)). Diabetic rats showed a significant reduction (75%) in SNP responses that coincided with a 70 and 60% reduction in responses to ES and SP. Their basal plasma extravasation (PE) was significantly higher while PE response to SP was significantly reduced. BQ-788, was more potent than BQ-123, improving responses to ES and SP in diabetic rats by 85%. Likewise, NAC was more potent than SOD normalizing the ES response and improving SP response by 85%. Combined treatment with BQ-123 and SOD normalized all vasodilatation responses in diabetic rats. BQ-123 and BQ-788 were equally potent normalizing the PE responses to SP whereas SOD and NAC had no effect. We conclude that endothelin and free radicals play a role in altering microvascular function in diabetes and that their effect could be reversed early in the disease.