Exaggerated renal sympathetic nerve and pressor responses during spontaneously occurring motor activity in hypertensive rats.

Stimulation of the mesencephalic locomotor region elicits exaggerated sympathetic nerve and pressor responses in spontaneously hypertensive rats (SHR) as compared with normotensive Wistar-Kyoto rats (WKY). This suggests that central command or its influence on vasomotor centers is augmented in hypertension. The decerebrate animal model possesses an ability to evoke intermittent bouts of spontaneously occurring motor activity (SpMA) and generates cardiovascular responses associated with the SpMA. It remains unknown whether the changes in sympathetic nerve activity and hemodynamics during SpMA are altered by hypertension. To test the hypothesis that the responses in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) during SpMA are exaggerated with hypertension, this study aimed to compare the responses in decerebrate, paralyzed SHR, WKY, and normotensive Sprague-Dawley (SD) rats. In all strains, an abrupt increase in RSNA occurred in synchronization with tibial motor discharge (an index of motor activity) and was followed by rises in MAP and heart rate. The centrally evoked increase in RSNA and MAP during SpMA was much greater (306 ± 110%) in SHR than WKY (187 ± 146%) and SD (165 ± 44%). Although resting baroreflex-mediated changes in RSNA were not different across strains, mechanically or pharmacologically induced elevations in MAP attenuated or abolished the RSNA increase during SpMA in WKY and SD but had no effect in SHR. It is likely that the exaggerated sympathetic nerve and pressor responses during SpMA in SHR are induced along a central command pathway independent of the arterial baroreflex and/or result from central command-induced inhibition of the baroreflex.

Diagnosis of colonic dysmotility associated with autonomic dysfunction in patients with chronic refractory constipation.

We report the first study assessing human colon manometric features and their correlations with changes in autonomic functioning in patients with refractory chronic constipation prior to consideration of surgical intervention. High-resolution colonic manometry (HRCM) with simultaneous heart rate variability (HRV) was performed in 14 patients, and the resulting features were compared to healthy subjects. Patients were categorized into three groups that had normal, weak, or no high amplitude propagating pressure waves (HAPWs) to any intervention. We found mild vagal pathway impairment presented as lower HAPW amplitude in the proximal colon in response to proximal colon balloon distention. Left colon dysmotility was observed in 71% of patients, with features of (1) less left colon HAPWs, (2) lower left colon HAPW amplitudes (69.8 vs 102.3 mmHg), (3) impaired coloanal coordination, (4) left colon hypertonicity in patients with coccyx injury. Patients showed the following autonomic dysfunction: (1) high sympathetic tone at baseline, (2) high sympathetic reactivity to active standing and meal, (3) correlation of low parasympathetic reactivity to the meal with absence of the coloanal reflex, (4) lower parasympathetic and higher sympathetic activity during occurrence of HAPWs. In conclusion, left colon dysmotility and high sympathetic tone and reactivity, more so than vagal pathway impairment, play important roles in refractory chronic constipation and suggests sacral neuromodulation as a possible treatment.

Sympathovagal equilibrium analysis in patients with COVID-19 / Análisis del equilibrio simpatovagal en pacientes con COVID-19

Introduction: With the increase of COVID-19 cases, an unusual manifestation for this type of virus began to appear anosmia and dysgeusia, which could indicate a neurologic alteration. In this context, it seems likely that subclinical manifestations of baroreflex involvement occur. The vegetative nervous system carries out the regulation of the baroreflex through the balance between sympathetic and parasympathetic activity. The objective of this study is to verify whether patients with COVID-19 present alteration of this equilibrium. Material and methods: Patients included had a confirmed diagnosis of COVID-19 admitted to the Internal Medicine Department of JB Iturraspe Hospital. A Holter recording was performed at rest for 5 minutes, determining the variables in the frequency domain using Fourier transform analysis. We excluded patients with diabetes, medicated with drugs that modify heart rate or with a history of irradiation to the neck. Results: 68 patients were studied. The mean age was 49±13 years. The median systolic blood pressure was 120 mmHg and the diastolic blood pressure 80 mmHg. The heart rate was 76±13 beats per minute and the median respiratory rate was 24 (16 to 40). Anosmia was observed in 22% and dysgeusia in 19% The variables in the frequency domain were: Low-frequency power (LF) 135.8ms2 (13.7-2861.7); High-frequency power (HF), 89.04ms2 (4.1-5234.4), LFnu 57.5±22.3, HFnu 43.1±22.6. LF:HF 2.1±2. 41.2% of the patients had a high LF:HF. Conclusions: LF and HF components can be obtained through frequency analysis. The relationship between these two elements would thus represent the sympathovagal balance and is expressed as the LF/HF ratio. We observed that 41.2% of the studied patients showed elevated LF/HF ratio. The 41.2% of the patients presented an increased LF:HF ratio, which could be interpreted as an alteration in autonomic function (AU)

Introducción: Con el aumento de casos de COVID-19, unas manifestaciones inusuales para este tipo de virus como la anosmia y disgeusia comenzaron a aparecer, lo que podría indicar una alteración neurológica. En este contexto, parece probable que se produzcan manifestaciones subclínicas de afectación barorrefleja. El sistema nervioso vegetativo lleva a cabo la regulación del barorreflejo a través del equilibrio entre la actividad simpática y parasimpática. El objetivo de este estudio es verificar si los pacientes con COVID-19 presentan alteración de este equilibrio. Material y métodos: Se evaluaron pacientes con diagnóstico confirmado de COVID-19 ingresados en el Servicio de Medicina Interna del Hospital JB Iturraspe. Se realizó un registro Holter en reposo durante 5 minutos, determinando las variables en el dominio de la frecuencia mediante análisis por transformada de Fourier. Se excluyeron pacientes con diabetes, medicados con fármacos que modifican la frecuencia cardiaca o con antecedentes de irradiación al cuello. Resultados: Se estudiaron 68 pacientes. La edad media fue de 49±13 años. La mediana de la presión arterial sistólica fue de 120 mmHg y la diastólica de 80 mmHg. La frecuencia cardiaca fue de 76±13 latidos por minuto y la mediana de la frecuencia respiratoria fue de 24 (16 a 40). Se observó anosmia en 22% y disgeusia en 19% Las variables en el dominio frecuencial fueron: Potencia de baja frecuencia (LF) 135,8ms2 (13,7-2861,7); Potencia de alta frecuencia (HF), 89,04 ms2 (4,1-5234,4), LFnu 57,5±22,3, HFnu 43,1±22,6. LF:HF 2.1±2. El 41,2% de los pacientes tenían una relación LF:HF alta. Conclusiones: Los componentes de LF y HF se pueden obtener a través del análisis de frecuencia. La relación entre estos dos elementos representaría así el equilibrio simpatovagal y se expresa como la relación LF/HF (AU)

Paroxysmal Sympathetic Hyperactivity in Patients Victims of Traumatic Brain Injury: Literature Review

The present literature review aims to present the physiology of paroxysmal sympathetic hyperactivity (PSH) as well as its clinical course, conceptualizing them, and establishing its diagnosis and treatment. Paroxysmal sympathetic hyperactivity is a rare syndrome, which often presents after an acute traumatic brain injury. Characterized by a hyperactivity of the sympathetic nervous system, when diagnosed in its pure form, its symptomatologic presentation is through tachycardia, tachypnea, hyperthermia, hypertension, dystonia, and sialorrhea. The treatment of PSH is basically pharmacological, using central nervous system suppressors; however, the nonmedication approach is closely associated with a reduction in external stimuli, such as visual and auditory stimuli. Mismanagement can lead to the development of serious cardiovascular and diencephalic complications, and the need for neurosurgeons and neurointensivists to know about PSH is evident in order to provide a fast and accurate treatment of this syndrome.

High-resolution structure-function mapping of intact hearts reveals altered sympathetic control of infarct border zones.

Remodeling of injured sympathetic nerves on the heart after myocardial infarction (MI) contributes to adverse outcomes such as sudden arrhythmic death, yet the underlying structural mechanisms are poorly understood. We sought to examine microstructural changes on the heart after MI and to directly link these changes with electrical dysfunction. We developed a high-resolution pipeline for anatomically precise alignment of electrical maps with structural myofiber and nerve-fiber maps created by customized computer vision algorithms. Using this integrative approach in a mouse model, we identified distinct structure-function correlates to objectively delineate the infarct border zone, a known source of arrhythmias after MI. During tyramine-induced sympathetic nerve activation, we demonstrated regional patterns of altered electrical conduction aligned directly with altered neuroeffector junction distribution, pointing to potential neural substrates for cardiac arrhythmia. This study establishes a synergistic framework for examining structure-function relationships after MI with microscopic precision that has potential to advance understanding of arrhythmogenic mechanisms.

Mitigating Initial Orthostatic Hypotension: Mechanistic Roles of Muscle Contraction Versus Sympathetic Activation.

BACKGROUND: Initial orthostatic hypotension (IOH) is defined by a large drop in blood pressure (BP) within 15 s of standing. IOH often presents during an active stand, but not with a passive tilt, suggesting that a muscle activation reflex involving lower body muscles plays an important role. To our knowledge, there is no literature exploring how sympathetic activation affects IOH. We hypothesized involuntary muscle contractions before standing would significantly reduce the drop in BP seen in IOH while increasing sympathetic activity would not. METHODS: Study participants performed 4 sit-to-stand maneuvers including a mental stress test (serial 7 mental arithmetic stress test), cold pressor test, electrical stimulation, and no intervention. Continuous heart rate and beat-to-beat BP were measured. Cardiac output and systemic vascular resistance were estimated from these waveforms. Data are presented as mean±SD. RESULTS: A total of 23 female IOH participants (31±8 years) completed the study. The drops in systolic BP following the serial 7 mental arithmetic stress test (-26±12 mm Hg; P=0.004), cold pressor test (-20±15 mm Hg; P<0.001), and electrical stimulation (-28±12 mm Hg; P=0.01) were significantly reduced compared with no intervention (-34±11 mm Hg). The drops in systemic vascular resistance following the serial 7 mental arithmetic stress test (-391±206 dyne×s/cm5; P=0.006) and cold pressor test (-386±179 dyne×s/cm5; P=0.011) were significantly reduced compared with no intervention (-488±173 dyne×s/cm5). Cardiac output was significantly increased upon standing (7±2 L/min) compared with during the sit (6±1 L/min; P<0.001) for electrical stimulation. CONCLUSION: Sympathetic activation mitigates the BP response in IOH, while involuntary muscle contraction mitigates the BP response and reduces symptoms. Active muscle contractions may induce both of these mechanisms of action in their pretreatment of IOH. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03970551.

Sympathetic neural responses to sleep disorders and insufficiencies.

Short sleep duration and poor sleep quality are associated with cardiovascular risk, and sympathetic nervous system (SNS) dysfunction appears to be a key contributor. The present review will characterize sympathetic function across several sleep disorders and insufficiencies in humans, including sleep deprivation, insomnia, narcolepsy, and obstructive sleep apnea (OSA). We will focus on direct assessments of sympathetic activation, e.g., plasma norepinephrine and muscle sympathetic nerve activity, but include heart rate variability (HRV) when direct assessments are lacking. The review also highlights sex as a key biological variable. Experimental models of total sleep deprivation and sleep restriction are converging to support several epidemiological studies reporting an association between short sleep duration and hypertension, especially in women. A systemic increase of SNS activity via plasma norepinephrine is present with insomnia and has also been confirmed with direct, regionally specific evidence from microneurographic studies. Narcolepsy is characterized by autonomic dysfunction via both HRV and microneurographic studies but with opposing conclusions regarding SNS activation. Robust sympathoexcitation is well documented in OSA and is related to baroreflex and chemoreflex dysfunction. Treatment of OSA with continuous positive airway pressure results in sympathoinhibition. In summary, sleep disorders and insufficiencies are often characterized by sympathoexcitation and/or sympathetic/baroreflex dysfunction, with several studies suggesting women may be at heightened risk.

Effect of liver resection-induced increases in hepatic venous pressure gradient on development of postoperative acute kidney injury.

BACKGROUND: The impact of changes in portal pressure before and after liver resection (defined as ΔHVPG) on postoperative kidney function remains unknown. Therefore, we investigated the effect of ΔHVPG on (i) the incidence of postoperative AKI and (ii) the renin-angiotensin system (RAAS) and sympathetic nervous system (SNS) activity. METHODS: We included 30 patients undergoing partial liver resection. Our primary outcome was postoperative AKI according to KDIGO criteria. For our secondary outcome we assessed the plasma renin, aldosterone, noradrenaline, adrenaline, dopamine and vasopressin concentrations prior and 2 h after induction of anaesthesia, on the first and fifth postoperative day. HVPG was measured prior and immediately after liver resection. RESULTS: ΔHVPG could be measured in 21 patients with 12 patients HVPG showing increases in HVPG (∆HVPG≥1 mmHg) while 9 patients remained stable. AKI developed in 7/12 of patients with increasing HVPG, but only in 2/9 of patients with stable ΔHVPG (p = 0.302). Noradrenalin levels were significantly higher in patients with increasing ΔHVPG than in patients with stable ΔHVPG. (p = 0.009). Biomarkers reflecting RAAS and SNS activity remained similar in patients with increasing vs. stable ΔHVPG. CONCLUSIONS: Patients with increased HVPG had higher postoperative creatinine concentrations, however, the incidence of AKI was similar between patients with increased versus stable HVPG.

Stress system dysfunction revealed by integrating reactivity of stress pathways to psychological stress in lean and overweight/obese men.

Although the patterns of response within the sympathoadrenal medullary (SAM) system and hypothalamo-pituitary adrenal (HPA) axis are interesting and important in their own accord, the overall response to acute psychological stress involves reactivity of both pathways. We tested the hypothesis that consideration of the integrated response of these pathways may reveal dysregulation of the stress systems, which is not evident when considering either system alone. Age-matched lean and overweight/obese men were subjected to a Trier Social Stress Test and reactivity of the SAM system (salivary α-amylase, systolic blood pressure, diastolic blood pressure, and heart rate) and the HPA axis (salivary cortisol) were measured. Relative reactivity of SAM system and HPA axis was calculated as the ratio between the measures from each pathway. Although analysis of reactivity of individual stress pathways showed no evidence of dysfunction in overweight/obese compared with lean men, analysis of HPA/SAM reactivity revealed significantly lower cortisol over systolic blood pressure (CoSBP) and cortisol over diastolic blood pressure (CoDBP) reactivity in overweight/obese compared with lean men. Other measures of HPA/SAM reactivity and all measures of SAM/HPA reactivity were unaltered in overweight/obese compared with lean men. These findings suggest that the cortisol response per unit of blood pressure response is blunted in men with elevated adiposity. Furthermore, these findings support a notion of a coordinated overall approach to activation of the stress pathways with the degree of activation in one pathway being related to the degree of activation in the other.

Effect of extracellular hyperosmolality on sweat rate during metaboreflex activation in passively heated young men.

Metaboreflex activation augments sweating during mild-to-moderate hyperthermia in euhydrated (isosmotic isovolemic) individuals. Recent work indicates that extracellular hyperosmolality may augment metaboreflex-mediated elevations in sympathetic nervous activity. Our primary objective was, therefore, to test the hypothesis that extracellular hyperosmolality would exacerbate metaboreflex-mediated increases in sweat rate. On two separate occasions, 12 young men [means (SD): 25 (5) yr] received a 90-min intravenous infusion of either 0.9% saline (isosmotic condition, ISO) or 3.0% saline (hyperosmotic condition, HYP), resulting in a postinfusion serum osmolality of 290 (3) and 301 (7) mosmol/kgH2O, respectively. A whole body water perfusion suit was then used to increase esophageal temperature by 0.8°C above resting. Participants then performed a metaboreflex activation protocol consisting of 90-s isometric handgrip exercise (40% of their predetermined maximum voluntary contraction), followed by 150 s of brachial occlusion (trapping produced metabolites within the limb). Metaboreflex-induced sweating was quantified as the change in global sweat rate (from preisometric handgrip exercise to brachial occlusion), estimated as the surface area-weighted average of local sweat rate on the abdomen, axilla, chest, bicep, quadriceps, and calf, measured using ventilated capsules (3.8 cm2). We also explored whether this response differed between body regions. The change in global sweat rate due to metaboreflex activation was significantly greater in HYP compared with ISO (0.03 mg/min/cm2 [95% confidence interval: 0.00, 0.06]; P = 0.047), but was not modulated by body region (site × condition interaction: P = 0.679). These findings indicate that extracellular hyperosmolality augments metaboreflex-induced increases in global sweat rate, with no evidence for region-specific differences.

ALM Fluid Therapy Shifts Sympathetic Hyperactivity to Parasympathetic Dominance in the Rat Model of Non-Compressible Hemorrhagic Shock.

ABSTRACT: Excessive sympathetic outflow following trauma can lead to cardiac dysfunction, inflammation, coagulopathy, and poor outcomes. We previously reported that buprenorphine analgesia decreased survival after hemorrhagic trauma. Our aim is to examine the underlying mechanisms of mortality in a non-compressible hemorrhage rat model resuscitated with saline or adenosine, lidocaine, magnesium (ALM). Anesthetized adult male Sprague-Dawley rats were randomly assigned to Saline control group or ALM therapy group (both n = 10). Hemorrhage was induced by 50% liver resection. After 15 min, 0.7 mL/kg 3% NaCl ±â€ŠALM intravenous bolus was administered, and after 60 min, 0.9% NaCl ±â€ŠALM was infused for 4 h (0.5 mL/kg/h) with 72 h monitoring. Animals received 6-12-hourly buprenorphine for analgesia. Hemodynamics, heart rate variability, echocardiography, and adiponectin were measured. Cardiac tissue was analyzed for adrenergic/cholinergic receptor expression, inflammation, and histopathology. Four ALM animals and one Saline control survived to 72 h. Mortality was associated with up to 97% decreases in adrenergic (ß-1, α-1A) and cholinergic (M2) receptor expression, cardiac inflammation, myocyte Ca2+ loading, and histopathology, indicating heart ischemia/failure. ALM survivors had higher cardiac output and stroke volume, a 30-fold increase in parasympathetic/sympathetic receptor expression ratio, and higher circulating adiponectin compared to Saline controls. Paradoxically, Saline cardiac adiponectin hormone levels were higher than ALM, with no change in receptor expression, indicating intra-cardiac synthesis. Mortality appears to be a "systems failure" associated with CNS dysregulation of cardiac function. Survival involves an increased parasympathetic dominance to support cardiac pump function with reduced myocardial inflammation. Increased cardiac α-1A adrenergic receptor in ALM survivors may be significant, as this receptor is highly protective during heart dysfunction/failure.

Paroxysmal sympathetic hyperactivity during traumatic brain injury.

Traumatic brain injury (TBI) is one of the leading causes of disability, morbidity, and mortality worldwide. Some of the more common etiologies of TBI include closed head injury, penetrating head injury, or an explosive blast head injury. Neuronal damage in TBI is related to both primary injury (caused by mechanical forces), and secondary injury (caused by the subsequent tissue and cellular damages). Recently, it has been well established that Paroxysmal Sympathetic Hyperactivity (PSH), also known as "Sympathetic Storm", is one of the main causes of secondary neuronal injury in TBI patients. The clinical manifestations of PSH include recurrent episodes of sympathetic hyperactivity characterized by tachycardia, systolic hypertension, hyperthermia, tachypnea with hyperpnea, and frank diaphoresis. Given the diverse manifestations of PSH and its notable impact on the outcome of TBI patients, we have comprehensively reviewed the current evidence and discussed the pathophysiology, clinical manifestations, time of onset and duration of PSH during TBI. This article reviews the different types of head injuries that most commonly lead to PSH, possible approaches to manage and minimize PSH complications in TBI and the current prognosis and outcomes of PSH in TBI patients.

Low-dose fentanyl reduces pain perception, muscle sympathetic nerve activity responses, and blood pressure responses during the cold pressor test.

Our knowledge about how low-dose (analgesic) fentanyl affects autonomic cardiovascular regulation is primarily limited to animal experiments. Notably, it is unknown if low-dose fentanyl influences human autonomic cardiovascular responses during painful stimuli in humans. Therefore, we tested the hypothesis that low-dose fentanyl reduces perceived pain and subsequent sympathetic and cardiovascular responses in humans during an experimental noxious stimulus. Twenty-three adults (10 females/13 males; 27 ± 7 yr; 26 ± 3 kg·m-2, means ± SD) completed this randomized, crossover, placebo-controlled trial during two laboratory visits. During each visit, participants completed a cold pressor test (CPT; hand in ∼0.4°C ice bath for 2 min) before and 5 min after drug/placebo administration (75 µg fentanyl or saline). We compared pain perception (100-mm visual analog scale), muscle sympathetic nerve activity (MSNA; microneurography, 11 paired recordings), and beat-to-beat blood pressure (BP; photoplethysmography) between trials (at both pre- and postdrug/placebo timepoints) using paired, two-tailed t tests. Before drug/placebo administration, perceived pain (P = 0.8287), ΔMSNA burst frequency (P = 0.7587), and Δmean BP (P = 0.8649) during the CPT were not different between trials. After the drug/placebo administration, fentanyl attenuated perceived pain (36 vs. 66 mm, P < 0.0001), ΔMSNA burst frequency (9 vs. 17 bursts/min, P = 0.0054), and Δmean BP (7 vs. 13 mmHg, P = 0.0174) during the CPT compared with placebo. Fentanyl-induced reductions in pain perception and Δmean BP were moderately related (r = 0.40, P = 0.0641). These data provide valuable information regarding how low-dose fentanyl reduces autonomic cardiovascular responses during an experimental painful stimulus.

Low-dose fentanyl does not alter muscle sympathetic nerve activity, blood pressure, or tolerance during progressive central hypovolemia.

Hemorrhage is a leading cause of battlefield and civilian trauma deaths. Several pain medications, including fentanyl, are recommended for use in the prehospital (i.e., field setting) for a hemorrhaging solider. However, it is unknown whether fentanyl impairs arterial blood pressure (BP) regulation, which would compromise hemorrhagic tolerance. Thus, the purpose of this study was to test the hypothesis that an analgesic dose of fentanyl impairs hemorrhagic tolerance in conscious humans. Twenty-eight volunteers (13 females) participated in this double-blinded, randomized, placebo-controlled trial. We conducted a presyncopal limited progressive lower body negative pressure test (LBNP; a validated model to simulate hemorrhage) following intravenous administration of fentanyl (75 µg) or placebo (saline). We quantified tolerance as a cumulative stress index (mmHg·min), which was compared between trials using a paired, two-tailed t test. We also compared muscle sympathetic nerve activity (MSNA; microneurography) and beat-to-beat BP (photoplethysmography) during the LBNP test using a mixed effects model [time (LBNP stage) × trial]. LBNP tolerance was not different between trials (fentanyl: 647 ± 386 vs. placebo: 676 ± 295 mmHg·min, P = 0.61, Cohen's d = 0.08). Increases in MSNA burst frequency (time: P < 0.01, trial: P = 0.29, interaction: P = 0.94) and reductions in mean BP (time: P < 0.01, trial: P = 0.50, interaction: P = 0.16) during LBNP were not different between trials. These data, the first to be obtained in conscious humans, demonstrate that administration of an analgesic dose of fentanyl does not alter MSNA or BP during profound central hypovolemia, nor does it impair tolerance to this simulated hemorrhagic insult.

Activation of the Organum Vasculosum of the Lamina Terminalis Produces a Sympathetically Mediated Hypertension.

Neurons in the organum vasculosum of the lamina terminalis (OVLT) sense extracellular NaCl and angiotensin II concentrations to regulate body fluid homeostasis and arterial blood pressure. Lesion of the anteroventral third ventricular region or OVLT attenuates multiple forms of neurogenic hypertension. However, the extent by which OVLT neurons directly regulate sympathetic nerve activity to produce hypertension is not known. Therefore, the present study tested this hypothesis by using a multi-faceted approach including optogenetics, single-unit and multifiber nerve recordings, and chemogenetics. First, optogenetic activation of OVLT neurons in conscious Sprague-Dawley rats (250-400 g) produced frequency-dependent increases in arterial blood pressure and heart rate. These responses were not altered by the vasopressin receptor antagonist (ß-mercapto-ß,ß-cyclopentamethylenepropionyl1,O-me-Tyr2,Arg8)-vasopressin but eliminated by the ganglionic blocker chlorisondamine. Second, optogenetic activation of OVLT neurons significantly elevated renal, splanchnic, and lumbar sympathetic nerve activity. Third, single-unit recordings revealed optogenetic activation of the OVLT significantly increased the discharge of bulbospinal, sympathetic neurons in the rostral ventrolateral medulla. Lastly, chronic chemogenetic activation of OVLT neurons for 7 days significantly increased 24-hour fluid intake and mean arterial blood pressure. When the 24-hour fluid intake was clamped at baseline intakes, chemogenetic activation of OVLT neurons still produced a similar increase in arterial blood pressure. Neurogenic pressor activity assessed by the ganglionic blocker chlorisondamine was greater at 7 days of OVLT activation versus baseline. Collectively, these findings indicate that acute or chronic activation of OVLT neurons produces a sympathetically mediated hypertension.

Impaired Kv7 channel activity in the central amygdala contributes to elevated sympathetic outflow in hypertension.

AIMS: Elevated sympathetic outflow is associated with primary hypertension. However, the mechanisms involved in heightened sympathetic outflow in hypertension are unclear. The central amygdala (CeA) regulates autonomic components of emotions through projections to the brainstem. The neuronal Kv7 channel is a non-inactivating voltage-dependent K+ channel encoded by KCNQ2/3 genes involved in stabilizing the neuronal membrane potential and regulating neuronal excitability. In this study, we investigated if altered Kv7 channel activity in the CeA contributes to heightened sympathetic outflow in hypertension. METHODS AND RESULTS: The mRNA and protein expression levels of Kv7.2/Kv7.3 in the CeA were significantly reduced in spontaneously hypertensive rats (SHRs) compared with Wistar-Kyoto (WKY) rats. Lowering blood pressure with coeliac ganglionectomy in SHRs did not alter Kv7.2 and Kv7.3 channel expression levels in the CeA. Fluospheres were injected into the rostral ventrolateral medulla (RVLM) to retrogradely label CeA neurons projecting to the RVLM (CeA-RVLM neurons). Kv7 channel currents recorded from CeA-RVLM neurons in brain slices were much smaller in SHRs than in WKY rats. Furthermore, the basal firing activity of CeA-RVLM neurons was significantly greater in SHRs than in WKY rats. Bath application of specific Kv7 channel blocker 10, 10-bis (4-pyridinylmethyl)-9(10H)-anthracnose (XE-991) increased the excitability of CeA-RVLM neurons in WKY rats, but not in SHRs. Microinjection of XE-991 into the CeA increased arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA), while microinjection of Kv7 channel opener QO-58 decreased ABP and RSNA, in anaesthetized WKY rats but not SHRs. CONCLUSIONS: Our findings suggest that diminished Kv7 channel activity in the CeA contributes to elevated sympathetic outflow in primary hypertension. This novel information provides new mechanistic insight into the pathogenesis of neurogenic hypertension.

Successful continuous positive airway pressure treatment reduces skin sympathetic nerve activity in patients with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with cardiovascular diseases and increased sympathetic tone. We previously demonstrated that patients with OSA have increased skin sympathetic nerve activity (SKNA). OBJECTIVE: The purpose of this study was to test the hypothesis that continuous positive airway pressure (CPAP) treatment reduces SKNA. METHODS: The electrocardiogram, SKNA, and polysomnographic recording were recorded simultaneously in 9 patients with OSA. After baseline recording, CPAP titration was performed and the pressure was adjusted gradually for the optimal treatment, defined by reducing the apnea-hypopnea index (AHI) to ≤5/h. Otherwise the treatment was considered suboptimal (AHI > 5/h). Fast Fourier transform analyses were performed to investigate the frequency spectrum of SKNA. RESULTS: There were very low frequency (VLF), low frequency (LF), and high frequency (HF) oscillations in SKNA. The HF oscillation matched the frequency of respiration. OSA episodes were more frequently associated with the VLF and LF than with the HF oscillations of SKNA. Compared with baseline, CPAP significantly decreased the arousal index and AHI and increased the minimal and mean oxyhemoglobin levels. Optimal treatment significantly increased the dominant frequency and reduced the heart rate, average SKNA (aSKNA), SKNA burst duration, and total burst area. The dominant frequency negatively correlated with aSKNA. CONCLUSION: VLF, LF, and HF oscillations are observed in human SKNA recordings. Among them, VLF and LF oscillations are associated with OSA while HF oscillations are associated with normal breathing. CPAP therapy reduces aSKNA and shifts the frequency of SKNA oscillation from VLF or LF to HF.

Central sympathetic nerve activation in subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a life-threatening condition, and although its two main complications-cerebral vasospasm (CVS)/delayed cerebral ischemia (DCI) and early brain injury (EBI)-have been widely studied, prognosis has not improved over time. The sympathetic nerve (SN) system is important for the regulation of cardiovascular function and is closely associated with cerebral vessels and the regulation of cerebral blood flow and cerebrovascular function; thus, excessive SN activation leads to a rapid breakdown of homeostasis in the brain. In the hyperacute phase, patients with SAH can experience possibly lethal conditions that are thought to be associated with SN activation (catecholamine surge)-related arrhythmia, neurogenic pulmonary edema, and irreversible injury to the hypothalamus and brainstem. Although the role of the SN system in SAH has long been investigated and considerable evidence has been collected, the exact pathophysiology remains undetermined, mainly because the relationships between the SN system and SAH are complicated, and many SN-modulating factors are involved. Thus, research concerning these relationships needs to explore novel findings that correlate with the relevant concepts based on past reliable evidence. Here, we explore the role of the central SN (CSN) system in SAH pathophysiology and provide a comprehensive review of the functional CSN network; brain injury in hyperacute phase involving the CSN system; pathophysiological overlap between the CSN system and the two major SAH complications, CVS/DCI and EBI; CSN-modulating factors; and SAH-related extracerebral organ injury. Further studies are warranted to determine the specific roles of the CSN system in the brain injuries associated with SAH.

Effects of ß-Blockers on the Sympathetic and Cytokines Storms in Covid-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causative virus in the development of coronavirus disease 2019 (Covid-19) pandemic. Respiratory manifestations of SARS-CoV-2 infection such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) leads to hypoxia, oxidative stress, and sympatho-activation and in severe cases leads to sympathetic storm (SS). On the other hand, an exaggerated immune response to the SARS-CoV-2 invasion may lead to uncontrolled release of pro-inflammatory cytokine development of cytokine storm (CS). In Covid-19, there are interactive interactions between CS and SS in the development of multi-organ failure (MOF). Interestingly, cutting the bridge between CS and SS by anti-inflammatory and anti-adrenergic agents may mitigate complications that are induced by SARS-CoV-2 infection in severely affected Covid-19 patients. The potential mechanisms of SS in Covid-19 are through different pathways such as hypoxia, which activate the central sympathetic center through carotid bodies chemosensory input and induced pro-inflammatory cytokines, which cross the blood-brain barrier and activation of the sympathetic center. ß2-receptors signaling pathway play a crucial role in the production of pro-inflammatory cytokines, macrophage activation, and B-cells for the production of antibodies with inflammation exacerbation. ß-blockers have anti-inflammatory effects through reduction release of pro-inflammatory cytokines with inhibition of NF-κB. In conclusion, ß-blockers interrupt this interaction through inhibition of several mediators of CS and SS with prevention development of neural-cytokine loop in SARS-CoV-2 infection. Evidence from this study triggers an idea for future prospective studies to confirm the potential role of ß-blockers in the management of Covid-19.