The Renin-Angiotensin System (RAS) is expressed in the central nervous system and has important functions that go beyond blood pressure regulation. Clinical and experimental studies have suggested that alterations in the brain RAS contribute to the development and progression of neurodegenerative diseases. However, there is limited information regarding the involvement of RAS components in Huntington’s disease (HD). Herein, we used the HD murine model, (BACHD), as well as samples from patients with HD to investigate the role of both the classical and alternative axes of RAS in HD pathophysiology. BACHD mice displayed worse motor performance in different behavioral tests alongside a decrease in the levels and activity of the components of the RAS alternative axis ACE2, Ang-(1-7), and Mas receptors in the striatum, prefrontal cortex, and hippocampus. BACHD mice also displayed a significant increase in mRNA expression of the AT1 receptor, a component of the RAS classical arm, in these key brain regions. Moreover, patients with manifest HD presented higher plasma levels of Ang-(1-7). No significant changes were found in the levels of ACE, ACE2, and Ang II. Our findings provided the first evidence that an imbalance in the RAS classical and counter-regulatory arms may play a role in HD pathophysiology.

New Findings: What is the central question of this study? Recently, there have been many studies exploring the biological effects of angiotensin‐(1–7), which has been proved to have cardioprotective actions. However, the effects of this peptide on cardiac arrhythmias in vivo and details regarding its mechanism of action are still undetermined. What is the main finding and its importance? We investigated protective effects of angiotensin‐(1–7) on cardiac arrhythmias in vivo, which were not properly explored in terms of cellular mechanisms. To verify effects of angiotensin‐(1–7), we used different but complementary experimental approaches. Our data provide new evidence on the cellular mechanism and an in vivo demonstration of the acute antiarrhythmic effect of angiotensin‐(1–7). Angiotensin‐(1–7) [Ang‐(1–7)] has been proved to have cardioprotective effects. However, the effects of this peptide on cardiac arrhythmias in vivo and details regarding its mechanism of action are still undetermined. The aim of this study was to investigate the protective effects of Ang‐(1–7) against cardiac arrhythmias, its in vivo effects and cellular mechanism of action. We analysed the ECG upon inducement of arrhythmias in vivo in rats using a combination of halothane and adrenaline. To analyse the effects of Ang‐(1–7) on cells, fresh mouse ventricular cardiomyocytes were isolated. The cardiomyocytes were superfused with a solution containing halothane and isoprenaline as a model to induce arrhythmias and used in three different approaches, namely a contractility assay, patch‐clamp technique and confocal microscopy. The in vivo ECG showed that the injection of Ang‐(1–7) (4 nm i.v.) significantly reduced cardiac arrhythmias [before, 49 ± 43 arrhythmic events versus after Ang‐(1–7), 16 ± 14 arrhythmic events]. This effect was blocked by injection of A‐779 and l‐NAME, without changes in haemodynamic parameters. In addition, contractility experiments showed that Ang‐(1–7) significantly decreased the number of arrhythmic events without changing the fractional shortening. This protection was associated with a reduction of the action potential repolarization and membrane hyperpolarization. Moreover, Ang‐(1–7) decreased the number of calcium waves without any changes in the amplitude of the calcium transient, despite a significant reduction in the decay rate. Our data provide new evidence on the cellular mechanism together with an in vivo demonstration of the antiarrhythmic effects of Ang‐(1–7).