The extended autonomic system, dyshomeostasis, and COVID-19.
ABSTRACT: The pandemic viral illness COVID-19 is especially life-threatening in the elderly and in those with any of a variety of chronic medical conditions. This essay explores the possibility that the heightened risk may involve activation of the "extended autonomic system" (EAS). Traditionally, the autonomic nervous system has been viewed as consisting of the sympathetic nervous system, the parasympathetic nervous system, and the enteric nervous system. Over the past century, however, neuroendocrine and neuroimmune systems have come to the fore, justifying expansion of the meaning of "autonomic." Additional facets include the sympathetic adrenergic system, for which adrenaline is the key effector; the hypothalamic-pituitary-adrenocortical axis; arginine vasopressin (synonymous with anti-diuretic hormone); the renin-angiotensin-aldosterone system, with angiotensin II and aldosterone the main effectors; and cholinergic anti-inflammatory and sympathetic inflammasomal pathways. A hierarchical brain network-the "central autonomic network"-regulates these systems; embedded within it are components of the Chrousos/Gold "stress system." Acute, coordinated alterations in homeostatic settings (allostasis) can be crucial for surviving stressors such as traumatic hemorrhage, asphyxiation, and sepsis, which throughout human evolution have threatened homeostasis; however, intense or long-term EAS activation may cause harm. While required for appropriate responses in emergencies, EAS activation in the setting of chronically decreased homeostatic efficiencies (dyshomeostasis) may reduce thresholds for induction of destabilizing, lethal vicious cycles. Testable hypotheses derived from these concepts are that biomarkers of EAS activation correlate with clinical and pathophysiologic data and predict outcome in COVID-19 and that treatments targeting specific abnormalities identified in individual patients may be beneficial.
Project description:Pulmonary arterial hypertension (PAH) is a chronic pulmonary vascular disease characterized by increased pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Autonomic nervous system involvement in the pathogenesis of PAH has been demonstrated several years ago, however the extent of this involvement is not fully understood. PAH is associated with increased sympathetic nervous system (SNS) activation, decreased heart rate variability, and presence of cardiac arrhythmias. There is also evidence for increased renin-angiotensin-aldosterone system (RAAS) activation in PAH patients associated with clinical worsening. Reduction of neurohormonal activation could be an effective therapeutic strategy for PAH. Although therapies targeting adrenergic receptors or RAAS signaling pathways have been shown to reverse cardiac remodeling and improve outcomes in experimental pulmonary hypertension (PH)-models, the effectiveness and safety of such treatments in clinical settings have been uncertain. Recently, novel direct methods such as cervical ganglion block, pulmonary artery denervation (PADN), and renal denervation have been employed to attenuate SNS activation in PAH. In this review, we intend to summarize the multiple aspects of autonomic nervous system involvement in PAH and overview the different pharmacological and invasive strategies used to target autonomic nervous system for the treatment of PAH.
Project description:Complex and bidirectional interactions between the renin-angiotensin system (RAS) and autonomic nervous system have been well established for cardiovascular regulation under both physiological and pathophysiological conditions. Most research to date has focused on deleterious effects of components of the vasoconstrictor arm of the RAS on cardiovascular autonomic control, such as renin, angiotensin II, and aldosterone. The recent discovery of prorenin and the prorenin receptor have further increased our understanding of RAS interactions in autonomic brain regions. Therapies targeting these RAS components, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, are commonly used for treatment of hypertension and cardiovascular diseases, with blood pressure-lowering effects attributed in part to sympathetic inhibition and parasympathetic facilitation. In addition, a vasodilatory arm of the RAS has emerged that includes angiotensin-(1-7), ACE2, and alamandine, and promotes beneficial effects on blood pressure in part by reducing sympathetic activity and improving arterial baroreceptor reflex function in animal models. The role of the vasodilatory arm of the RAS in cardiovascular autonomic regulation in clinical populations, however, has yet to be determined. This review will summarize recent developments in autonomic mechanisms involved in the effects of the RAS on cardiovascular regulation, with a focus on newly discovered pathways and therapeutic targets for this hormone system.
Project description:The central nervous system has a key role in regulating the circulatory system by modulating the sympathetic and parasympathetic nervous systems, pituitary hormone release, and the baroreceptor reflex. Digoxin- and ouabain-like immunoreactive materials were found >20 years ago in the hypothalamic nuclei. These factors appeared to localize to the paraventricular and supraoptic nuclei and the nerve fibers at the circumventricular organs and supposed to affect electrolyte balance and blood pressure. The turnover rate of these materials increases with increasing sodium intake. As intracerebroventricular injection of ouabain increases blood pressure via sympathetic activation, an endogenous digitalis-like factor (EDLF) was thought to regulate cardiovascular system-related functions in the brain, particularly after sodium loading. Experiments conducted mainly in rats revealed that the mechanism of action of ouabain in the brain involves sodium ions, epithelial sodium channels (ENaCs) and the renin-angiotensin-aldosterone system (RAAS), all of which are affected by sodium loading. Rats fed a high-sodium diet develop elevated sodium levels in their cerebrospinal fluid, which activates ENaCs. Activated ENaCs and/or increased intracellular sodium in neurons activate the RAAS; this releases EDLF in the brain, activating the sympathetic nervous system. The RAAS promotes oxidative stress in the brain, further activating the RAAS and augmenting sympathetic outflow. Angiotensin II and aldosterone of peripheral origin act in the brain to activate this cascade, increasing sympathetic outflow and leading to hypertension. Thus, the brain Na(+)-ENaC-RAAS-EDLF axis activates sympathetic outflow and has a crucial role in essential and secondary hypertension. This report provides an overview of the central mechanism underlying hypertension and discusses the use of antihypertensive agents.
Project description:Chronic activation of the brain renin-angiotensin system contributes to the development of hypertension by altering autonomic balance. Beyond the essential role of Ang II (angiotensin II) type 1 receptors, ADAM17 (A disintegrin and metalloprotease 17) is also found to promote brain renin-angiotensin system overactivation. ADAM17 is robustly expressed in various cell types within the central nervous system. The aim of this study was to determine whether ADAM17 modulates presympathetic neuronal activity to promote autonomic dysregulation in salt-sensitive hypertension. To test our hypothesis, ADAM17 was selectively knocked down in glutamatergic neurons using Cre-loxP technology. In mice lacking ADAM17 in glutamatergic neurons, the blood pressure increase induced by deoxycorticosterone acetate-salt treatment was blunted. Deoxycorticosterone acetate-salt significantly elevated cardiac and vascular sympathetic drive in control mice, while such effects were reduced in mice with ADAM17 knockdown. This blunted sympathoexcitation was extended to the spleen, with a lesser activation of the peripheral immune system, translating into a sequestration of circulating T cells within this organ, compared with controls. Within the paraventricular nucleus, Ang II-induced activation of kidney-related presympathetic glutamatergic neurons was reduced in ADAM17 knockdown mice, with the majority of cells no longer responding to Ang II stimulation, confirming the supportive role of ADAM17 in increasing presympathetic neuronal activity. Overall, our data highlight the pivotal role of neuronal ADAM17 in regulating sympathetic activity and demonstrate that activation of ADAM17 in glutamatergic neurons leads to a selective increase of sympathetic output, but not vagal tone, to specific organs, ultimately contributing to dysautonomia and salt-sensitive hypertension.
Project description:The American Heart Association recommends no more than 1500 mg of sodium/day as ideal. Some cohort studies suggest low-sodium intake is associated with increased cardiovascular mortality. Extremely low-sodium diets (?500 mg/d) elicit activation of the renin-angiotensin-aldosterone system and stimulate sympathetic outflow. The effects of an American Heart Association-recommended diet on sympathetic regulation of the vasculature are unclear. Therefore, we assessed whether a 1000 mg/d diet alters sympathetic outflow and sympathetic vascular transduction compared with the more commonly recommended 2300 mg/d. We hypothesized that sodium reduction from 2300 to 1000 mg/d would not affect resting sympathetic outflow but would reduce sympathetic transduction in healthy young adults. Seventeen participants (age: 26±2 years, 9F/8M) completed 10-day 2300 and 1000 mg/d sodium diets in this randomized controlled feeding study (crossover). We measured resting renin activity, angiotensin II, aldosterone, blood pressure, muscle sympathetic nerve activity, and norepinephrine. We quantified beat-by-beat changes in mean arterial pressure and leg vascular conductance (femoral artery ultrasound) following spontaneous sympathetic bursts to assess sympathetic vascular transduction. Reducing sodium to 1000 mg/d increased renin activity, angiotensin II, and aldosterone ( P<0.01 for all) but did not alter mean arterial pressure (78±2 versus 77±2 mm?Hg, P=0.56), muscle sympathetic nerve activity (13.9±1.3 versus 13.9±0.8 bursts/min, P=0.98), or plasma/urine norepinephrine. Sympathetic vascular transduction decreased ( P<0.01). These data suggest that reducing sodium from 2300 to 1000 mg/d stimulates the renin-angiotensin-aldosterone system, does not increase resting basal sympathetic outflow, and reduces sympathetic vascular transduction in normotensive adults.
Project description:The sympathetic nervous system interacts with the renin-angiotensin-aldosterone system (RAAS) contributing to cardiovascular diseases. In this study, we sought to determine if renal denervation (RDN) inhibits aldosterone expression and associated cardiovascular pathophysiological changes in angiotensin II (Ang II)-induced hypertension. Bilateral RDN or SHAM operation was performed before chronic 14-day Ang II subcutaneous infusion (200ng/kg/min) in male Sprague-Dawley rats. Bilateral RDN blunted Ang II-induced hypertension and ameliorated the mesenteric vascular dysfunction. Cardiovascular hypertrophy in response to Ang II was significantly attenuated by RDN as shown by histopathology and transthoracic echocardiography. Moreover, Ang II-induced vascular and myocardial inflammation and fibrosis were suppressed by RDN with concurrent decrease in fibronectin and collagen deposition, macrophage infiltration, and MCP-1 expression. Interestingly, RDN also inhibited Ang II-induced aldosterone expression in the plasma, kidney and heart. This was associated with the reduction of calcitonin gene-related peptide (CGRP) in the adrenal gland. Ang II promoted aldosterone secretion which was partly attenuated by CGRP in the adrenocortical cell line, suggesting a protective role of CGRP in this model. Activation of transforming growth factor-? (TGF-?)/Smad and mitogen-activated protein kinases (MAPKs) signaling pathway was both inhibited by RDN especially in the heart. These results suggest that the regulation of the renal sympathetic nerve in Ang II-induced hypertension and associated cardiovascular pathophysiological changes is likely mediated by aldosterone, with CGRP involvement.
Project description:Sodium balance determines the extracellular fluid volume and sets arterial blood pressure (BP). Chronically raised BP (hypertension) represents a major health risk in Western societies. The relationship between BP and renal sodium excretion (the pressure/natriuresis relationship) represents the key element in defining the BP homeostatic set point. The renin-angiotensin-aldosterone system (RAAS) makes major adjustments to the rates of renal sodium secretion, but this system works slowly over a period of hours to days. More rapid adjustments can be made by the sympathetic nervous system, although the kidney can function well without sympathetic nerves. Attention has now focussed on regulatory mechanisms within the kidney, including extracellular nucleotides and the P2 receptor system. Here, we discuss how extracellular ATP can control renal sodium excretion by altering the activity of epithelial sodium channels (ENaC) present in the apical membrane of principal cells. There remains considerable controversy over the molecular targets for released ATP, although the P2Y(2) receptor has received much attention. We review the available data and reflect on our own findings in which ATP-activated P2Y and P2X receptors make adjustments to ENaC activity and therefore sodium excretion.
Project description:Heart failure (HF) represents a growing financial burden on healthcare systems and despite therapeutic advances, mortality remains high. Current treatments focus on blocking neurohormonal pathways, such as the renin-angiotensin aldosterone system (RAAS). Recent research has focused on the natriuretic peptide system, which confers beneficial effects in HF, whereas activation of the RAAS and of the sympathetic nervous system has detrimental effects. LCZ696 (sacubutril/valsartan), a first-in-class angiotensin II AT receptor neprilysin inhibitor, has a unique mode of action that targets both pathways. Clinical studies to date indicate that LCZ696 is effective and safe in mild to moderate arterial hypertension and in HF patients with preserved ejection fraction, and has been shown to be superior to enalapril in patients with moderate to severe HF due to reduced left ventricular ejection fraction.
Project description:The clinical syndrome of heart failure (HF) can be described as the reduced capacity of the heart to deliver blood throughout the body. To compensate for inadequate tissue perfusion, the renin-angiotensin aldosterone system (RAAS) and the sympathetic nervous system (SNS) become activated, resulting in increased blood pressure, heart rate, and blood volume. Consequent activation of the natriuretic peptide system (NPS) typically balances these effects; however, the NPS is unable to sustain compensation for excessive neurohormonal activation over time. Until recently, mortality benefits have been provided to patients with HF only by therapies that target the RAAS and SNS, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, and beta-blockers. Sacubitril/valsartan, the first-in-class angiotensin receptor/neprilysin inhibitor (ARNI), targets both the NPS and RAAS to further improve clinical outcomes. This review discusses the focused management of patients with HF with reduced ejection fraction (HFrEF) and suggests changes to current management paradigms. From this assessment, the evidence supports favoring sacubitril/valsartan over ACEIs or ARBs, and this therapy should be used in conjunction with beta-blockers to further decrease morbidity and mortality in patients with HFrEF.
Project description:The surge in arterial pressure during arousal in the waking period is thought to be largely due to activation of the sympathetic nervous system. In this study we compared in SHR the effects of chronic administration of the centrally acting sympatholytic agent rilmenidine with an angiotensin converting enzyme inhibitor perindopril on the rate of rise and power of the surge in mean arterial pressure (MAP) that occurs with arousal associated with the onset of night. Recordings were made using radiotelemetry in 17 adult SHR before and after treatment with rilmenidine (2mg/kg/day), perindopril (1mg/kg/day) or vehicle in the drinking water for 2 weeks. Rilmenidine reduced MAP by 7.2 ± 1.7mmHg while perindopril reduced MAP by 19 ± 3mmHg. Double logistic curve fit analysis showed that the rate and power of increase in systolic pressure during the transition from light to dark was reduced by 50% and 65%, respectively, but had no effect on diastolic pressure. Rilmenidine also reduced blood pressure variability in the autonomic frequency in the active period as assessed by spectral analysis which is consistent with reduction in sympathetic nervous system activity. Perindopril had no effect on the rate or power of the arousal surge in either systolic or diastolic pressure. These results suggest that the arousal induced surge in blood pressure can largely be reduced by an antihypertensive agent that inhibits the sympathetic nervous system and that angiotensin converting enzyme inhibition, while effective in reducing blood pressure, does not alter the rate or power of the surge associated with arousal.