Efeitos cardiovasculares e metabólicos produzidos pelo aumento crônico dos níveis cerebrais de angiotensina-(1-7) em modelos experimentais de estudo da síndrome metabólica

Abstract

The metabolic syndrome (MetS) is a cluster of risk factors, such as increase in arterial pressure, insulin resistance, and abdominal obesity, which increase the chance of development of cardiovascular and renal diseases, and type II diabetes. Inappropriate overactivity of the renin-angiotensin system (RAS) in favor of angiotensin (Ang) II/ AT1 receptor actions and an imbalance of the autonomic nervous system (ANS) in favor of the sympathetic activity play a major role in the development and aggravation of cardiovascular and metabolic disorders related to MetS. The other axis of RAS, represented by the actions of Ang-(1-7)/ Mas receptor is mostly known by its opposing effects to Ang II/ AT1 receptor in different pathological conditions. The peripheral increase in Ang-(1-7) levels ameliorates cardiovascular and metabolic disorders in experimental models to investigate MetS. In the central nervous system (CNS), Ang-(1-7) modulates SNA, facilitates the baroreflex bradycardia (BRS) and reduces mean arterial pressure (MAP) in hypertensive animals. In this study, we sought to evaluate the effects of chronic intracerebroventricular (ICV) infusion of Ang-(1-7) (200 ng/ h A7) or 0.9% sterile saline (control groups) (Alzet osmotic minipumps model 2004) on cardiovascular and metabolic parameters in experimental models to investigate MetS: adult (15 16 weeks/ age) lean (LZR) and obese (OZR) Zucker rats (genetic model) and Sprague-Dawley (SD; 67 weeks/ age) fed 10% fructose solution for 10 weeks (diet model Fructose group). Compared to control groups, chronic ICV infusion of ang-(1-7) (21 days) improved BRS in both LZR and OZR, normalized MAP in OZR, with no change in metabolic parameters in LZR or OZR. These effects were accompanied by a reduction in mRNA expression of neuronal nitric oxide enzyme (nNOS) in the dorsomedial region of medulla in both LZR-A7 and OZR-A7. In fructose-fed SD rats, chronic ICV infusion of Ang-(1-7), from 6th 10th week of diet (28 days, Frut+A7 group), normalized MAP, BRS, reduced cardiac sympathetic tone, as well as increased serum levels of high density lipoproteins (HDL), normalized relative hepatic weight, glycemia, insulinemia, glucose tolerance, and hepatic and muscular glycogen content, without changing body weight gain, the increased relative weight of retroperitoneal adipose tissue and hyperleptinemia. Compared to Fructose and control rats, Frut+A7 rats also shown increased mRNA expression of Mas receptor, and reduced mRNA expression of NR1 subunit of NMDA receptor in hypothalamus, as well as reduced mRNA of nNOS in the dorsomedial region of medulla. These data show that chronic increase of Ang-(1-7) levels in the brain ameliorates cardiovascular and metabolic disorders related to MetS, and suggest that such effects were likely mediated through Mas receptor in hypothalamic nuclei and by ANS modulation. Moreover, these results suggest that the metabolic improvements mediated by increasing Ang-(1-7) levels in the brain in particular glucose metabolism might be related to the time-course progression of these disorders and/ or to the intracellular signaling of leptin in the CNS. The present study suggests that pharmacological approaches that increase Ang-(1-7) levels in the brain should be considered to the treatment of MetS, especially in the beginning of the development of physiological disorders.