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Depressive symptoms are a source of significant morbidity in Parkinson's disease (PD). Electroconvulsive therapy (ECT) is a promising treatment for depression in PD (dPD); however, data remain limited, including data on optimal electrode placement. In this retrospective study, the investigators aimed to characterize the effects of bifrontal ECT for dPD on psychiatric and motor symptoms, as well as autonomic response.Clinical data were retrieved from a university-affiliated ECT service in Vancouver, British Columbia, for patients with dPD receiving bifrontal ECT between 2014 and 2018. Clinical Global Impression (depressive symptoms) and Unified Parkinson's Disease Rating Scale (motor symptoms) scores and cardiovascular measurements during ECT, as well as doses of dopaminergic medications, were recorded.Eight patients met criteria for inclusion. Six patients (75%) met response criteria for improvement of depressive symptoms, including 83% of patients who completed a full ECT course. Five patients went on to receive maintenance ECT, with only one patient relapsing by the 1-year follow-up (20%). For patients with motor scales reported, 60% showed a clinically significant improvement in motor symptoms. Among patients who completed ECT, a reduction in the median dopaminergic medication dose was also observed (-350 mg). Two patients discontinued ECT as a result of tolerability concerns. Participants demonstrated a relatively typical pattern of autonomic response to ECT, with low incidence of bradycardic events.The results provide preliminary evidence of the benefit of bifrontal ECT in dPD for both depressive and motor symptoms. The autonomic data suggest that most patients with dPD respond in a typical physiological manner to ECT stimulus; however, further investigation is needed.

Introduction: Autonomic dysfunction is an integral part of Parkinson disease (PD) complex and can be seen both in early and advanced stages. There is a paucity of medicines available to manage autonomic dysfunction in PD and this adds to the considerable morbidity associated with the illness.Areas covered: The pathophysiology and the available therapeutic options of autonomic dysfunction seen in PD are discussed in detail. The potential targets for novel regimens are reviewed and the available literature on the drugs emerging in management of autonomic dysfunction in PD is highlighted.Expert opinion: In the current scenario, there are several drugs that can be tried for constipation viz stool laxatives, prucalopride, prokinetic agents and a high fiber diet. Bladder dysfunction has been treated with β-agonists and with mirabegron, a selective β-3 agonist, the anticholinergic side effects are minimized, and the drug has been found to be effective. Orthostatic hypotension is managed with midodrine while droxidopa is a new drug with promising efficacy. Botulinum toxin works best for management of sialorrhea, but repeated injections are needed.

Negative social experiences influence both depression and cardiovascular dysfunction. Many individuals who experience negative mood states or cardiovascular conditions have limited social support. Therefore, investigation of drug treatments that may protect against the consequences of social stress will aid in designing effective treatment strategies. The current study used an animal model to evaluate the protective effect of sertraline administration on behavioral and cardiovascular consequences of social stress. Specifically, male prairie voles (Microtus ochrogaster), which are socially monogamous rodents that share several behavioral and physiological characteristics with humans, were isolated from a socially-bonded female partner, and treated with sertraline (16 mg/kg/day, ip) or vehicle during isolation. Unexpectedly, sertraline did not protect against depression-relevant behaviors, and it was associated with increased short- and long-term heart rate responses. However, sertraline administration improved heart rate variability recovery following a behavioral stressor, including increased parasympathetic regulation, and altered long-term neuronal activity in brain regions that modulate autonomic control and stress reactivity. These results indicate that sertraline may partially protect against the consequences of social stressors, and suggest a mechanism through which sertraline may beneficially influence neurobiological control of cardiac function.

BACKGROUND Firefighters' activities require constant adjustments of the cardiovascular system with cardiac autonomic function (CAF) playing an important role. Despite the crucial role of CAF in regulating stress response, little is known about firefighters' CAF. OBJECTIVE We aimed to characterize the resting on-duty and off-duty CAF of male firefighters, in association with cardiorespiratory fitness (CRF). METHODS We evaluated 38 firefighters in an on-duty rest condition and 26 firefighters in an off-duty laboratory-controlled condition. CAF was addressed by means of heart rate variability (HRV). We compared HRV measurements between CRF categories (

Background The impact of manual therapy interventions on the autonomic nervous system have been largely assessed, but with heterogeneous findings regarding the direction of these effects. We conducted an overview of systematic reviews to describe if there is a specific autonomic effect elicited by manual therapy interventions, its relation with the type of technique used and the body region where the intervention was applied. Methods We conducted an overview according to a publicly registered protocol. We searched the Cochrane Database of Systematic Reviews, MEDLINE, EPISTEMONIKOS and SCOPUS, from their inception to march 2021. We included systematic reviews for which the primary aim of the intervention was to assess the autonomic effect elicited by a manual therapy intervention in either healthy or symptomatic individuals. Two authors independently applied the selection criteria, assessed risk of bias from the included reviews and extracted data. An established model of generalisation guided the data analysis and interpretation. Results We included 12 reviews (5 rated as low risk of bias according the ROBIS tool). The findings showed that manual therapies may have an effect on both sympathetic and parasympathetic systems. However, the results from included reviews were inconsistent due to differences in their methodological rigour and how the effects were measured. The reviews with a lower risk of bias could not discriminate the effects depending on the body region to which the technique was applied. Conclusion The magnitude of the specific autonomic effect elicited by manual therapies and its clinical relevance is uncertain. We point out some specific recommendations in order to improve the quality and relevance of future research in this field.

Background and objective: This is the first study to investigate the effect of high-flow oxygen therapy, using a normobaric chamber on cognitive, biochemical (oxidative stress parameters and the level of neurotrophins), cardiovascular and autonomic functioning. Materials and methods: 17 healthy volunteers, eight males and nine females, with a mean age of 37.5 years, were examined. The experimental study involved ten two-hour exposures in a normobaric chamber with a total pressure of 1500 hPa, in air adjusted to 37% oxygen, 1.079% carbon dioxide and 0.44% hydrogen. Cognitive function was assessed by using Trail Making Test parts A, B and difference in results of these tests (TMT A, TMT B and TMT B-A); California Verbal Learning Test (CVLT); Digit symbol substitution test (DSST); and Digit Span (DS). Fatigue (Fatigue Severity Scale (FSS)), cardiovascular, autonomic and baroreceptor functioning (Task Force Monitor) and biochemical parameters were measured before and after intervention. Results: After 10 sessions in the normobaric chamber, significant decreases in weight, caused mainly by body fat % decrease (24.86 vs. 23.93%, p = 0.04 were observed. TMT part A and B results improved (p = 0.0007 and p = 0.001, respectively). In contrast, there was no statistically significant influence on TMT B-A. Moreover, decrease in the number of symbols left after a one-minute test in DSST was noted (p = 0.0001). The mean number of words correctly recalled in the CVLT Long Delay Free Recall test improved (p = 0.002), and a reduction in fatigue was observed (p = 0.001). Biochemical tests showed a reduction in levels of malondialdehyde (p < 0.001), with increased levels of Cu Zn superoxide dismutase (p < 0.001), Neurotrophin 4 (p = 0.0001) and brain-derived neurotrophic factor (p = 0.001). A significant increase in nitric oxide synthase 2 (Z = 2.29, p = 0.02) and Club cell secretory protein (p = 0.015) was also noted. Baroreceptor function was significantly improved after normobaric exposures (p = 0.003). Significant effect of normobaric exposures and BDNF in CVLT Long Delay Free Recall was noted. Conclusions: This study demonstrates that 10 exposures in a normobaric chamber have a positive impact on visual information and set-shifting processing speed and increase auditory-verbal short-term memory, neurotrophic levels and baroreceptor function. A response of the respiratory tract to oxidative stress was also noted. There is a need to rigorously examine the safety of normobaric therapy. Further studies should be carried out with physician examination, both pre and post treatment.

Purpose Electronic cigarettes (ECs) are the fastest growing tobacco product in the USA, and ECs, like tobacco cigarettes (TCs), have effects on the cardiovascular autonomic nervous system, with clinical implications. The purpose of this review was to collect and synthesize available studies that have investigated the autonomic cardiovascular effects of EC use in humans. Special attention is paid to the acute and chronic effects of ECs, the relative contributions of the nicotine versus non-nicotine constituents in EC emissions and the relative effects of ECs compared to TCs. Methods Using the methodology described in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement, we conducted a literature search of the Ovid PubMed and Embase databases on 6 December 2019 using keywords in titles and abstracts of published literature. Acute (minutes to hours) and chronic (days or longer) changes in heart rate variability (HRV), heart rate (HR) and blood pressure (BP) were used as estimates of cardiovascular autonomic effects. Results Nineteen studies were included in this systematic review, all of which used earlier generation EC devices. Acute EC vaping increased HR and BP less than acute TC smoking. Nicotine but not non-nicotine constituents in EC aerosol were responsible for the sympathoexcitatory effects. The results of chronic EC vaping studies were consistent with a chronic sympathoexcitatory effect as estimated by HRV, but this did not translate into chronic increases in HR or BP. Conclusions Electronic cigarettes are sympathoexcitatory. Cardiac sympathoexcitatory effects are less when vaping using the earlier generation ECs than when smoking TCs. Additional studies of the latest pod-like EC devices, which deliver nicotine similarly to a TC, are necessary.

Overactive bladder (OAB) coexists with depression in women. Here, we assessed the effects of a 1-week treatment with blebbistatin, a myosin II inhibitor, on changes in behavior and detrusor overactivity (DO) symptoms induced by a 6-week administration of 13-cis-retinoic acid (13-cis-RA), with the aid of the forced swim test (FST), spontaneous locomotor activity test, and in vivo cystometric investigations in female Wistar rats. 13-cis-RA-induced depressive-like behavior and DO symptoms were associated with increased corticotropin-releasing factor (CRF) level in the plasma, prefrontal cortex (PFC), hippocampus (Hp), Barrington’s nucleus (BN), and urinary bladder. Moreover, 13-cis-RA decreased brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in plasma, PFC, Hp, and BN, while it increased BDNF and NGF levels in urinary bladder. Blebbistatin exerted antidepressant-like effect and attenuated changes in the cystometric parameters as well as the central and peripheral levels of CRF, BDNF, and NGF that were induced by 13-cis-RA, while it did not affect urine production, mean, systolic or diastolic blood pressure, or heart rate. The results point to blebbistatin as a potential treatment option for OAB coexisting with depression.

Purpose The water drinking test (WDT) is currently used to temporarily elevate intraocular pressure (IOP) and predict peak IOP in glaucoma. This study investigates neurovascular changes associated with WDT in normal subjects. Methods The effect of WDT (1 L in 5 min) on IOP, mean brachial blood pressure, heart rate, and pattern electroretinogram was assessed within the next hour in 16 healthy subjects (mean age: 33.5±7.9 y). As a control, testing was repeated in the same subjects without WDT 1 week later. Results Compared with control, WDT resulted in significant peak changes of the following parameters compared with baseline: IOP: +1.7±1.8 mm Hg after 30', mean brachial blood pressure: +3.9±6.3 mm Hg after 15'; heart rate: -9.2±9.8 bpm after 15', pattern electroretinogram latency: +2.1±0.9 ms after 15'. Conclusions In addition to IOP elevation, WDT was associated with significant changes of hemodynamic parameters and retinal ganglion cell function in young healthy subjects. As these represent risk factors for glaucoma, their assessment upon WDT might increase its predictive power for glaucoma development.

Purpose The blood pressure ‘error signal’ represents the difference between an individual’s mean diastolic blood pressure and the diastolic blood pressure at which 50% of cardiac cycles are associated with a muscle sympathetic nerve activity burst (the ‘‘T50’’). In this study we evaluated whether T50 and the error signal related to the extent of change in blood pressure during autonomic blockade in young and older women, to study potential differences in sympathetic neural mechanisms regulating blood pressure before and after menopause. Methods We measured muscle sympathetic nerve activity and blood pressure in 12 premenopausal (25 ± 1 years) and 12 postmenopausal women (61 ± 2 years) before and during complete autonomic blockade with trimethaphan camsylate. Results At baseline, young women had a negative error signal (-8 ± 1 versus 2 ± 1 mmHg, p\0.001; respectively) and lower muscle sympathetic nerve activity (15 ± 1 versus 33 ± 3 bursts/min, p\0.001; respectively) than older women. The change in diastolic blood pressure after autonomic blockade was associated with baseline T50 in older women (r = -0.725, p = 0.008) but not in young women (r = -0.337, p = 0.29). Women with the most negative error signal had the lowest muscle sympathetic nerve activity in both groups (young: r = 0.886, p\0.001; older: r = 0.870, p\0.001). Conclusions Our results suggest that there are differences in baroreflex control of muscle sympathetic nerve activity between young and older women, using the T50 and error signal analysis. This approach provides further information on autonomic control of blood pressure in women.

Background This study assessed the effect of blockading neural transmission in the ganglionated plexi by injecting lidocaine into fat pads in the vagal nerve stimulation canine model and patients with persistent atrial fibrillation (AF). Methods and Results An efficacy test of lidocaine injection was performed in 7 canines. During vagal nerve stimulation, AF was sustained for >5 minutes. The lidocaine was injected into ganglionated plexi during sinus rhythm and reinduction of AF was attempted. Six patients with persistent AF were studied at open heart surgery. Lidocaine was injected into ganglionated plexi. Atrial electrograms were recorded from 96 epicardial electrodes covering Bachmann's bundle and atrial appendages. In the canine vagal nerve stimulation AF model, AF was not inducible in 4 of 7 after lidocaine injection. In patients with persistent AF, during baseline AF, there was a left atrium (LA)‐to‐right atrium (RA) frequency gradient (LA, mean cycle length [CL] 175±17 ms; RA, mean CL 192±17 ms; P, See Editorial Hanna et al

Background and objectives: As a result of ergogenic properties, caffeine has been increasingly taken prior to physical exercise, yet its effects on post-exercise recovery, considering the differences in the cardiorespiratory capacity of the individuals, has not yet been studied or fully elucidated. Optimizing the post-exercise recovery can convey advantages to physical activity practitioners. We evaluated the acute effects of caffeine on heart rate (HR) autonomic control recovery following moderate aerobic exercise in males with different cardiorespiratory capacities. Materials and Methods: We split young adult men into two groups based on their various oxygen consumption peaks (VO2 peak): (1) Higher VO2 (HO): Sixteen volunteers, peak VO2 &gt, 42.46 mL/kg/min and (2) Low VO2 (LO): Sixteen individuals, VO2 &lt, 42.46 mL/kg/min). The volunteers were submitted to placebo and caffeine protocols, which entailed 300 mg of caffeine or placebo (starch) in capsules, followed by 15 min of rest, 30 min of moderate exercise on a treadmill at 60% of the VO2 peak, followed by 60 min of supine recovery. Heart rate variability (HRV) indexes in the time and frequency domains were examined. Results: Effect of time for RMSSD (square root of the average of the square of the differences between normal adjacent RR intervals) and SDNN (standard deviation of all normal RR intervals recorded in a time interval) was achieved (p &lt, 0.001). Significant adjustments were observed (rest versus recovery) at the 0 to 5th min of recovery from exercise for the LO during the placebo protocol and at the 5th at 10th min of recovery for the caffeine protocol. For the HO in both procedures we found significant alterations only at the 0 to 5th min of recovery. Conclusion: Caffeine delayed parasympathetic recovery from exercise in individuals with lower cardiorespiratory capacity.

Several review articles have been published on the neurobehavioral actions of acetaldehyde and other ethanol metabolites as well as in major alcohol-related disorders such as cancer and liver and lung disease. However, very few reviews dealt with the role of alcohol metabolism in the adverse cardiac and autonomic effects of alcohol and their potential underlying mechanisms, particularly in vulnerable populations. In this chapter, following a brief overview of the dose-related favorable and adverse cardiovascular effects of alcohol, we discuss the role of ethanol metabolism in its adverse effects in the brain stem and heart. Notably, current knowledge dismisses a major role for acetaldehyde in the adverse autonomic and cardiac effects of alcohol because of its low tissue level in vivo. Contrary to these findings in men and male rodents, women and hypertensive individuals are more sensitive to the adverse cardiac effects of similar amounts of alcohol. To understand this discrepancy, we discuss the autonomic and cardiac effects of alcohol and its metabolite acetaldehyde in a model of hypertension, the spontaneously hypertensive rat (SHR) and in female rats. We present evidence that enhanced catalase activity, which contributes to cardioprotection in hypertension (compensatory) and in the presence of estrogen (inherent), becomes detrimental due to catalase catalysis of alcohol metabolism to acetaldehyde. Noteworthy, studies in SHRs and in estrogen deprived or replete normotensive rats implicate acetaldehyde in triggering oxidative stress in autonomic nuclei and the heart via: (i) the Akt/extracellular signal-regulated kinases (ERK)/nitric oxide synthase (NOS) cascade, and (ii) estrogen receptor-alpha (ERα) mediation of the higher catalase activity, which generates higher ethanol-derived acetaldehyde in female heart. The latter is supported by the ability of ERα blockade or catalase inhibition to attenuate alcohol-evoked myocardial oxidative stress and dysfunction. More mechanistic studies are needed to further understand the mechanisms of this public health problem.

Fingolimod exerts its therapeutic effect in multiple sclerosis by modulating sphingosine-1P receptors which are expressed in the heart mediating fingolimod first dose effects. Understanding potential interactions of baseline characteristics and autonomic profile with fingolimod first dose effects may add novel safety information and help explain cases requiring extension of the 6-hour ECG monitoring period. We aimed at characterizing the patient population treated with the first dose of fingolimod in clinical practice in an observational, multicenter, prospective 6-hours (up to 24) study. ECG was recorded for 15 min before first fingolimod administration and for 6 h after. Heart rate (HR) and HR variability in the frequency domain were derived from ECG traces. Out of the 625 enrolled patients, 580 (92.8%) were discharged at the sixth hour after fingolimod first dose; 45 (7.2%) required monitoring extension. Data confirm the well characterized cardiovascular fingolimod profile upon treatment initiation. Ten (1.6%) patients showed an atrioventricular block, all asymptomatic and self-resolving. Normalized spectral power in the High Frequency band (marking vagal modulation) and previous annualized relapse rate were independently correlated with the probability of undergoing extended monitoring. Our results could provide useful information for the stratification and individualized monitoring of MS patients prescribed with fingolimod.

This article reviews the case series reported from several countries describing patients with suspected severe side effects to the HPV vaccines. The described symptom clusters are remarkably similar and include disabling fatigue, headache, widespread pain, fainting, gastrointestinal dysmotility, limb weakness, memory impairment episodes of altered awareness, and abnormal movements. This constellation of symptoms and signs has been labeled with different diagnoses such as complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), small fiber neuropathy (SFN), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), or fibromyalgia. It is known that autoimmunity and autoantibodies are present in a subset of patients with CRPS, POTS, SFN, ME/CFS, and fibromyalgia. This article proposes that vaccine-triggered, immune-mediated autonomic dysfunction could lead to the development of de novo post-HPV vaccination syndrome possibly in genetically susceptible individuals. Being cognizant that a temporal relationship between vaccination and symptom onset does not necessarily equate to causality, mounting evidence of case series calls for well-designed case-control studies to determine the prevalence and possible causation between these symptom clusters and HPV vaccines. Since personalized medicine is gaining momentum, the use of adversomics and pharmacogenetics may eventually help identify individuals who are predisposed to HPV vaccine adverse events.

Postural tachycardia syndrome (POTS) is a disorder characterized by the presence of orthostatic symptoms (including lightheadedness, palpitations, nausea, dyspnea, and tremulousness) as well as excessive upright tachycardia. POTS predominantly affects women of childbearing age. Treating POTS involves a multi-faceted approach using non-pharmacological and pharmacological interventions. There are no pharmacological treatments that are currently United States Food and Drug Administration (FDA) approved for POTS due to lack of randomized controlled trials. Yet, several medications can improve POTS symptoms and are supported by small prospective studies or retrospective case series. Drugs that are most commonly used for POTS target the following mechanisms 1) blood volume expansion, 2) reduction of heart rate, 3) peripheral vasoconstriction and 4) sympatholysis. Pharmacological approaches can also be used to target specific symptoms including "brain fog," fatigue, sleep, and depression. This review outlines pharmacological approaches for treating POTS and summarizes evidence supporting each treatment approach.

Background Kuan-Sin-Yin (KSY) is a traditional Chinese medicine (TCM) decoction, which has been shown to have cytostatic effects on cancer cells and involved in the TCM theory of promoting yin-yang balance.Sonce many cancer patients suffer from autonomic dysfunction (AD), which correspond to yin-yang imbalance in TCM. The aim of this study is to evaluate the possible effect of KSY in metastatic colon cancer (mCRC) patients with AD. Methods We conducted a single-group experiment. Total 52 qualified patients were enrolled. Participants took the KSY daily for 2 weeks. The primary outcome was KSY efficacy as reflected in the heart rate variability (HRV) and electrical conductivity (µA) over 12 meridian points. Autonomic function was examined before and after the KSY intervention. The vagal and sympathetic tone were recorded by HRV; 12 meridian energies were measured using a meridian energy analysis device. Secondary outcomes were cancer-related symptoms and patient quality of life (QoL). Results The results showed that the KSY intervention improved AD via increasing the vagal tone (HF: P = .041), but not the sympathetic tone (LF: P = .154); total autonomic activity was significantly enhanced (HRV activity: P = .013). Intriguingly, energy increased more over the yin meridian (P = .010) than over the yang meridian (P = .015). Cancer-related symptoms and QoL were significantly improved (P < .05). Conclusion The safety and effectiveness of KSY in improving AD in mCRC patients are through regulating the vagal-sympathetic dynamic balance, which correspond to the TCM yin-yang concept of energy.

Multiple chemical sensitivity (MCS) is a prevalent medically unexplained symptom characterized by symptom reactions to everyday chemical exposure below hygienic thresholds. The aim of this study was to investigate the expressions of hyper-reactivity in MCS during whole-body exposure to low concentrations of the odorant n-butanol. We exposed 18 participants with MCS and 18 non-ill controls to a low concentration of the odorant n-butanol using an exposure chamber. The first 10 min constituted blank exposure, after which the n-butanol concentration increased and reached a plateau at 11.5 mg/m3. MCS participants, compared with controls, reported greater perceived odor intensities, more unpleasantness to the exposure and increasing symptoms over time. MCS participants also expressed higher pulse rate and lower pulse rate variability than controls did. No group differences were found for breathing rate or tonic electrodermal activity responses. We conclude that MCS sufferers differ from healthy controls in terms of autonomic responses, symptoms and chemosensory perception during chemical exposure.

Single centre, single ascending dose study. To compare the pharmacokinetics and assess the safety of capromorelin, a compound that has potential to treat constipation following spinal cord injury (SCI), in groups of able-bodied and SCI volunteers. Local population from Victoria, Australia. Following initial screening and baseline blood collections, participants received ascending oral doses (20, 50 and then 100 mg at least 1-week apart) of capromorelin after pre-dose blood collection, followed by blood collections over the following 12 h for pharmacokinetic analysis and 1-week and 4-week follow-up blood collections for safety evaluations. Blood pressure and heart rate were monitored. No serious adverse events were recorded following any dose in either the able-bodied group or the SCI group. There were no abnormal blood pressure or heart rate changes. Minor adverse events resolved quickly without the need for treatment. Pharmacokinetic behaviour was broadly similar between groups, with both exhibiting dose-dependent increases in Cmax and AUC0–∞. The SCI participants showed greater variance in pharmacokinetic parameters and had a slightly delayed Tmax and half-life. Capromorelin at the doses tested was safe and well tolerated in both SCI and able-bodied participants and also showed similar pharmacokinetics with dose-dependent increases in concentration and drug exposure. Support for the study was provided by the Victorian State Government Transport Accident Commission.

Fil: Pérez Lloret, Santiago. Universidad de Toulouse III. Hospital Universitario. Departamento de Farmacología Clínica y Neurociencia; Francia Fil: Pérez Lloret, Santiago. Pontificia Universidad Católica Argentina. Laboratorio de Clínica Farmacológica y Epidemiología; Argentina Fil: Rey, Verónica. Universidad de Toulouse III. Hospital Universitario. Departamento de Farmacología Clínica y Neurociencia; Francia Fil: Rey, Verónica. Pontificia Universidad Católica Argentina. Laboratorio de Clínica Farmacológica y Epidemiología; Argentina Fil: Pavy-Le Traon, Anne. Universidad de Toulouse III. Hospital Universitario. Departamento de Farmacología Clínica y Neurociencia; Francia Fil: Rascol, Olivier. Universidad de Toulouse III. Hospital Universitario. Departamento de Farmacología Clínica y Neurociencia; Francia Abstract: Autonomic dysfunction, including orthostatic hypotension (OH), sialorrhea, sexual dysfunction, urinary dysfunction and constipation is a common feature of Parkinson’s disease (PD). Even though its treatment has been recognized as a major unmet need in PD, there is a paucity of clinical trials to assess their treatment. Areas covered: Evidence about the efficacy and safety of available treatments for autonomic dysfunction is summarized. Potential targets for upcoming therapies are then discussed in light of what is currently known about the physiopathology of each disorder in PD. Proof-of-concept trials and circumstantial evidence about treatments for autonomic dysfunction as well as upcoming clinical trials are discussed. Finally, critical aspects of clinical trials design are considered. Expert opinion: Botulinum toxin (BTX) or glycopyrrolate might be used for sialorrhea whereas macrogol could be useful in constipation. There is preliminary evidence suggesting that fludrocortisone, domperidone, droxidopa or fipamezole may be effective for the treatment of OH. Tropicamide, clonidine or radiotherapy are under development for sialorrhea. Sildenafil may be effective for the treatment of erectile dysfunction; BTX or behavioral therapy for urinary incontinence and lubiprostone and probiotics for constipation. Sound clinical trials are needed in order to allow firm evidence-based recommendations about these treatments

Abstract —Flow-mediated dilatation (FMD) of conduit arteries is dependent on an intact endothelium, although the mechanisms are not fully understood. Using high-resolution ultrasound, we examined the role of endothelial mediators in radial artery dilatation in response to transient (short period of reactive hyperemia) and sustained (prolonged period of reactive hyperemia, hand warming, or an incremental infusion of acetylcholine into the distal radial artery) hyperemia. After short episodes of reactive hyperemia, FMD was abolished by local infusion of the nitric oxide synthesis inhibitor N G monomethyl-L-arginine (5.3±1.2% versus 0.7±0.7%, P

a b s t r a c t Objective: To evaluate the role of the chemical burns caused by hydroxide ion in the fatal effects of tetramethylammonium ion (TMA) in dermal exposure to tetramethylammonium hydroxide (TMAH), we conducted a rat study consisting of two-step treatments with dermal exposure to NaOH and tetramethylammonium chloride (TMACl). Methods: In the first step, NaOH or saline was administered in the gauze on the shaved skin for 5 min, and in the second step, TMAH, TMACl, or saline was administered in the same way. The mean blood pressure (MBP), heart rate (HR), and survival in rats were compared among seven groups. Results: Dermal exposure to saline and then 2.75 M TMACl introduced limited and temporary non-fatal effects. Exposure to 2.75 M NaOH and then saline had almost no effects and caused no deaths. Treatments with more concentrated NaOH or TMACl resulted in suppressions of MBP and HR, and deaths were observed after the dosing of TMACl. Conclusion: The toxicity of dermal exposure to TMA alone is limited, but fatal effects can be introduced by pre-treatment with hydroxide ion. Therefore, the chemical burn caused by hydroxide ion plays an essential role in the toxicity, implicating that effective neutralizing may help decreasing the fatality rate.

We studied the effect of losartan on baroreflex sensitivity (BRS) and heart rate variability (HRV) of adult Wistar rats during acute and chronic inhibition of nitric oxide synthesis by NG-nitro-L-arginine methyl ester (L-NAME). Chronic L-NAME administration (50 mg/kg per day for 7 days, orally through gavage) increased mean arterial pressure (MAP), heart rate but significantly decreased BRS. In addition, a significant fall of standard deviation of normal RR intervals, total spectral power, high frequency spectral power and a rise of low frequency to high frequency (LF: HF) ratio was seen. Acute L-NAME administration (30 mg/kg, i.v. bolus dose) also raised MAP and impaired HRV but it was associated with augmented BRS for bradycardia reflex. Losartan treatment (10 mg/kg, i.v.) in both acute and chronic L-NAME treated rats, decreased MAP but the difference was not significant. On the other hand, losartan administration normalized depressed BRS for bradycardia reflex and significantly reduced LF to HF ratio in chronic L-NAME treated rats. But this improvement was not observed in acute L-NAME group. These results indicate importance of mechanisms other than renin-angiotensin system in the pressor response of both acute as well as chronic L-NAME. However, autonomic dysregulation especially following chronic L-NAME appears to be partly angiotensin dependent.

This study reviewed Kentucky Medicaid claims data for children with autism spectrum disorders to determine psychotropic drug (PTD) use in this population. Children with autism spectrum disorders (ICD-9 code 299.XX) in 3 different age-groups from 2005 to 2008 were identified; PTD use was defined as at least 1 prescription per year. PTD use in all age ranges was higher than in previously reported studies. High PTD use in children between 1 and 5 years is particularly of concern and may reflect perceived inadequacies of comprehensive educational/behavioral services for these children.

RATIONALE: Pupillometry can be used to characterize autonomic drug effects. OBJECTIVE: This study was conducted to determine the autonomic effects of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), administered alone and after pretreatment with reboxetine, duloxetine, clonidine, carvedilol, and doxazosin, on pupillary function. METHODS: Infrared pupillometry was performed in five placebo-controlled randomized studies. Each study included 16 healthy subjects (eight men, eight women) who received placebo-MDMA (125 mg), placebo-placebo, pretreatment-placebo, or pretreatment-MDMA using a crossover design. RESULTS: MDMA produced mydriasis, prolonged the latency, reduced the response to light, and shortened the recovery time. The impaired reflex response was associated with subjective, cardiostimulant, and hyperthermic drug effects and returned to normal within 6 h after MDMA administration when plasma MDMA levels were still high. Mydriasis was associated with changes in plasma MDMA concentration over time and longer-lasting. Both reboxetine and duloxetine interacted with the effects of MDMA on pupillary function. Clonidine did not significantly reduce the mydriatic effects of MDMA, although it produced miosis when administered alone. Carvedilol and doxazosin did not alter the effects of MDMA on pupillary function. CONCLUSIONS: The MDMA-induced prolongation of the latency to and reduction of light-induced miosis indicate indirect central parasympathetic inhibition, and the faster recovery time reflects an increased sympathomimetic action. Both norepinephrine and serotonin mediate the effects of MDMA on pupillary function. Although mydriasis is lasting and mirrors the plasma concentration-time curve of MDMA, the impairment in the reaction to light is associated with the subjective and other autonomic effects of MDMA and exhibits acute tolerance.

Background: Ozone (O3) is a well-documented respiratory oxidant, but increasing epidemiological evidence points to extrapulmonary effects, including positive associations between ambient O3 concentrations and cardiovascular morbidity and mortality. Objective: With preliminary reports linking O3 exposure with changes in heart rate (HR), we investigated the hypothesis that a single inhalation exposure to O3 will cause concentration-dependent autonomic modulation of cardiac function in rats. Methods: Rats implanted with telemeters to monitor HR and cardiac electrophysiology [electrocardiography (ECG)] were exposed once by whole-body inhalation for 4 hr to 0.2 or 0.8 ppm O3 or filtered air. A separate cohort was tested for vulnerability to aconitine-induced arrhythmia 24 hr after exposure. Results: Exposure to 0.8 ppm O3 caused bradycardia, PR prolongation, ST depression, and substantial increases in atrial premature beats, sinoatrial block, and atrioventricular block, accompanied by concurrent increases in several HR variability parameters that were suggestive of increased parasympathetic tone. Low-O3 exposure failed to elicit any overt changes in autonomic tone, heart rhythm, or ECG. However, both 0.2 and 0.8 ppm O3 increased sensitivity to aconitine-induced arrhythmia formation, suggesting a latent O3-induced alteration in myocardial excitability. Conclusions: O3 exposure causes several alterations in cardiac electrophysiology that are likely mediated by modulation of autonomic input to the heart. Moreover, exposure to low O3 concentrations may cause subclinical effects that manifest only when triggered by a stressor, suggesting that the adverse health effects of ambient levels of air pollutants may be insidious and potentially underestimated.

Autonomic nervous system dysfunction may manifest with a variety of symptoms, with orthostatic intolerance (including orthostatic hypotension or tachycardia) and sweating abnormalities (increased or decreased sweating) being common problems requiring medical evaluation and treatment. Determination of the underlying diagnosis for these symptoms is critical in terms of classification of the disorder and its prognosis. Recent advances in evaluation of patients with these conditions and treatment modalities have enabled physicians to improve overall management of patients with these disorders. These advances include testing for ganglionic acetylcholine receptor antibody in patients with suspected autoimmune autonomic neuropathy and use of pyridostigmine for treatment of patients with orthostatic hypotension or tachycardia.

Background Murraya paniculata is traditionally used for management of gut, air way and cardiovascular disorders. The study was conducted for provision of pharmacological rationalization for folkloric uses of Murraya paniculata in gut, air way and cardiovascular problems. Methods Aqueous-ethanolic extract of Mp.Cr was tested using in vitro techniques on isolated tissue of rabbit (jejunum, trachea and aorta) to detect the possible presence of spasmolytic activity. The responses of tissues were recorded using isotonic transducers coupled with PowerLab data acquisition system. Results Application of the extract of Mp.Cr relaxed spontaneous and high K+ (80mM)-induced contraction in rabbit jejunum preparation. Because it shifted the CRCs (Calcium response curve) towards the right side so the possible blockade was of calcium channel similar to verapamil. In rabbit trachea, extract of Mp.Cr produced relaxation of carbachol and high K+ induced contractions. When plant extract was checked further on isolated aorta for its possible vasodilator effect, it caused relaxation of phenylephrine and high K+-induced spastic contractions at different doses. Conclusion These results indicate that Murraya paniculata shows anti-spasmodic, bronchodilator and vasodilator activity facilitated through Ca++ antagonist mechanisms.

One characteristic of the most common types of glaucoma is increased intraocular pressure (IOP), which has a damaging effect on optic nerve axons, leading to progressive loss of retinal ganglion cells. Therefore, ocular hypotensive drugs are the mainstay of pharmacological therapy for glaucoma. This review article, which is the second part of a two-part series, is dedicated to autonomic drugs which lower IOP by decreasing the aqueous humour production. These agents are subdivided into two groups: β-adrenergic antagonists and selective α2-adrenergic agonists. This paper summarizes the current state of knowledge on the mechanism of action of these drugs and their effect on IOP in dogs and cats. Moreover, it discusses their possible undesirable side effects of these medications and presents the current ideas about their role and position in the medical management of glaucoma in small animals.

One characteristic of the most common types of glaucoma is increased intraocular pressure (IOP), which has a damaging effect on optic nerve axons, leading to progressive loss of retinal ganglion cells. Therefore, ocular hypotensive drugs are the mainstay of pharmacological therapy for glaucoma. This review article, which is the first part of a two-part series, is dedicated to autonomic drugs which lower IOP by increasing the outflow of aqueous humour. These agents are subdivided into two groups: (a) drugs that lower IOP by increasing the trabecular outflow and the uveoscleral outflow (i.e. nonselective adrenergic agonists), and (b) medications that lower IOP by opening of the drainage angle and by increasing the conventional outflow via the trabecular outflow (i.e. parasympathomimetics). This paper summarizes the current state of knowledge on the mechanism of action of these drugs and their effect on IOP in dogs and cats. Moreover, it discusses possible undesirable side effects of these medications and presents the current ideas about their role and position in the medical management of glaucoma in small animals

Patients with autonomic failure are characterized by orthostatic hypotension, supine hypertension, high blood pressure variability, blunted heart rate variability, and often have a "non-dipping" or "reverse dipping" pattern on 24-h ambulatory blood pressure monitoring. These alterations may lead to cardiovascular and cerebrovascular changes, similar to the target organ damage found in hypertension. Often patients with autonomic failure are on treatment with anti-hypotensive drugs, which may worsen supine hypertension. The aim of this review is to summarize the evidence for cardiac, vascular, renal, and cerebrovascular damage in patients with autonomic failure.

The tachykinins and their receptors are strategically distributed within the gut wall, spinal cord, and central nervous system to be potential targets of therapeutic agents for gastrointestinal motility disorders. However, the development of effective tachykinin receptor agonists or antagonists to treat these disorders has had very limited success so far. This is, in part, due to the complex and multilevel of regulation of gastrointestinal motility function and the challenges faced in targeting the specific type of gut contraction to normalize function in disease state.

Purpose: We examined the effects of saw palmetto extract (SPE) on the rat micturition reflex and on autonomic receptors in the lower urinary tract. Materials and Methods: The effect of SPE was examined on cystometrograms of anesthetized rats induced by intravesical infusion of saline or 0.1% acetic acid. SHR/NDmc-cp (cp/cp) rats received repeat oral administration of SPE and nighttime urodynamic function was determined. The autonomic receptor binding activity of SPE in the rat bladder and prostate was examined by radioligand binding assay. Results: Intraduodenal administration of SPE (60 mg/kg) in anesthetized rat cystometry caused a significant increase in the micturition interval, micturition volume and bladder capacity during intravesical saline infusion. Also, similar administration of SPE at doses of 12 and 20 mg/kg significantly reversed the shortened micturition interval as well as the decreased micturition volume and bladder capacity due to 0.1% acetic acid infusion in a dose dependent manner. In conscious SHR/NDmc-cp (cp/cp) rats repeat oral administration of SPE (6 mg/kg daily) constantly increased the micturition interval and concomitantly decreased voiding frequency. SPE inhibited specific binding of [ 3 H]NMS ([N-methyl- 3 H]scopolamine methyl chloride) (bladder) and [ 3 H]prazosin (prostate) with IC 50 values of 46.1 and 183 μg/ml, respectively. Conclusions: SPE significantly alleviates urodynamic symptoms in hyperactive rat bladders by increasing bladder capacity and subsequently prolonging the micturition interval. Our data may support the clinical efficacy of SPE for the treatment of lower urinary tract symptoms.

Chondroitin sulfate proteoglycans are synthesized and deposited in the spinal cord following injury. These proteoglycans may restrict regeneration and plasticity and contribute to the limited recovery seen after an injury. Chondroitinase, a bacterial enzyme that catalyzes the hydrolysis of the chondroitin chains on proteoglycans, has been shown to improve motor and sensory function following partial transection lesions of the spinal cord. To assess the effects of chondroitinase in a clinically relevant model of spinal cord injury, 128 female Long-Evans rats received either a severe, moderate, or mild contusion injury at the vertebral level T9/T10 with a forceps model and were treated for 2 weeks with chondroitinase ABCI at 0.06 Units per dose, penicillinase, or vehicle control via an intrathecal catheter placed near the injury. Motor behavior was measured by open-field testing of locomotion and bladder function monitored by measuring daily residual urine volumes. Animals treated with chondroitinase showed significant improvements in open-field locomotor activity as measured by the Basso, Beattie and Bresnahan scoring system after both severe and moderate SCI (p

The parasympathetic and sympathetic divisions of the autonomic nervous system are involved in homeostatic control of a wide variety of ocular functions, including accommodation, pupillomotor control, lacrimation, eyelid position, and aqueous humor production. Familiarity with the functional anatomy of the autonomic nervous system is paramount to the understanding and application of the large number of autonomic drugs used in veterinary ophthalmology. The cholinergic and adrenergic agents discussed in this article are commonly employed to facilitate routine ophthalmic examination, in the diagnosis of autonomic dysfunction, and in the treatment of a variety of ocular diseases.

Prolonged nearwork has long been associated with myopia development, however, there is no well described linking mechanism. One theory suggests that if accommodation accuracy during nearwork is not maintained, the defocused retinal image leads to myopia development. Here we review the findings of research aimed at determining whether the autonomic inputs to the ciliary smooth muscle are involved in this type of environmental myopia. We examine whether an autonomic imbalance could be a precursor to axial elongation and the resulting myopia. Accommodation responses, such as tonic accommodation and nearwork-induced accommodative adaptation, as a function of refractive error, are described in relation to an autonomic imbalance model. The collective results of this research point to anomalous accommodation responses, possibly as a result of underlying anomalous autonomic input to the ciliary muscle, being involved in myopia development and progression.

The effect of jasmine tea odor on the autonomic nervous system was investigated by a power spectral analysis of the heart rate variability. We assigned eight volunteers to two groups with either a predilection for or antipathy toward the jasmine tea odor. We tested both high- and low-intensity jasmine tea odors. The low-intensity odor was produced by diluting 20-fold the jasmine tea used for the high-intensity odor test. The low-intensity odor produced an increase in parasympathetic nervous activity in both the predilection and antipathy groups. The high-intensity odor produced an increase in parasympathetic nervous activity in the predilection group, but an increase in sympathetic nervous activity in the antipathy group. The odor of Chinese green tea, a basic ingredient of jasmine tea, produced no effects similar to those of the jasmine tea odor. These results suggest that the jasmine tea odor activated the parasympathetic nerve, whereas the higher-intensity odor activated the sympathetic nerve in those subjects who disliked the odor.

We have previously demonstrated that a number of rats fed a moderately high-fat diet (MHFD) become obese and hypertensive and had compromised sympathoinhibitory and vasodilator responses to the gut hormones cholecystokinin (CCK) and gastric leptin. This has implications for increased resistance in vascular beds that attract a large proportion of cardiac output after a meal and may be an important mechanism underlying the development of hypertension in obesity in which food consumption is greatly increased. The aim of this study was to determine whether swapping a MHFD for a low-fat diet (LFD) would induce weight loss in obese animals, reverse the signs of hypertension and restore sympathoinhibitory reflexes. Male Sprague-Dawley rats were placed on a LFD (controls; n = 8) or a MHFD (n = 24) for 11 weeks after which the latter displayed either an obesity-prone (OP) or obesity-resistant (OR) phenotype. All animals were fed a LFD for a further 6 weeks after which they were anaesthetised with isoflurane and artificially ventilated for evaluation of resting arterial pressure (AP) and renal sympathetic nerve responses to CCK (0.1-4 μg/kg) and leptin (15 μg/kg). Weight gain in OP animals remained higher than OR or controls following diet switch (P0.05 for both). Resting AP was not significantly different between OP (103 ± 4 mmHg), OR (102 ± 3 mmHg) or control (104 ± 3 mmHg) animals and sympathoinhibitory responses to CCK or leptin were not different between the groups (P0.05). These results demonstrate that diet modification can have beneficial effects on sympathetic function and restore normotension without the need for weight reduction.

The venous system contains approximately 70% of the blood volume. The sympathetic nervous system is by far the most important vasopressor system in the control of venous capacitance. The baroreflex system responds to acute hypotension by concurrently increasing sympathetic tone to resistance, as well as capacitance vessels, to increase blood pressure and venous return, respectively. Studies in experimental animals have shown that interference of sympathetic activity by an alpha1- or alpha2-adrenoceptor antagonist or a ganglionic blocker reduces mean circulatory filling pressure and venous resistance and increases unstressed volume. An alpha1- or alpha2-adrenoceptor agonist, on the other hand, increases mean circulatory filling pressure and venous resistance and reduces unstressed volume. In humans, drugs that interfere with sympathetic tone can cause the pooling of blood in limb as well as splanchnic veins; the reduction of cardiac output; and orthostatic intolerance. Other perturbations that can cause postural hypotension include autonomic failure, as in dysautonomia, diabetes mellitus, and vasovagal syncope; increased venous compliance, as in hemodialysis; and reduced blood volume, as with space flight and prolonged bed rest. Several alpha-adrenoceptor agonists are used to increase venous return in orthostatic intolerance; however, there is insufficient data to show that these drugs are more efficacious than placebo. Clearly, more basic science and clinical studies are needed to increase our knowledge and understanding of the venous system.

An international multicenter study entitled Collaborative Study on Drug Use in Pregnancy (DUP) was initiated in 1987 by the Mario Negri Institute (Milano) and co-sponsored by the WHO Regional Office for Europe (Copenhagen). The study covered the use of medicines during pregnancy, labour and postpartum period. The Novi Sad centre contributed with 296 questionnaires. The aim of the study was to evaluate the pharmacotherapy by means of comparison, to identify problems in a particular settings and to plan actions toward improvement. The prescribing of some medicines in the Novi Sad center was found to be at the extreme, being among the lowest in the use of iron preparations during pregnancy and among the highest in the use of ergot alkaloids in the postpartum period. Educational efforts have been made to change this practice after the conclusion of the study in 1989. Ten years later, in 1999, the same questionnaire was applied to 100 women in the postpartum period in the same nursery, the Department of Obstetrics and Gynecology in Novi Sad. The results have shown a distinct improvement with the increase of iron prescribing during pregnancy and almost complete abandonment of postpartum use of ergot alkaloids. In the second study period some other inconsistencies with accepted therapeutical principles were identified. For example, although the use of analgesics fell from 22.3 to 8%, the selection changed towards the high use of metamizole (noraminophenazone) and no use of paracetamol (acetaminophen). It was concluded that international pharmacoepidemiological studies such as DUP, could substantially contribute to the improvement of pharmacotherapy if followed by appropriate actions in changing the prescribing behaviour of the physicians and information directed to the target population. Copyright © 2001 John Wiley & Sons, Ltd.

Objective: The objective of this study was to investigate the relationship between acute decreases in right ventricular volume during Valsalva strain (with resultant changes in autonomic neural tone) and measures of local endocardial repolarization time independent of heart rate and autonomic neural tone. Methods: Patients implanted with a stimulus to T wave (Stim-T) sensing pacemaker specially adapted to output a validated measure of beat to beat local repolarization ( n =9) performed Valsalva manoeuvers (40 mmHg for 15 s) while paced at a cycle length of 500 ms. Stim-T intervals were measured before and after autonomic blockade (Block: 0.03 mg/kg i.v. atropine±0.15 mg/kg propranolol). Right ventricular end diastolic volume was estimated by simultaneous 2D-echocardiography. Results: Without autonomic blockade, compared to baseline, repolarization significantly prolonged during Valsalva strain (1.1±0.7%) and shortened during release (−1.4±1.0%). After block, strain related repolarization prolongation was also observed (1.0±0.6%), with significantly less release related repolarization shortening (−0.8±0.8%) compared to pre-block ( P

The disorders of autonomic control associated with orthostatic intolerance are a diverse group of infirmities that can result in syncope and near syncope (as well as a host of other complaints). A basic understanding of these disorders is essential to both diagnosis and proper treatment. These infirmities are not new, what has changed is our ability to recognize them. It has been said that "the world undergoes change in the human consciousness. As this consciousness changes, so does the world." On going studies will continue to help better define the broad spectrum of these disorders, and to elaborate better diagnostic and treatment modalities.