期刊
NEUROPEPTIDES
卷 41, 期 6, 页码 375-387出版社
CHURCHILL LIVINGSTONE
DOI: 10.1016/j.npep.2007.09.005
关键词
bradykinin; B-1 receptor; diabetes mellitus; insulin resistance; allodynia; neuropathy; arterial hypertension; oxidative stress; alpha-lipoic acid
Diabetes Mellitus leads to pain neuropathy and cardiovascular complications which remain resistant to current therapies involving the control of glycaemia. This study aims at defining the contribution of kinin B-1 receptor (B1R) and the oxidative stress on sensory abnormalities and arterial hypertension in a rat model of insulin resistance. Rats were fed with 10% D-glucose for a chronic period of 12-14 weeks and the impact of a diet supplemented with alpha-lipoic acid, a potent antioxidant, was determined on tactile and cold allodynia, arterial hypertension and the expression of kinin B1R (real-time PCR and autoradiography) in several tissues. Acute effects of brain penetrant (LF22-0542) and peripherally acting (R-715) B1R antagonists were also assessed. Glucose-fed rats exhibited tactile and cold allodynia along with increases in systolic blood pressure between 4 and 12 weeks; these alterations were alleviated by alpha-lipoic acid. The latter regimen also decreased significantly increased plasma levels of insulin and glucose and insulin resistance (HOMA index) at 14 weeks. B1R mRNA was virtually absent in liver, aorta, lung, kidney and spinal cord isolated from control rats, yet B1R mRNA was markedly increased in all tissues in glucose-fed rats. Up-regulated B1R mRNA and BIR binding sites (spinal cord) were significantly reduced by cc-lipoic acid in glucose-fed rats. LF22-0542 reduced tactile and cold allodynia, (3 h) and reversed arterial hypertension (3-48 h) in glucose-fed rats. R-715 abolished tactile and cold allodynia but had not effect on blood pressure. Data suggest that the oxidative stress contributes to the induction and up-regulation of BIR in the model of insulin resistance induced by glucose feeding. The over expressed BIR contributes centrally to arterial hypertension and in the periphery to sensory abnormalities. (C) 2007 Elsevier Ltd. All rights reserved.
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