Metformina reduz disfunção vascular em ratas ovariectomizadas

Abstract

Both menopause and estrogen deprivation by ovariectomy are related with vascular dysfunction. Metformin is hypoglycemic drug with pleiotropic effects that are linked with improvement of cardiovascular system. The aim of this study was to evaluate the effects of metformin treatment on vascular function in ovariectomized rats. At 8 weeks of age, female Wistar rats were ovariectomized (OVX) or sham (SHAM) operated and after 21 days was divided into 3 groups and treated for 14 days: SHAM (vehicle), OVX (vehicle) and MET (metformin-treated OVX rats, 300mg/kg/day). Then, was studied the vascular reactivity of relaxation to acetylcholine (ACh) and sodium nitroprusside (SNP) in ex vivo mesenteric vascular bed. OVX shows impairment of response to ACh and MET partially reversed this impairment (SHAM > MET > OVX). In presence of L-NAME (100μM) these responses were reduced and equalized, indicating that the initial differences were due to nitric oxide (NO) pathway. The addition of indomethacin (INDO; 10µM) together to the L-NAME did not alter did not alter the response already obtained with L-NAME alone, showing no significant participation of prostanoids in this response. At the same time, there was no difference among groups in the residual response in combined presence of L-NAME and INDO, that representing the endothelium-derived hyperpolarizing factor (EDHF)-mediated response. Inhibition of Voltage-Gated Potassium Channels (KV) by 4-aminopyridine (1mM), evoked larger attenuation in AChinduced response in MET than in SHAM and OVX. The inhibition of NADPH oxidase (NOX) by apocynin (APO; 30μM) lead to a smaller change in MET response than in the other groups, indicating together an enhancement of KV function and a reduction in NOX/oxidative stress, in MET group. SNP-induced response of OVX was smaller than SHAM. Metformin treatment was able to normalize this response. APO did not alter SNP response in SHAM, but increase in OVX, indicating that the impairment was related to NOX/oxidative stress in OVX group. APO enhanced SNP response in MET group. eNOS protein expression was reduced in OVX compared to SHAM group and metformin was able to restore the expression of eNOS in ovariectomized animals. NOX2 protein expression was increased in OVX compared to SHAM group and metformin was able to reverse this increase. We conclude that metformin improves vascular function in OVX rats through NO pathway, with increased action of NO and eNOS expression, beyond a larger participation of KV channels, and reduction in NOX/oxidative stress and NOX2 expression, suggesting have therapeutic potential for postmenopausal women, however, more studies are needed to confirm this potential.