Cardiovascular Reflex Control Research Articles

Chapter 13 - Electrophysiological assessment of peripheral and central autonomic disorders

The autonomic nervous system (ANS) coordinates multiple reflex actions which are essential for life. The tests employed to evaluate the ANS provide valuable information of the functional state of these reflex arcs. The ideal test should be simple to perform, noninvasive, reproducible, sensitive, specific, safe, and appropriate for longitudinal studies. The availability of computer-based techniques has facilitated the electrophysiological assessment of ANS-mediated reflexes. The information provided by autonomic testing must be analyzed in combination with the clinical history and physical examination of the patient, allowing for a hypothesis that can be tested. Properly performed and interpreted, ANS testing can be used to confirm the presence of an ANS disturbance and the involved functional pathways, as well as the extent, intensity, and site of injury. This chapter describes the most important electrophysiological tests used to evaluate the ANS control of cardiovascular reflexes and sweat gland activity.

Autonomic cardiovascular reflex control of hemodynamics during exercise in heart failure with reduced ejection fraction and the effects of exercise training.

Heart failure with reduced ejection fraction is associated with increased exercise intolerance, morbidity, and mortality. Importantly, exercise intolerance in heart failure with reduced ejection fraction is a key factor limiting patient quality of life and survival. Exercise intolerance in heart failure with reduced ejection fraction stems from a multi-organ failure to maintain homeostasis at rest and during exercise, including the heart, skeletal muscle, and autonomic nervous system, lending itself to a system constantly trying to "catch-up". Hemodynamic control during exercise is regulated primarily by the autonomic nervous system, whose operation, in turn, is partly regulated via reflexive information from exercise-stimulated receptors throughout the body (e.g., arterial baroreflex, central and peripheral chemoreceptors, and the muscle metabo- and mechanoreflexes). Persons with heart failure with reduced ejection fraction exhibit malfunctioning autonomic reflexes, which lead to exaggerated sympathoexcitation and attenuated parasympathetic tone. Chronic elevation of sympathetic activity is associated with increased morbidity and mortality. In this review, we provide an overview of how each main exercise-related autonomic reflex is changed in heart failure with reduced ejection fraction, and the role of exercise training in attenuating or reversing the counterproductive changes.

Alternations in the Cardiovascular Autonomic Regulation and Growth Factors in Autism.

Autism spectrum disorder (ASD) represents a serious neurodevelopmental disorder associated with autonomic nervous system dysregulation. The aim was to study complex cardiovascular autonomic regulation using heart rate variability (HRV) and systolic blood pressure variability (SBPV) linear/non-linear analysis at rest and during orthostasis, and to assess plasma levels of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) in autistic children. Twenty-five ASD boys and 25 age and gender-matched children at the age 7-15 years were examined. After venous blood taking, continuous ECG and blood pressure biosignals were recorded at rest and during orthostasis. Evaluated parameters: RR intervals, high- and low-frequency band of HRV spectral analysis (HF-HRV, LF-HRV), symbolic dynamics parameters 0V%, 1V%, 2LV%, 2UV%, low- and high-frequency band of SBPV (LF-SBPV, HF-SBPV), systolic, diastolic, mean blood pressure, EGF, VEGF plasma levels. RR intervals were significantly shortened and the HF-HRV, LF-SBPV, HF-SBPV parameters were significantly lower at rest, the HF-HRV and LF-SBPV remained lower during orthostasis in autistic children compared to controls (p<0.05). EGF plasma levels were significantly lower in ASD compared to controls (p=0.046). No significant differences were found in remaining parameters. Our study revealed tachycardia, cardiovagal underactivity, and blunted sympathetic vasomotor regulation at rest and during orthostasis in autistic children. Additionally, complex heart rate dynamics are similar in autistic children than controls. Furthermore, EGF was reduced in autistic children without significant correlations with any autonomic parameters. We suggest that the abnormal complex cardiovascular reflex control could contribute to understanding the pathway linking autonomic features and autism.

Peripheral Vascular Abnormalities in Anorexia Nervosa: A Psycho-Neuro-Immune-Metabolic Connection.

Immune, neuroendocrine, and autonomic nervous system dysregulation in anorexia nervosa lead to cardiovascular complications that can potentially result in increased morbidity and mortality. It is suggested that a complex non-invasive assessment of cardiovascular autonomic regulation—cardiac vagal control, sympathetic vascular activity, and cardiovascular reflex control—could represent a promising tool for early diagnosis, personalized therapy, and monitoring of therapeutic interventions in anorexia nervosa particularly at a vulnerable adolescent age. In this view, we recommend to consider in the diagnostic route, at least in the subset of patients with peripheral microvascular symptoms, a nailfold video-capillaroscopy as an easy not invasive tool for the early assessing of possible cardiovascular involvement.

522 Reduced sympatho-vagal responses to orthostatic stress in drug-naïve idiopathic restless legs syndrome

Abstract Introduction Restless legs syndrome (RLS) is a risk factor for cardiovascular disease (CVD). However, there are no electrophysiological biomarkers to assess this risk. This study aimed to evaluate the heart rate variability (HRV) and autonomic control of cardiovascular reflexes in the supine and standing positions in patients with RLS during wakefulness. Methods Fourteen drug-naïve RLS patients (12 women, 2 men; mean age: 42.14 ± 7.81 years) and 10 healthy controls underwent tests for blood pressure, heart rate when in the supine-rest and standing positions, deep breathing, and handgrip in controlled laboratory conditions. Five-minute R-R intervals in each position were collected and analyzed for HRV. Results Cardiovascular changes during deep breathing and isometric handgrip maneuvers were normal and similar between the two groups. The normalized unit of the low frequency component and low frequency/high frequency (LH/HF) ratio during standing were lower in the RLS patients than in the controls. LF/HF ratio responses during positional change from supine-rest to standing were significantly reduced in the RLS patients (RLS patients: mean ± SD, 2.94 ± 3.11; controls: 7.51 ± 5.58; P = 0.042). In Spearman’s rank correlation, ISI and PSQI were associated with HRV parameters. Conclusion The RLS patients showed reduced sympatho-vagal responses during positional change from supine-rest to standing during wakefulness, and RLS-related sleep disturbance was an important contributing factor for autonomic nervous system dysfunction. Reduced HRV responses during wakefulness might be a good predictor for CVD risk. Support (if any):

Angiotensin II-Vasopressin Interactions in The Regulation of Cardiovascular Functions. Evidence for an Impaired Hormonal Sympathetic Reflex in Hypertension and Congestive Heart Failure.

Angiotensin II (ANG II) and vasopressin (VP) interact in several physiological mechanisms, playing a role in arterial hypertension and congestive heart failure. Aim and Methods of Search: To overview the primary mechanism involved in the regulation of cardiovascular function, PubMed/Medline was searched, and authors selected original articles and reviews written in English. Angiotensin II (ANG II) and vasopressin (VP) are involved in several physiological mechanisms. ANG II stimulates VP release via angiotensin receptor 1. ANG II and VP stimulate aldosterone synthesis and secretion and enhance its action at the renal collecting duct level. VP is also involved in the cardiovascular reflex control of the sympathetic nervous system (SNS). Also, VP potentiates vasoconstriction and cardiac contractility, enhancing the effect of ANG II on sympathetic tone and arterial pressure. On the other hand, ANG II and VP act antagonistically in regulating baroreflex control of the SNS. There is evidence that high VP plasma levels increase baroreflex sympatho-inhibitory responses, and the arterial baroreflex response is shifted to lower pressure. This cardiovascular reflex control is mediated mainly in the brain, specifically in the circumventricular organ area postrema (AP). The modulation of cardiovascular reflex control induced by VP is abolished after lesions of the AP. VP modulation of baroreflex function is also under the control of α2-adrenergic pathway arising from the nucleus of the solitary tract (NTS) and synapsing on VP-ergic neurons of supraoptic and paraventricular nuclei. Presynaptic α2-adrenergic stimulation within the NTS inhibits VP release induced by hypovolemia and the effects of VP and AP on baroreflex control of SNS, thus showing baroreceptor afferent inputs are processed within the NTS and contribute to the increased baroreflex sympatho-inhibitory responses. In patients with congestive heart failure (CHF), plasma VP levels are elevated, inducing an up-regulation of aquaporin 2 water channel expression in renal collecting duct (CD) cells provoking exaggerated water retention and dilutional hyponatremia. Antagonists of VP and ANG II receptors reduce edema, body weight, and dyspnea in CHF patients. Hormonal imbalance between ANG II, VP, and SNS may induce hypertension and impaired water-electrolyte balance in cardiovascular diseases.

PENGARUH SLOW DEEP BREATHING TERHADAP TEKANAN DARAH PADA PASIEN HIPERTENSI

ABSTRAK&#x0D; Pendahuluan : Tekanan darah tinggi menjadi adalah masalah kesehatan masyarakat yang meningkat dengan signifikan. Angka kejadian hipertensi di Indonesia berjumlah 34.1% dan untuk di Jakarta 35%. Hipertensi dapat diobati dengan cara farmakologis dan non farmakologis dan juga dengan terapi alternatif. Slow deep breathing merupakan salah satu teknik latihan dan relaksasi yang membantu menjaga keadaan normal tekanan darah. Tujuan dari penelitian ini adalah untuk mengetahui pengaruh slow deep breathing pada tekanan darah di antara pasien dengan hipertensi. Metode : Design penelitian ini adalah one group pretest-posttest design. Sampel berjumlah 15 responden yang ditentukan dengan teknik purposive sampling. Analisa data dengan menggunakan t-test dependent. Latihan slow deep breathing diberikan kepada responden dua kali sehari selama satu jam selama satu minggu. Tekanan darah diukur dengan sphygmomanometer elektronik sebelum serta setelah intervensi di setiap sampel. Hasil : Latihan slow deep breathing efektif dalam mengurangi tekanan darah sistolik dan diastolik pada tingkat tersebut dengan nilai p &lt;0,05. Diskusi : Slow deep breathing dapat menurunkan tekanan darah dengan efek melalui sistem kontrol refleks kardiovaskuler dan sensitivitas barorefleks serta penurunan tekanan darah.&#x0D; &#x0D; Kata kunci : Hipertensi, slow deep breathing, tekanan darah

Mechanisms Underlying Neuroplasticity in the Nucleus Tractus Solitarii Following Hindlimb Unloading in Rats

Hindlimb unloading (HU) in rats induces cardiovascular deconditioning (CVD) analogous to that observed in individuals exposed to microgravity or bed rest. Among other physiological changes, HU rats exhibit autonomic imbalance and altered baroreflex function. Lack of change in visceral afferent activity that projects to the brainstem in HU rats suggests that neuronal plasticity within central nuclei processing cardiovascular afferents may be responsible for these changes in CVD and HU. The nucleus tractus solitarii (nTS) is a critical brainstem region for autonomic control and integration of cardiovascular reflexes. In this study, we used patch electrophysiology, live-cell calcium imaging and molecular methods to investigate the effects of HU on glutamatergic synaptic transmission and intrinsic properties of nTS neurons. HU increased the amplitude of monosynaptic excitatory postsynaptic currents and presynaptic calcium entry evoked by afferent tractus solitarii stimulus (TS-EPSC); spontaneous (s) EPSCs were unaffected. The addition of a NMDA receptor antagonist (AP5) reduced TS-EPSC amplitude and sEPSC frequency in HU but not control. Despite the increase in glutamatergic inputs, HU neurons were more hyperpolarized and exhibited intrinsic decreased excitability compared to controls. After block of ionotropic glutamatergic and GABAergic synaptic transmission (NBQX, AP5, Gabazine), HU neuronal membrane potential depolarized and neuronal excitability was comparable to controls. These data demonstrate that HU increases presynaptic release and TS-EPSC amplitude, which includes a NMDA receptor component. Furthermore, the decreased excitability and hyperpolarized membrane after HU are associated with enhanced GABAergic modulation. This functional neuroplasticity in the nTS may underly the CVD induced by HU.

Role of Neuroendocrine, Immune, and Autonomic Nervous System in Anorexia Nervosa-Linked Cardiovascular Diseases.

Anorexia nervosa represents a severe mental disorder associated with food avoidance and malnutrition. In patients suffering from anorexia nervosa, cardiovascular complications are the main reason leading to morbidity and mortality. However, the origin and pathological mechanisms leading to higher cardiovascular risk in anorexia nervosa are still unclear. In this aspect, the issue of exact pathological mechanisms as well as sensitive biomarkers for detection of anorexia nervosa-linked cardiovascular risk are discussed. Therefore, this review synthesised recent evidence of dysfunction in multiple neuroendocrine axes and alterations in the immune system that may represent anorexia nervosa-linked pathological mechanisms contributing to complex cardiovascular dysregulation. Further, this review is focused on identification of non-invasive biomarkers for the assessment of increased cardiovascular risk in anorexia nervosa that can be linked to a clinical application. Complex non-invasive assessment of cardiovascular autonomic regulation—cardiac vagal control (heart rate variability), sympathetic vascular activity (blood pressure variability), and cardiovascular reflex control (baroreflex sensitivity)—could represent a promising tool for early diagnosis, personalized therapy, and monitoring of therapeutic interventions in anorexia nervosa particularly at a vulnerable adolescent age.

Mechanisms underlining excitatory synaptic plasticity in the Nucleus Tractus Solitarii following Cardiovascular Deconditioning

The nucleus tractus solitarii (nTS) is a critical central region for autonomic control and integration of cardiovascular reflexes. Neuroplasticity in nTS contributes to several cardiovascular dysfunctions. Our previous data showed that Hindlimb‐unloading (HU), a well‐established model of cardiovascular deconditioning in rats, increases glutamatergic neurotransmission yet reduces the excitability of nTS neurons. In this study we aimed to investigate the mechanisms underlining these alterations. For this purpose, stainless wire rings were placed in the tail of male Sprague‐Dawley rats (3 weeks). After one week of recovery the rings was connected to a suspension apparatus and rats were suspended at an angle of 30–35° for two weeks with free access to food and water. Control animals were maintained in normal postural conditions. After the HU protocol, coronal brainstem slices were generated and the whole‐cell patch clamp technique was performed to evaluate the synaptic neurotransmission and electrophysiological properties of nTS neurons. Compared to control rats, HU increased the amplitude of excitatory postsynaptic currents evoked by afferent tractus solitarii stimulus (TS‐EPSC). The addition of a NMDA receptor antagonist (AP5, 10 μM) significantly reduced TS‐EPSC amplitude in HU but not controls. Despite the increase in glutamatergic inputs, the neurons of HU vs control rats are hyperpolarized and have decreased excitability. The block of both NMDA and non‐NMDA (NBQX, 10 μM) glutamatergic receptors did not affect these parameters. However, in the presence of a GABAA receptor antagonist (Gabazine, 25 μM) the resting membrane potential depolarized and excitability of HU neurons were comparable to neurons from control rats. The results indicate that HU increases TS‐EPSC amplitude via a NMDA receptor component. Furthermore, the decreased excitability and hyperpolarized membrane is associated with enhanced GABAergic modulation to these neurons. This functional neuroplasticity in the nTS may contribute to the cardiovascular deconditioning induced by HU.Support or Funding InformationHL132836 AAS lundbeck fellowship

Neuropeptide Y predicts cardiovascular events in chronic kidney disease patients: a cohort study.

Neuropeptide Y (NPY) is a multifaceted sympathetic neurotransmitter regulating reflex cardiovascular control, myocardial cell growth, inflammation and innate immunity. Circulating NPY levels predict cardiovascular mortality in patients with end stage kidney disease on dialysis but this relationship has never been tested in predialysis chronic kidney disease (CKD) patients. We investigated the relationship between circulating NPY and the risk for cardiovascular events (Fine & Gray competing risks model) in a cohort of 753 stages 2-5 CKD patients over a median follow-up of 36 months. Independently of other risk factors, plasma NPY was directly related with the glomerular filtration rate (β = -0.19, P < 0.001) but was independent of systemic inflammation as quantified by serum IL6 and C reactive protein. Over follow-up 112 patients had cardiovascular events and 12 died. In analyses fully adjusted for traditional risk factors and a large series of CKD-specific risk factors and considering death as a competing event (Fine and Gray model) a 0.25 μmol/l increase in NPY robustly predicted the incident risk for cardiovascular events (subdistribution hazard ratio: 1.25; 95% confidence interval: 1.09-1.44; P = 0.002). Furthermore, the fully adjusted NPY - cardiovascular outcomes relationship was modified by age (P = 0.012) being quite strong in young patients but weaker in the old ones. NPY is an independent, robust predictor of cardiovascular events in predialysis CKD patients and the risk for such events is age-dependent being maximal in young patients. These findings suggest that NPY may play a role in the high risk of cardiovascular disease in this population.

Abnormal oxygen homeostasis in the nucleus tractus solitarii of the spontaneously hypertensive rat

New Findings What is the central question of this study? Arterial hypertension is associated with impaired neurovascular coupling in the somatosensory cortex. Abnormalities in activity‐dependent oxygen consumption in brainstem regions involved in the control of cardiovascular reflexes have not been explored previously. What is the main finding and its importance? Using fast‐cyclic voltammetry, we found that changes in local tissue PO2 in the nucleus tractus solitarii induced by electrical stimulation of the vagus nerve are significantly impaired in spontaneously hypertensive rats. This is consistent with previous observations showing that brainstem hypoxia plays an important role in the pathogenesis of arterial hypertension. The effects of arterial hypertension on cerebral blood flow remain poorly understood. Haemodynamic responses within the somatosensory cortex have been shown to be impaired in the spontaneously hypertensive rat (SHR) model. However, it is unknown whether arterial hypertension affects oxygen homeostasis in vital brainstem areas that control cardiovascular reflexes. In this study, we assessed vagus nerve stimulation‐induced changes in local tissue PO2 (PtO2) in the caudal nucleus tractus solitarii (cNTS) of SHRs and normotensive Wistar rats. Measurements of PtO2 were performed using a novel application of fast‐cyclic voltammetry, which allows higher temporal resolution of O2 changes than traditional optical fluorescence techniques. Electrical stimulation of the central cut end of the vagus nerve (ESVN) caused profound reductions in arterial blood pressure along with biphasic changes in PtO2 in the cNTS, characterized by a rapid decrease in PtO2 (‘initial dip’) followed by a post‐stimulus overshoot above baseline. The initial dip was found to be significantly smaller in SHRs compared with normotensive Wistar rats even after ganglionic blockade. The post‐ESVN overshoot was similar in both groups but was reduced in Wistar rats after ganglionic blockade. In conclusion, neural activity‐dependent changes in tissue oxygen in brainstem cardiovascular autonomic centres are significantly impaired in animals with arterial hypertension.

Dysfunction of Astrocytes in the Nucleus Tractus Solitarii Leads to Cardiorespiratory Compromise

We have previously shown that saporin (SAP) microinjected into the nucleus tractus solitarii (NTS) causes loss of astrocytes while producing no immunohistochemical evidence of damage to NTS neurons. Loss of NTS astrocytes leads to loss of cardiovascular reflex control and, in some animals, sudden death as a result of asystole. Knowing that respiratory dysfunction and apnea may lead to asystole, we hypothesized that astrocytic dysfunction compromises respiratory control and may lead to apnea and sudden death. We sought to test that hypothesis in rats treated with bilateral NTS injections of the ribosomal toxin SAP, a chronic model of astrocytic loss, or fluorocitrate, which produces an acute model of astrocytic dysfunction. We first sought to determine if the loss of astrocytes due to SAP was due to necrosis or apoptosis by injection of SAP unilaterally into the NTS. We found loss of immunoreactivity for glial fibrillary acidic protein (GFAP), a marker of astrocytes, two hours, six hours, one day and seven days after SAP injection and increased immunoreactivity for the necrosis marker, receptor interacting protein (RIP), 6 hours and one day after SAP injection. In contrast, SAP treatment did not lead to apoptosis as documented by absence of positive cells in TUNEL reaction in the NTS. Injection of SAP into the NTS of neonatal rats (P13) led to loss of GFAP immunoreactivity seven days later as it also does in the adult rat brain. Therefore, in brain slices from P20–23 rats that had been treated unilaterally with SAP seven days previously, we performed patch clamp recording from neurons in the NTS and found that their intrinsic electrophysiological properties were unremarkable compared to neurons on the control side. In adult animals we monitored breathing chronically in a plethysmographic chamber after bilateral NTS microinjection of SAP. Seven days after injection, awake, treated rats, in contrast to control rats, began to manifest slow, irregular breathing patterns during eupneic breathing. During acute studies of astrocytic dysfunction, rats were anesthetized with isoflurane and respiration was monitored by intercostal electromyographic recording concurrent with recording arterial blood pressure and heart rate. Bilateral injections of fluorocitrate were made into NTS at 15 minute intervals for 2 hours. Fluorocitrate treated rats, but not rats treated with vehicle or PBS, developed slowed breathing followed by periodic apnea. These studies suggest that SAP causes necrosis of astrocytes and spares neuronal function. Either astrocytic necrosis or transient astrocytic dysfunction in the NTS interferes with normal cardiorespiratory regulation and leads to hypopnea and apnea that may contribute to death.Support or Funding InformationNIH R01HL088090 and VA Merit Review

Forebrain neurocircuitry associated with human reflex cardiovascular control.

Physiological homeostasis depends upon adequate integration and responsiveness of sensory information with the autonomic nervous system to affect rapid and effective adjustments in end organ control. Dysregulation of the autonomic nervous system leads to cardiovascular disability with consequences as severe as sudden death. The neural pathways involved in reflexive autonomic control are dependent upon brainstem nuclei but these receive modulatory inputs from higher centers in the midbrain and cortex. Neuroimaging technologies have allowed closer study of the cortical circuitry related to autonomic cardiovascular adjustments to many stressors in awake humans and have exposed many forebrain sites that associate strongly with cardiovascular arousal during stress including the medial prefrontal cortex, insula cortex, anterior cingulate, amygdala and hippocampus. Using a comparative approach, this review will consider the cortical autonomic circuitry in rodents and primates with a major emphasis on more recent neuroimaging studies in awake humans. A challenge with neuroimaging studies is their interpretation in view of multiple sensory, perceptual, emotive and/or reflexive components of autonomic responses. This review will focus on those responses related to non-volitional baroreflex control of blood pressure and also on the coordinated responses to non-fatiguing, non-painful volitional exercise with particular emphasis on the medial prefrontal cortex and the insula cortex.

Chronic dopaminergic treatment in restless legs syndrome: does it affect the autonomic nervous system?

ObjectiveThe link between the autonomic nervous system and restless legs syndrome (RLS) has been recently postulated. Since dopaminergic agents are used as first-line treatment for RLS, the purpose of our study is to verify whether chronic pramipexole treatment could influence the autonomic control of cardiovascular reflexes and heart rate variability (HRV) in RLS during wakefulness. MethodsConsecutive drug naive RLS patients underwent polysomnography (PSG), subjective scales, and cardiovascular function tests including head-up tilt test (HUTT), Valsalva maneuver, deep breathing, handgrip and cold face before and after 3-month pramipexole therapy. HRV analysis was performed in the frequency domain using both autoregressive and fast Fourier transform algorithms in rest supine condition and during HUTT. ResultsTwenty RLS patients reported a significant reduction of RLS symptoms after pramipexole treatment, while PSG did not show significant improvements except for periodic limb movement index. Pramipexole induced a trend to a lower systolic blood pressure and a significant higher variation of systolic and diastolic blood pressure at HUTT. Cardiovascular responses to the other tests were unchanged. No significant differences in HRV spectral analysis between drug naive and treated patients were observed. Moreover, the within-group analysis of HRV between orthostatic and supine position did not show any significant change in sympathetic and parasympathetic components both in the drug naive and pramipexole groups. ConclusionsChronic pramipexole treatment does not seem to affect autonomic balance during wakefulness. Considering that neither PSG data nor autonomic parameters are significantly modified by pramipexole, we hypothesize a non-dopaminergic autonomic dysfunction in RLS.

Non‐targeted Effects of a Targeted Toxin

Saporin (SAP) alone or conjugated either with stabilized substance P (SSP‐SAP) or with an antibody to dopamine β‐hydroxylase (anti‐DBH‐SAP) leads to attenuation of arterial baroreflexes when injected bilaterally into the nucleus tractus solitarii (NTS) of rats. Effects on cardiovascular reflex control could be due to an impact of the toxin on cells that express not only the target protein but also other receptors. To test that hypothesis we assessed effects of glutamate, N‐methyl‐D‐aspartate (NMDA), or α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐proprionic acid (AMPA) injected into the NTS at the same site as a prior injection of SAP, anti‐DBH‐SAP, SSP‐SAP, 6‐hydroxydopamine (6‐OHDA) or phosphate buffered saline (PBS). 6‐OHDA was included because our previous studies showed that its injection into the NTS led to loss of noradrenergic neurons while not affecting other neuronal types. Also, 6‐OHDA did not lead to loss of astrocytes as seen after injection of anti‐DBH‐SAP, SSP‐SAP, or SAP into NTS. In control rats that received PBS, glutamate agonists produced dose‐related hypotensive, bradycardic effects, which were significantly reduced in animals treated with SAP containing toxins. Prior injection of 6‐OHDA did not affect bradycardic or hypotensive responses elicited by glutamate receptor agonists in the NTS. This study provides a cautionary note in interpreting physiological responses resulting from use of saporin conjugates in that, while selectively damaging neurons with a specific target, the toxins will also disrupt other neuronal functions medicated by the same neuron but through different mechanisms. Further, the study supports the concept that astrocytes in NTS play a role in mediating central cardiovascular control. Support: VA Merit Review and NIH R01 HL59593

Quiste coloide hemorrágico del tercer ventrículo: deterioro fulminante

Colloid cysts are benign tumors of the third ventricle. Most of them remain asymptomatic. However, some patients can develop since intermittent headaches to an acute deterioration and even sudden death. Several theories exist for which there would be a sudden death in these patients, among which include the rapid increase in size of the cyst, its rupture, the disturbance of hypothalamus-mediated cardiovascular reflex control and the unusual bleeding of the cyst, with only 15 cases described in the literature. A 45 year old male with hypertension with acute hydrocephalus due to a hemorrhagic colloid cyst in the third ventricle. An external ventricular drain on each side was introduced and he was admitted to the ICU, where brain death was certified. After removal of the cyst through transcortical frontal approach, the diagnosis of colloid cyst with remains of hemolyzed blood was confirmed. Bleeding in colloid cysts is exceptional, and can occur in both symptomatic and asymptomatic patients, making it difficult to recognize this complication.

A historical perspective on peripheral reflex cardiovascular control from animals to man.

Although drug treatment of human hypertension has greatly improved, there is renewed interest in non-drug methods of blood pressure reduction. Animal experiments have now shown that arterial baroreflexes do control long-term blood pressure levels, particularly by nervously mediated renal excretion of sodium and water. This Paton Lecture provides a review of the historical development of knowledge of peripheral circulatory control in order to supplement prior Paton Lectures concerned with cerebral cortical and other areas of influence. I also discuss how improved understanding of nervous control of the circulation has led to current methods of non-drug blood pressure control in man by implanted carotid baroreceptor pacemakers or by renal denervation. Finally, the role of other therapy, particularly listening to music, is reviewed.

Effects of digitoxin treatment on reflex cardiovascular control in rats with heart failure (1132.2)

There is evidence that digitalis promote changes in the autonomic and reflex control of the cardiovascular system and enhances survival in rats with Heart Failure (HF). The major aim of the present study was to evaluate the effects of digitoxin treatment on basal renal sympathetic nerve activity (rSNA) and on the reflex control of the cardiovascular system by the arterial baroreceptors and cardiopulmonary reflex in HF rats. Male Wistar rats (±200g) were divided into two experimental groups: HF and HF treated with digitoxin in the diet for 60 days (1mg/Kg/day) (HF+DIG). A significant increase in rSNA were found in HF (190 ± 29pps; N= 5) compared to control rats (98 ± 14pps, N=5). Digitoxin treatment leads to a significant decrease and normalizes rSNA in HF+DIG rats (98 ± 14pps, N= 7). The baroreflex sensitivity for the control of rSNA was significantly decreased by treatment (slope: ‐0.69 ± 0.10pps/mmHg, N= 7) when compared to HF group (slope: ‐2.66 ± 0.12pps/mmHg, N= 5). A similar result was found for the cardiopulmonary reflex, digitoxin reduced the fall in heart rate (HF: 180 ± 7bpm, N=8; HF+DIG: ‐126 ± 14bpm, N=9) in response to acute phenylbiguanide administration. Altogether the results demonstrate that the fall in rSNA in response to digitoxin in HF rats is not related to improvement in the reflex control of the cardiovascular system. Central actions of digitoxin may explain the sympathoinhibitory effects of digitalis.Grant Funding Source: CAPES, CNPq and FAPESP (2009/54225‐8)

Circulating testosterone and estradiol, autonomic balance and baroreflex sensitivity in middle-aged and elderly men with heart failure

Background: Heart failure (HF) is considered as a cardiogeriatric syndrome. Its fundamental pathophysiological feature is autonomic imbalance (and associated abnormalities within cardiovascular reflex control), but recent evidence suggests the involvement of deranged hormone metabolism. Both these neural and endocrine pathologies have serious clinical and prognostic consequences in patients with HF. We investigated the relations between autonomic status, baroreflex sensitivity (BRS) and hormone status in men with mild systolic HF.Methods: We examined 46 men with stable systolic HF (age: 62 ± 10 years, NYHA class I/II: 10/36 [22%/78%], ischemic aetiology: 72%, left ventricular ejection fraction: 32 ± 8%). Serum hormone levels (i.e. total testosterone [TT], dehydroepiandrosterone sulphate [DHEAS], oestradiol [E2], insulin-like growth factor type 1 [IGF-1] and cortisol) were assessed using immunoassays. Estimated free testosterone (eFT) was estimated using the Vermeulen’s equation. Heart rate variability (HRV) was assessed in time and frequency domains, based on 10-min resting recordings. BRS was estimated using the sequence method (BRS-Seq) and the phenylephrine test (BRS-Phe).Results: Deficiencies in circulating TT, eFT, DHEAS and IGF-1 (defined as a serum hormone ≤the 10th percentile calculated for the adequate age category in the cohort of healthy men) were found in respectively 13%, 30%, 55% and 93% of men with systolic HF. Serum SHBG ≥50 nmol/L and cortisol ≥700 nmol/L characterised, respectively 44% and 29% of men with HF. In multivariable models after the adjustment for clinical variables, the following relationships were found in examined men: DHEAS and SDNN (time domain of HRV defined as a standard deviation of average R–R intervals) (β = 0.29, p = 0.03); E2 and: HRV-LF (ms2) (β = 0.37, p = 0.01), HRV-HF (ms2) (β = 0.44, p = 0.02) and BRS-Phe (β = 0.51, p = 0.008); TT and: HRV-HF (%) (β = 0.35, p = 0.02), HRV-LF/HF ratio (β = −0.35, p = 0.02) and BRS-Seq (β = 0.33, p = 0.04).Conclusions: The observed associations between reduced circulating androgens, oestrogens and lower HRV and depleted BRS, irrespectively of HF severity suggest the pathophysiological links between these two mechanisms. These results constitute the premises to investigate whether the pharmacological supplementation of depleted hormones would enable to restore the autonomic balance and improve the efficacy of reflex control within the cardiovascular system in men with systolic HF.