Involvement of kinin B1 receptor and oxidative stress in sensory abnormalities and arterial hypertension in an experimental rat model of insulin resistance.
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 (B(1)R) 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 B(1)R (real-time PCR and autoradiography) in several tissues. Acute effects of brain penetrant (LF22-0542) and peripherally acting (R-715) B(1)R 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. B(1)R mRNA was virtually absent in liver, aorta, lung, kidney and spinal cord isolated from control rats, yet B(1)R mRNA was markedly increased in all tissues in glucose-fed rats. Up-regulated B(1)R mRNA and B(1)R binding sites (spinal cord) were significantly reduced by alpha-lipoic acid in glucose-fed rats. LF22-0542 reduced tactile and cold allodynia (3h) and reversed arterial hypertension (3-48h) 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 B(1)R in the model of insulin resistance induced by glucose feeding. The over expressed B(1)R contributes centrally to arterial hypertension and in the periphery to sensory abnormalities.
Lungu
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Department of Physiology, Faculty of Medicine, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montreal, Quebec, Canada H3C 3J7.
Dias
J P
JP
França
C Estevão de
CE
Ongali
B
B
Regoli
D
D
Moldovan
F
F
Couture
R
R
D000818:Animals; D004195:Disease Models, Animal; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism; D007333:Insulin Resistance; D007705:Kinins; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000502:physiology*; D012678:Sensation Disorders / Q000209:etiology* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D007705:Kinins; D043783:Receptor, Bradykinin B1; D005947:Glucose