Pharmacological evaluation of metformin and N-benzylbiguanide, a novel analogue of metformin, on the vasopressor responses to adrenergic system stimulation in pithed rats with fructose-induced insulin resistance

Metformin has been associated with cardioprotection, vasorelaxation and normalization of endothelial function during type 2 Diabetes Mellitus. However, few studies have analysed its effects on vascular adrenergic system. Our study has evaluated the vasopressor responses induced by sympathetic stimulation or by i.v. bolus injections of the agonists noradrenaline (α1/2), methoxamine (α1) and UK 14,304 (α2) in rats with fructose-induced insulin resistance chronically pretreated with either metformin or EGL-6M (N-benzylbiguanide), a novel analogue of metformin. Rats were treated with fructose (15%) or tap water (control) during 16 weeks. Next, both groups were treated daily during 4 weeks with: (1) vehicle; (2) metformin (50 mg/kg); or (3) EGL-6M (50 mg/kg). Blood glucose and plasma insulin were determined before and after administration of glucose during oral glucose tolerance test. Animals treated with fructose showed hyperinsulinemia and insulin resistance, which were decreased by metformin and EGL-6M. In animals treated with fructose, the vasopressor responses induced by: (1) sympathetic stimulation were decreased; (2) noradrenaline were increased; and (3) methoxamine and UK 14,304 remained unaffected compared with control group. In control animals, metformin failed to modify the vasopressor responses analysed, while EGL-6M increased the vasopressor responses to sympathetic stimulation. In rats treated with fructose, metformin decreased vasopressor response to noradrenaline but did not modify the sympathetic stimulation responses. EGL-6M increased the vasopressor responses to sympathetic stimulation without modifying those to noradrenaline, methoxamine or UK 14,304. Collectively, these data suggest that EGL-6M is capable to increase insulin sensitivity and the vasopressor sympathetic outflow in rats.