Chronic metformin reduces systemic and local inflammatory proteins and improves hypertension-related cardiac autonomic dysfunction.

BACKGROUND AND AIMS: Metformin has been known to promote cardiovascular benefits in humans and animal models, even in non-diabetic subjects. However, its chronic effects on hypertension-related autonomic dysfunction remain poorly understood. Therefore, we evaluate the cardiac autonomic effects of chronic metformin in hypertensive rats. METHODS AND RESULTS: Twelve-week-old male SHR and Wistar rats were separated into 3 groups: WN (Wistar normotensive); SC (SHR hypertensive control); and SM (SHR: Metformin 300 mg/kg/day for 30 days). Spontaneous and induced (by phenylephrine and sodium nitroprusside) baroreflexes were analysed in catheterised rats. Next, cardiac autonomic tone was evaluated through heart rate shift by atropine (parasympathetic) or atenolol (sympathetic). Plasma TNFα was assessed by ELISA. Western blot analyses of inflammatory, oxidant and antioxidant proteins were performed. Cardiac parasympathetic tone and baroreflex function were lower in SC than in WN, whereas cardiac sympathetic tone was higher. Metformin treatment in non-diabetic hypertensive rats reduced the resting heart rate, attenuated the cardiac sympathetic tone and improved baroreflex (especially in the offsetting of rising BP), while blood pressure and glycaemia remained unchanged. Cardiac sympathetic tone correlated negatively with spontaneous baroreflex. Metformin reduced plasma TNFα levels and decreased tissue expression of COX2 and NOX2 (which were positively correlated), without affecting SOD1 and SOD2. CONCLUSION: Chronic metformin presented anti-inflammatory and antioxidant effects and, independently of alterations in glycaemia, it improved cardiac autonomic parameters that are impaired in hypertension, being related to end-organ damage and mortality. These findings open up perspectives for future innovative uses of metformin in cardiovascular diseases, especially in hypertension.

Metformin ameliorates ovariectomy-induced vascular dysfunction in non-diabetic Wistar rats.

Metformin is an antihyperglycaemic drug with pleiotropic effects that result in cardiovascular improvement. The aim of the present study was to evaluate the effects of metformin treatment on vascular dysfunction in ovariectomized rats. At 8 weeks of age, female Wistar rats were subjected to ovariectomy or a sham surgery. After 21 days, the animals were divided into three groups: SHAM (sham-operated rats), OVX (ovariectomized rats) and MET (ovariectomized rats treated with metformin at 300 mg/kg of body weight per day), and treated for 14 days. The vasorelaxation responses to ACh (acetylcholine) and SNP (sodium nitroprusside) were evaluated in mesenteric vascular beds, oxidative stress was evaluated and Western blot analysis of eNOS (endothelial NO synthase) and the NADPH oxidase Nox2 was performed. ACh-induced relaxation was reduced in the OVX group and partially restored in the MET group. L-NAME (NG-nitro-L-arginine methyl ester) attenuated and equalized the ACh-induced response in all groups. Attenuation of the ACh-induced responses by 4-aminopyridine (a blocker of voltage-gated potassium channels) was greater in the MET group compared with the OVX group. The SNP-induced responses were reduced in the OVX group and restored in the MET group. Inhibition of NADPH oxidase by apocynin (10 µM) restored the SNP-induced responses in the OVX group, enhanced these responses in the MET group and had no effect in the SHAM group. The OVX group exhibited reduced levels of eNOS protein and increased levels of oxidative stress and Nox2 protein; metformin treatment corrected all of these parameters. In conclusion, the pathophysiological changes observed in the mesenteric beds of ovariectomized rats were ameliorated by metformin. If this translates to humans, metformin could have additional benefits for post-menopausal women treated with this drug for glycaemic control.