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Valensi Cardiovasc Diabetol (2021) 20:170 https://doi.org/10.1186/s12933-021-01356-w Cardiovascular Diabetology REVIEW Open Access Autonomic nervous system activity changes in patients with hypertension and overweight: role and therapeutic implications Paul Valensi* Abstract The incidence and prevalence of hypertension is increasing worldwide, with approximately 1.13 billion of people currently afected by the disease, often in association with other diseases such as diabetes mellitus, chronic kidney disease, dyslipidemia/hypercholesterolemia, and obesity. The autonomic nervous system has been implicated in the pathophysiology of hypertension, and treatments targeting the sympathetic nervous system (SNS), a key component of the autonomic nervous system, have been developed; however, current recommendations provide little guid‑ ance on their use. This review discusses the etiology of hypertension, and more specifcally the role of the SNS in the pathophysiology of hypertension and its associated disorders. In addition, the efects of current antihypertensive management strategies, including pharmacotherapies, on the SNS are examined, with a focus on imidazoline recep‑ tor agonists. Keywords: Autonomic nervous system, Hypertension, Obesity, Type 2 diabetes, Selective imidazoline receptor agonists Introduction 6]. Te prevalence of hypertension is higher in low- and Hypertension is one of the leading causes of premature middle-income countries [5] and increases with age [1]. death worldwide with 1.13 billion people having hyper- Te autonomic nervous system has been implicated tension. It is associated with an increased risk of cardio- in the pathophysiology of hypertension [7, 8] and treat- vascular diseases (CVD; e.g., stroke, angina, myocardial ments targeting the sympathetic nervous system (SNS) infarction, heart failure, peripheral artery disease, and have been developed [9, 10] although largely forgotten or abdominal aortic aneurysm) as well as end-stage renal ruled out in international recommendations [1, 2]. Te disease [1, 2]. Hypertension often co-occurs with other aim of this review, therefore, is to examine the patho- CVD risk factors such as diabetes mellitus, dyslipidemia/ physiology of hypertension, in particular the role of the hypercholesterolemia, obesity and chronic kidney dis- autonomic nervous system (ANS) and medications that ease [1, 3, 4]. Despite several actions set up to improve target the SNS to help control hypertension. A search diagnosis, management and awareness about hyperten- of PubMed was conducted using search terms such as sion, the incidence and prevalence are still increasing [5, “hypertension”, “blood pressure”, “sympathetic nervous system” and “SNS”, with no restrictions on date of pub- lication. Supplemental, focussed ad-hoc searching was conducted where necessary. *Correspondence: [email protected] Unit of Endocrinology, Diabetology and Nutrition, Jean Verdier Hospital, CINFO, CRNH‑IdF, AP‑HP, Paris Nord University, Avenue du 14 Juillet, 93140 Bondy, France © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Valensi Cardiovasc Diabetol (2021) 20:170 Page 2 of 12 Hypertension While animal studies have demonstrated extensive and According to the ESC/ESH guidelines, hyperten- reciprocal interactions between SNS and RAAS impor- sion is defned as ofce systemic blood pressure tant to cardiovascular regulation and the development of values ≥ 140 mmHg and/or diastolic blood pressure val- hypertension, supportive evidence in humans is currently ues ≥ 90 mmHg [2]. lacking [17, 18]. Te aetiology of hypertension is currently still poorly known, although several risk factors have been identifed for its development such as overweight, diet (e.g., sodium The sympathetic nervous system intake), physical activity, and alcohol consumption [11, Physiological role of the sympathetic nervous system 12]. Its pathogenesis is multifactorial and highly com- Maintenance of cardiovascular homeostasis requires plex, involving multiple organ systems and numerous continual redirection of blood fow to ensure adequate independent and interdependent pathways [13]. Known blood supply to active tissues. Under normal function- systems involved in blood pressure control include car- ing, the autonomic nervous system, comprising the sym- diovascular, renal, neural, and endocrine systems, as well pathetic, parasympathetic and enteric nervous systems, as local tissues, with the kidneys playing a central role makes unconscious adjustments in regional blood fow [13]. In addition, genetic factors, and activation of neu- and cardiac output, and coordinates with the central res- rohormonal systems are involved in the pathogenesis of piratory network in order to respond to varying meta- hypertension. Te neurohormonal system is responsible bolic and thermoregulatory demands [19]. Te SNS is for maintenance of cardiovascular homeostasis, with the activated when baroreceptors, specialised stretch recep- sympathetic nervous system (SNS) and the renin–angio- tors located within thin areas of blood vessels and heart tensin–aldosterone system (RAAS) being two key com- chambers, sense changes in pressure [20]. When arterial ponents [14]. RAAS is involved in the maintenance of pressure drops, the SNS is immediately activated result- arterial blood pressure, plasma sodium concentration ing in increased cardiac output and vasoconstriction of and extracellular volume, and needed for the function peripheral vessels (Fig. 1) [20]. Subsequent constriction of the heart and kidneys. RAAS dysfunction can lead to of renal aferent arterioles results in activation of the chronic diseases development as hypertension or heart renin–angiotensin–aldosterone system and secretion of failure [15, 16]. renin [14]. Fig. 1 Control of blood pressure by the sympathetic nervous system (SNS) and the renin–angiotensin–aldosterone system (RAAS) Valensi Cardiovasc Diabetol (2021) 20:170 Page 3 of 12 Te SNS plays an important role in the regulation of ventricular hypertrophy and increased arterial stifening liver metabolic processes, with the sympathetic and para- [25–29]. Te SNS also appears to afect haemostasis, with sympathetic systems working in tandem to respectively acute activation of the SNS resulting in hypercoagulabil- stimulate and suppress hepatic gluconeogenesis, and ity due to increased platelet aggregability [29, 30]. insulin stimulating glycolysis and lipogenesis, and sup- Sympathetic activity is increased in hypertension and pressing gluconeogenesis [21]. Overall, the SNS enhances heart failure, and is responsible for initiation and devel- the production of glucose by the liver and mobilises met- opment of the diseases [7, 8, 31]. While specifc causes abolic fuels for use by the tissues [21]. In the pancreas, of this increase are mostly unknown, genetic infuences, Langerhans islets are innervated by autonomic nervous behavioural and lifestyle factors appear to be involved [7, system fbres resulting in modulation of insulin secretion 8]. Increased SNS activity is believed to contribute to the with parasympathetic nerves stimulating insulin secre- pathophysiology of heart failure through multiple mecha- tion and sympathetic nerves having the opposite efect nisms, including desensitization of cardiac β-adrenergic [22, 23]. Enhanced lipolysis in adipose tissue by the SNS receptors, adverse efects on excitation–contraction cou- is part of a control mechanism designed to break down pling, and fbrosis [16, 32]. fats [24]. Te efects of the SNS activation are mediated by adr- energic neurotransmitters (norepinephrine, epineph- SNS overdrive in hypertension rine and dopamine) having vasoconstriction properties Te consequences of sympathetic overdrive leading to [18]. It has been shown that the norepinephrine spillo- hypertension are numerous and include cardiovascular, ver is increased in patients with high blood pressure, renal and metabolic efects (Fig. 2) [25–27]. A state of and this increase is mainly seen in the heart and the sympathetic activation is associated with increased heart kidneys, both tightly involved in blood pressure control rate, and appears to promote cardiac and vascular altera- [18]. Te release of these adrenergic neurotransmitters tions [25, 28], contributing to the development of major induces action on cardiovascular and metabolic systems complications of hypertension such as arrhythmia, left by targeting organs involved in homeostasis control as Fig. 2 The role of the sympathetic nervous system (SNS) in energy balance

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