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Systemic arterial hypertension and heart failure are cardiovascular diseases that affect millions of individuals worldwide. They are characterized by a change in the autonomic nervous system balance, highlighted by an increase in sympathetic activity associated with a decrease in parasympathetic activity. Most therapeutic approaches seek to treat these diseases by medications that attenuate sympathetic activity. However, there is a growing number of studies demonstrating that the improvement of parasympathetic function, by means of pharmacological or electrical stimulation, can be an effective tool for the treatment of these cardiovascular diseases. Therefore, this review aims to describe the advances reported by experimental and clinical studies that addressed the potential of cholinergic stimulation to prevent autonomic and cardiovascular imbalance in hypertension and heart failure. Overall, the published data reviewed demonstrate that the use of central or peripheral acetylcholinesterase inhibitors is efficient to improve the autonomic imbalance and hemodynamic changes observed in heart failure and hypertension. Of note, the baroreflex and the vagus nerve activation have been shown to be safe and effective approaches to be used as an alternative treatment for these cardiovascular diseases. In conclusion, pharmacological and electrical stimulation of the parasympathetic nervous system has the potential to be used as a therapeutic tool for the treatment of hypertension and heart failure, deserving to be more explored in the clinical setting., (© 2021 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Background: Acetylcholinesterase inhibition prevents autonomic imbalance, reduces inflammation, and attenuates the development of hypertension. Considering that vascular dysfunction is a crucial feature of arterial hypertension, we investigated the effects of chronic administration of acetylcholinesterase inhibitors-pyridostigmine or donepezil-on vascular reactivity of spontaneously hypertensive rats (SHR)., Methods: Endothelium-dependent relaxant responses to acetylcholine (ACh) and contractile responses induced by electric field stimulation (EFS) and alpha-adrenergic agonist were studied in mesenteric resistance arteries from SHR and Wistar Kyoto rats. SHR were treated for 16 weeks with vehicle, pyridostigmine (1.5 mg/kg/day) or donepezil (1.4 mg/kg/day)., Results: Pyridostigmine and donepezil decreased the vasoconstrictor responses to EFS, which were increased in vehicle-treated SHR. Acetylcholinesterase inhibition increased the modulatory effects of nitric oxide (NO) on SHR vascular reactivity, that is, N(ω)-nitro-(L)-arginine methyl ester (L-NAME) increased EFS-induced contractions and reduced ACh-induced relaxation, with more significant effects in pyridostigmine- and donepezil-treated SHR. The acetylcholinesterase inhibitors also decreased vascular reactive oxygen species levels., Conclusions: This study demonstrates for the first time that long-term administration of acetylcholinesterase inhibitors, pyridostigmine or donepezil, attenuates vascular reactivity dysfunction in SHR by decreasing reactive oxygen species generation and increasing NO bioavailability; possibly via increased endothelial NO synthase activity, and inhibition of NADPH oxidase activity., (© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The analysis of heart rate variability (HRV) by nonlinear methods has been gaining increasing interest due to their ability to quantify the complexity of cardiovascular regulation. In this study, multiscale entropy (MSE) and refined MSE (RMSE) were applied to track the complexity of HRV as a function of time scale in three pathological conscious animal models: rats with heart failure (HF), spontaneously hypertensive rats (SHR), and rats with sinoaortic denervation (SAD). Results showed that HF did not change HRV complexity, although there was a tendency to decrease the entropy in HF animals. On the other hand, SHR group was characterized by reduced complexity at long time scales, whereas SAD animals exhibited a smaller short- and long-term irregularity. We propose that short time scales (1 to 4), accounting for fast oscillations, are more related to vagal and respiratory control, whereas long time scales (5 to 20), accounting for slow oscillations, are more related to sympathetic control. The increased sympathetic modulation is probably the main reason for the lower entropy observed at high scales for both SHR and SAD groups, acting as a negative factor for the cardiovascular complexity. This study highlights the contribution of the multiscale complexity analysis of HRV for understanding the physiological mechanisms involved in cardiovascular regulation., (Copyright © 2016 the American Physiological Society.)

Background: It is hypothesized that chronic increase of availability of acetylcholine, resulting from the effect of antiacetylcholinesterases, may prevent autonomic imbalance and reduce inflammation yielding benefic effects for cardiovascular disorders in hypertension. The effect of long-term administration of antiacetylcholinesterase agents with central and/or peripheral action, i.e., donepezil and pyridostigmine, were investigated on arterial pressure (AP), sympathovagal balance, plasma cytokine levels, and cardiac remodeling in spontaneously hypertensive rats (SHR)., Methods: Chronic treatment with donepezil or pyridostigmine started before the onset of hypertension. AP was measured by plethysmography every 4 weeks. At the end of 16 weeks of treatment, methylatropine was used to evaluate the cardiac vagal tone; AP and pulse interval (PI) variability were also evaluated followed by plasma and heart collection for analysis., Results: Pyridostigmine, which does not cross the blood-brain barrier, increased cardiac vagal tone, and reduced cardiomyocyte diameter and collagen density, but did not affect the AP and plasma cytokine levels. Donepezil, which crosses the blood-brain barrier, attenuated the development of hypertension, increased cardiac vagal tone, and improved AP and PI variability. Likewise, donepezil reduced the plasma levels of tumor necrosis factor-α, interleukin 6, and interferon γ, besides reducing cardiomyocyte diameter and collagen density., Conclusions: Donepezil attenuated the development of hypertension in SHR probably involving antiinflammatory effects, indicating that acetylcholinesterase inhibition yields benefic effects for antihypertensive therapy., (© American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

This study aimed to characterize the role played by baroreceptors and chemoreceptors in the hypertensive response to bilateral carotid occlusion (BCO) in conscious C57BL mice. On the day before the experiments the animals were implanted with pneumatic cuffs around their common carotid arteries and a femoral catheter for measurement of arterial pressure. Under the same surgical approach, groups of mice were submitted to aortic or carotid sinus denervation or sham surgery. BCO was performed for 30 or 60 s, promoting prompt and sustained increase in mean arterial pressure and fall in heart rate. Compared with intact mice, the hypertensive response to 30 s of BCO was enhanced in aortic-denervated mice (52 ± 4 vs. 41 ± 4 mmHg; P < 0.05) but attenuated in carotid sinus-denervated mice (15 ± 3 vs. 41 ± 4 mmHg; P < 0.05). Suppression of peripheral chemoreceptor activity by hyperoxia [arterial partial pressure of oxygen (Pa(O(2))) > 500 mmHg] attenuated the hypertensive response to BCO in intact mice (30 ± 6 vs. 51 ± 5 mmHg in normoxia; P < 0.05) and abolished the bradycardia. It did not affect the hypertensive response in carotid sinus-denervated mice (20 ± 4 vs. 18 ± 3 mmHg in normoxia; P < 0.05). The attenuation of the hypertensive response to BCO by carotid sinus denervation or hyperoxia indicates that the hypertensive response in conscious mice is mediated by both baro- and chemoreceptors. In addition, aortic denervation potentiates the hypertensive response elicited by BCO in conscious mice.