Efeitos do aumento central de angiotensina-(1-7) sobre a simpatoexcitação de ratos com insuficiência cardíaca: participação do núcleo paraventricular do hipotálamo

Abstract

Heart failure (HF) is characterized by an exacerbated increase in sympathetic activity, neurohumoral alterations and respiratory disorders. Studies have shown that changes in cardiovascular reflexes and in the paraventricular nucleus of hypothalamus (PVN) activity are related to renin-angiotensin system (RAS), especially Ang II/AT1 receptor, and contribute to HF progression. The other axis of RAS, represented by Ang-(1-7)/receptor Mas is widely known for its opposite effects to Ang II/AT1 receptor under different pathological conditions. The aim of this study was to evaluate the chronic effect of central infusion of Ang-(1-7) on cardiovascular, ventilatory and autonomic parameters in rats with HF induced by myocardial infarction, and to investigate whether their effects occur through NO, NMDA receptors and/or proinflammatory cytokines-dependent mechanism in PVN. Myocardial infarction was induced by left descending coronary artery ligation in Wistar rats (240-280g - CEUA 236/2017). Chronic central infusion of Ang-(1-7) (0.1μg/h/28 days) or saline (0.9%) was performed through an intracerebroventricular osmotic minipump implanted 3 weeks after myocardial infarction. The experiments were performed four weeks after the beginning of central infusion. Chronic treatment with Ang-(1-7) reduced mortality rate, improved baroreflex sensitivity and cardiac autonomic imbalance, and reduced basal sympathetic activity and PVN neurons activity in the HF group. These effects were accompanied by increased in NOS expression and reduced levels of proinflammatory cytokine IL-1β in PVN. Treatment with Ang-(1-7), however, did not alter NMDA receptor expression in PVN. These results show that chronic increase of Ang-(1-7) levels in the brain, probably counteracting the Ang II actions, was effective in reducing the increase in sympathetic nerve activity of HF animals, reinforcing the hypothesis of central RAS as a potential therapeutic target for the treatment of cardiovascular diseases, contributing to control the HF progression, improving the quality and life expectancy of individuals in this condition.