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.

Nandrolone alter left ventricular contractility and promotes remodelling involving calcium-handling proteins and renin-angiotensin system in male SHR.

AIMS: Hypertension is a highly prevalent disease that has been correlated to severe organ damage and mortality. However, the role of androgens in hypertension is controversial. The aim of this study was to evaluate the cardiac effects of the nandrolone decanoate (NDL) in male SHR. MAIN METHODS: At 12 weeks of age, male SHR rats were separated into three groups: Control (CON), Nandrolone 10 mg/kg twice weekly (NDL), and NDL plus Enalapril 10 mg/kg/day (NDL-E) groups. The animals were treated for 4 weeks. Haemodynamic parameters were acquired through ventricular catheter implantation. The left ventricle was stained with haematoxylin/eosin or picrosirius red. Western blot analysis of TNF-α, ACE, AT1R, ß1-AR, PLB, p-PLBser16 and SERCA2a was performed. KEY FINDINGS: Nandrolone increased hypertension in SHR rats and enalapril reduced blood pressure to values below those of the control. NDL increased +dP/dtmax, -dP/dtmax and cardiac hypertrophy, which were prevented in the NDL-E group. Cardiac collagen deposition was increased in the NDL group, with this effect being attenuated by enalapril in NDL-E animals. TNF-α, ACE, AT1R and ß1-AR proteins were increased in the NDL, and enalapril decreased them, except for TNF-α. The ratio p-PLBser16/PLB revealed an increase after nandrolone, which was prevented in the NDL-E group. The SERCA2a expression protein and SERCA2a/PLB were increased in NDL animals, which did not occur in the NDL-E group. SIGNIFICANCE: Nandrolone has distinct effects on cardiac function and remodelling in male SHR, altering the hypertension development process in the heart through modulation of calcium handling proteins and the renin-angiotensin system.