Decrease In Sympathetic Tone Research Articles

A novel technology for heart failure that utilizes the respiratory effort to shift fluids from the lung and alleviate cardiac workloads; feasibility study in sheep

Abstract Introduction Hemodynamic congestion is governed by inflow from RV and drainage through LV. However, ventricle functions are affected by the intrathoracic/pleural pressure: Negative pleural pressure (PPL) increases RV outflow while decreasing LV outflow, and vice versa at high PPL. Cardiac decompensation is associated with an increase in the respiratory effort (the peak-to-peak changes in PPL). We suggest to utilize this respiratory effort to shift fluid out of the lung and alleviate hemodynamic congestion. It is done by pacing the heart when PPL is high and the LV stroke volume is larger than the RV stroke volume. Purpose To test the feasibility of the novel technology in sheep. To verify that it is possible to modify the distribution of the heart beat within the respiratory cycle (slightly modify the rhythm according to the PPL) with insignificant effect on mean heart rate. Methods The utility was validated in sheep (N=9), under spontaneous breathing before and after induction of acute infarction by balloon inflation in the mid-LAD artery. The device senses the intracardiac electrical activity and respiratory effort and paces the right atrium when the PPL is high. The R-R interval of the paced beats was shorter than the sinus R-R interval by less than 10%. The effects of PPL and device pacing on LV and RV stroke-volumes were derived from simultaneous measurements of RV and LV pressure-volume loops, utilizing two impedance catheters (CD-Leycom) within both ventricles. Results The respiratory effort had significant effects on RV and LV outputs before and after infarction. The stroke volumes of the two ventricles were in antiphase! At low PPL the RV output increased while the LV decreased by about 10%, and the opposite occurred at high PPL. The pacing increased cardiac beating probability at high PPL. Sequential pacing for one minute increased the systolic pressure by 5 mmHg while decreasing the pulmonary artery pressure. Based on the pressure-volume loops, each paced breath cycle increased the LV outflow by 1.14 ml and decreased RV outflow by 0.36ml, yielding a shift of 1.5 ml from the lung. Interestingly, it was associated with a decrease in the sinus rate, which further decreased cardiac beating at low PPL and may represent a decrease in sympathetic tone. Conclusions Pacing only 1% of the ∼20,000 daily breath-cycles can shift 300 ml from the lung per day! The technology is agnostic of the heart-failure etiology. Preclinical studies in a model of chronic heart failure are required to further validate the novel approach.

Changes in Heart Rate Variability with Induction of Gastric Ulcers in Adult Horses.

Gastric ulceration can be induced by athletic training and is a significant welfare concern. The objective of this study was to evaluate the effect of gastric ulcer induction on heart rate variability (HRV) in the horse. We hypothesized that induction of gastric ulcers would decrease HRV and increase low frequency fluctuations, consistent with increased sympathetic tone. A convenience sample of 8 horses in a larger study were enrolled. Horses were randomly assigned to receive water or 2 mg/kg omeprazole orally once daily for 28 days. Gastric ulcers were induced through intermittent feed withholding on days 21 to 28. Gastroscopy was performed and gastric ulcers were graded (0-IV) by three blinded reviewers on days 21 and 28. Continuous electrocardiograms were obtained for one hour at the start and end of ulcer induction. HRV was assessed in 1-hour recordings for time domain variables and 5 minute sections for frequency domain analysis. HRV and ulcer grade across treatments were compared by a mixed effect model, with treatment and time as fixed effects and horse as a random effect. Gastric ulcer grade increased with induction protocol (P < .0001) and decreased with omeprazole treatment (P=.0007). Omeprazole treatment increased R-R intervals (P=.01) and decreased ratio of low frequency/high frequency signal (P=.008) as compared to horses receiving water. This was attributable to decreasing low frequency fluctuations (P=.05). While limited by the small sample size (four horses/treatment), this study suggests that omeprazole treatment decreases heart rate, and LF/HF ratio during ulcer induction, consistent with a decrease in sympathetic tone.

Autonomic nerve regulation in joint hypermobility patients with myofascial trigger points by Musculoskeletal Interfiber Counterirritant Stimulation (MICS).

Joint hypermobility (JH) conditions suggest dysfunction in the autonomic nervous system (ANS) (dysautonomia), associated with multifactor non-articular local musculoskeletal pain, and remains a complex treatment. This study aims to determine the effects of musculoskeletal interfiber counterirritant stimulation (MICS) as an innovative treatment of myofascial trigger points (MTrPs) on the upper trapezius muscle in JH patients. We evaluate the ANS activity by wavelet transform spectral analysis of heart rate variability (HRV) in sixty women, equally divided: MTrP, MTrP+general joint hypermobility (GJH), and MTrP+joint hypermobility syndrome (JHS). The protocol phases were rest, stimulation, and recovery, with clinical and home treatment for three-days. All groups show a significantly decreased in pain perception during and post-treatment, and an increased parasympathetic ANS activity under MICS in the GJH and JHS groups. The variables low-frequency (LF) vs. high-frequency (HF) showed significant differences during the protocol phases, and the LF/HF ratio maintained a predominance of sympathetic activity (SA) throughout the protocol. The new MICS technique reduces the pain perception and modulates the ANS activity by an increase in vagal tone, and a decrease in sympathetic tone. This modulation was followed by an increase in the HRV in JH patients after treatment with MICS. Clinical Trials: RBR-88z25c5.

Extreme obesity and leptin receptor deficiency. A case report

Leptin is vital for maintaining energy homeostasis, by controlling food intake and regulating energy expenditure (fatty acids). It also participates in glycemic homeostasis, thyroid activity, and reproductive and immune functions. Leptin resistance is a phenomenon that appears gradually and does not simultaneously affect all organs and tissues equally. In models of obesity induced by a high-fat diet, leptin resistance initially manifests in the hypothalamus. This type of central resistance can justify an alteration in eating patterns (hyperphagia) and a decrease in sympathetic tone, which can contribute to the increase in fat deposits in adipose tissue

Fatty acid amide hydrolase activity in the dorsal periaqueductal gray attenuates neuropathic pain and associated dysautonomia.

The complexity of neuropathic pain and its associated comorbidities, including dysautonomia, make it difficult to treat. Overlap of anatomical regions and pharmacology of sympathosensory systems in the central nervous system (CNS) provide targets for novel treatment strategies. The dorsal periaqueductal gray (dPAG) is an integral component of both the descending pain modulation system and the acute stress response and is critically involved in both analgesia and the regulation of sympathetic activity. Local manipulation of the endocannabinoid signaling system holds great promise to provide analgesia without excessive adverse effects and also influence autonomic output. Inhibition of fatty acid amide hydrolase (FAAH) increases brain concentrations of the endocannabinoid N-arachidonoylethanolamine (AEA) and reduces pain-related behaviors in neuropathic pain models. Neuropathic hyperalgesia and reduced sympathetic tone are associated with increased FAAH activity in the dPAG, which suggests the hypothesis that inhibition of FAAH in the dPAG will normalize pain sensation and autonomic function in neuropathic pain. To test this hypothesis, the effects of systemic or intra-dPAG FAAH inhibition on hyperalgesia and dysautonomia developed after spared nerve injury (SNI) were assessed in male and female rats. Administration of the FAAH inhibitor PF-3845 into the dPAG reduces hyperalgesia behavior and the decrease in sympathetic tone induced by SNI. Prior administration of the CB1 receptor antagonist AM281, attenuated the antihyperalgesic and sympathetic effects of FAAH inhibition. No sex differences were identified. These data support an integrative role for AEA/CB1 receptor signaling in the dPAG contributing to the regulation of both hyperalgesia behavior and altered sympathetic tone in neuropathic pain.

Adoption of Dexmedetomidine in Different Doses at Different Timing in Perioperative Patients.

Dexmedetomidine (Dex) is an alpha-2 agonist used for sedation during various procedures. Dex activates 2-adrenoceptors, and causes the decrease of sympathetic tone, with attenuation of the neuroendocrine and hemodynamic responses to anesthesia and surgery; it reduces anesthetic and opioid requirements; and causes sedation and analgesia. Objective: it was to compare the perioperative effects of different doses of Dex at different timing in patients using Dex during the perioperative period adopting a medical data classification algorithm based on optimized semi-supervised collaborative training (Tri-training). Methods: 495 patients requiring surgical treatment in Xingtai People's Hospital were randomly selected as the study subjects. The patients were divided into group A (used before induction), group B (used during induction), and group C (used after induction) according to different induction timing, with 165 cases in each group. Then, groups A, B, and C were divided into groups A1, B1, and C1 (0.4 μg/(kg·h) rate), groups A2, B2, and C2 (0.6 μg/(kg·h) rate), and groups A3, B3, and C3 (0.8 μg/(kg·h) rate) according to the dose used, with 55 cases in each group. Intraoperative anesthesia and postoperative adverse reactions were compared among the 9 groups. Results: the similarity between the Tri-training algorithm optimized by Naive Bayes (NB) classification algorithm and the actual classification (93.49%) was clearly higher than that by decision tree (DT) and K-nearest neighbor (kNN) classification algorithm (76.21%, 74.31%); heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) values decreased obviously after Dex used in groups B1, C1, B2, C2, B3, and C3 (P <0.05), but did not change significantly in groups A1, A2, and A3 (P >0.05); the proportion of patients with satisfactory Ramsay score in group A3 was distinctly superior than that in groups A1, A2, B1, B2, B3, C1, C2, and C3 (P <0.05); the incidence of adverse reactions in group A3 was significantly inferior than that in groups A1, A2, B1, B2, B3, C1, C2, and C3 (P <0.05). Conclusion: the optimization effect of NB classification algorithm was the best, and the injection of Dex at the injection rate of 0.8 μg/(kg·h) before induction of anesthesia could apparently improve the fluctuation of HR, SBP, and DBP during perioperative period, and effectively reduce the occurrence of adverse reactions in patients, with better sedative effect on patients.

Safety of surgical denervation of the common hepatic artery in insulin-resistant dogs.

The objective of this study was to assess the safety of surgical common hepatic artery denervation (CHADN). This procedure has previously been shown to improve glucose tolerance in dogs fed a high‐fat high‐fructose (HFHF) diet. We assessed the hypoglycemic response of dogs by infusing insulin at a constant rate (1.5 mU/kg/min) for 3 h and monitoring glucose and the counterregulatory hormones (glucagon, catecholamine, and cortisol). After an initial hypoglycemic study, the dogs were randomly assigned to a SHAM surgery (n = 4) or hepatic sympathetic denervation (CHADN, n = 5) and three follow‐up studies were performed every month up to 3 months after the surgery. The level of norepinephrine (NE) in the liver and the pancreas was significantly reduced in the CHADN dogs, showing a decrease in sympathetic tone to the splanchnic organs. There was no evidence of any defect of the response to hypoglycemia after the CHADN surgery. Indeed, the extent of hypoglycemia was similar in the SHAM and CHADN groups (~45 mg/dl) for the same amount of circulating insulin (~50 µU/ml) regardless of time or surgery. Moreover the responses of the counterregulatory hormones were similar in extent and pattern during the 3 h of hypoglycemic challenge. Circulating lactate, glycerol, free fatty acids, and beta‐hydroxybutyrate were also unaffected by CHADN during fasting conditions or during the hypoglycemia. There were no other notable surgery‐induced changes over time in nutrients, minerals, and hormones clinically measured in the dogs nor in the blood pressure and heart rate of the animals. The data suggest that the ablation of the sympathetic nerve connected to the splanchnic bed is not required for a normal counterregulatory response to insulin‐induced hypoglycemia and that CHADN could be a safe new therapeutic intervention to improve glycemic control in individuals with metabolic syndrome or type 2 diabetes.

Cardiovascular and Cerebral Responses During a Vasovagal Reaction Without Syncope.

This clinical case report presents synchronous physiological data from an individual in whom a spontaneous vasovagal reaction occurred without syncope. The physiological data are presented for three main phases: Baseline (0–200 s), vasovagal reaction (200–600 s), and recovery period (600–1200 s). The first physiological changes occurred at around 200 s, with a decrease in blood pressure, peak in heart rate and vastus lateralis tissue oxygenation, and a drop in alpha power. The vasovagal reaction was associated with a progressive decrease in blood pressure, heart rate and cerebral oxygenation, whilst the mean middle cerebral artery blood flow velocity and blood oxygen saturation remained unchanged. Heart rate variability parameters indicated significant parasympathetic activation with a decrease in sympathetic tone and increased baroreflex sensitivity. The total blood volume and tissue oxygenation index (TOI) dropped in the brain but slightly increased in the vastus lateralis, suggesting cerebral hypoperfusion with blood volume pooling in the lower body part. Cerebral hypoperfusion during the vasovagal reaction was associated with electroencephalography (EEG) flattening (i.e., decreased power in beta and theta activity) followed by an EEG high-amplitude “slow” phase (i.e., increased power in theta activity). The subject developed signs and symptoms of pre-syncope with EEG flattening and slowing during prolonged periods of symptomatic hypotension, but did not lose consciousness.

Evolution of a New Class of Antihypertensive Drugs: Targeting the Brain Renin-Angiotensin System.

In addition to the circulating renin-angiotensin system, activation of the brain renin-angiotensin system plays an important role in the pathophysiology of hypertension. One of the major components of the brain renin-angiotensin system implicated in the development of hypertension is Ang III (angiotensin III). Brain Ang III, produced from Ang II (angiotensin II) by APA (aminopeptidase A), exerts a tonic stimulatory control over blood pressure in hypertensive rats. Targeting Ang III by inhibiting brain APA is now considered a potentially important target in the management of hypertension. This has led to development of RB150, an orally active prodrug of the specific and selective APA inhibitor, EC33. Orally administered RB150 crosses the gastrointestinal and blood-brain barriers, enters the brain where it generates 2 active molecules of EC33 that block brain APA activity. This results in decreased brain Ang III formation and reduced blood pressure in hypertensive rats. The RB150-induced blood pressure decrease is due to a reduced vasopressin release, which increases diuresis, reducing extracellular volume, a decrease in sympathetic tone, leading to a reduction of vascular resistances, and the improvement of the baroreflex function. RB150 was renamed firibastat by the World Health Organization. Phase Ia/Ib clinical trials showed that firibastat is clinically and biologically well tolerated in healthy volunteers. Clinical efficacy of firibastat in hypertensive patients was, therefore, demonstrated in 2 phase II studies. Accordingly, firibastat could represent the first drug of a novel class of antihypertensive drugs targeting the brain renin-angiotensin system.

P4554Central-acting aminopeptidase a inhibitors for new treatment of hypertension: from discovery to clinical trial

Abstract The hyperactivity of the brain renin–angiotensin system (RAS) has been implicated in the development and maintenance of arterial hypertension (HTA). Our aim was to demonstrate that normalizing brain RAS hyperactivity could constitute a new therapeutic approach for HTA treatment We first demonstrated in the brain that aminopeptidase A (APA) is the enzyme generating angiotensin III (AngIII) from AngII. Then, using the specific and selective APA inhibitor, EC33 ((3S)-3-amino-4-sulfanyl-butane-1-sulfonic acid), we showed that AngIII is one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control over blood pressure (BP) in hypertensive rats. This suggests that brain APA may be a potential therapeutic target for HTA treatment. We then designed RB150 {4,4-dithio[bis(3-aminobutyl sulfonic acid)]}, an orally active prodrug of EC33. RB150, given orally in conscious deoxycorticosterone acetate-salt (DOCA-salt) rats or spontaneously hypertensive rats, crosses the intestinal, hepatic and blood-brain barriers, enters the brain, where it is cleaved by brain reductases, generating two active molecules of EC33 which inhibit brain APA activity, block the formation of brain AngIII and induce a marked and sustained decrease in BP. The RB150-induced BP decrease is due to a reduced vasopressin release, which increases diuresis, reducing extracellular volume, a decrease in sympathetic tone, leading to a reduction of vascular resistances and the improvement of the baroreflex function (Figure below). RB150 was renamed firibastat by OMS. Phase Ia/Ib clinical trials showed that firibastat is clinically and biologically well-tolerated in healthy volunteers. Firibastat could constitute the first drug candidate of a new class of antihypertensive agents targeting the brain RAS, the clinical efficacy of which (Phase IIa and Phase IIb) in hypertensive patients was achieved. Acknowledgement/Funding INSERM, College de France, ANR LabCom, Quantum Genomics

Эффекты добавочного дыхательного сопротивления у подростков с повышенным тонусом симпатической нервной системы

Изучены закономерности изменения вегетативного компонента регуляции деятельности сердца при включении дозированного дыхания с добавочным сопротивлением (ДДС) у подростков с исходным преобладанием тонуса симпатической нервной системы (ПТСНС). Методы. В исследовании приняли участие 17 человек, из них 8 юношей и 9 девушек, в возрасте от 14 до 17 лет. Всем добровольцам проводили регистрацию кардиоинтервалограммы с анализом вариабельности сердечного ритма (ВСР) до и во время дыхания c ДДС. Проводили анализ ВСР с выявлением вегетативного тонуса у детей с исходно ПТСНС. Результаты. Выявлено значимое снижение тонуса симпатической и возрастание тонуса парасимпатической нервной системы у детей с ПТСНС. Результаты работы позволяют прогнозировать изменения вегетативной регуляции деятельности сердца у детей в условиях закрытого помещения с длительно находящимися там людьми. Changes in neurogenic regulation of the heart function were studied after the onset of dosed lung ventilation with artificially increased total airway resistance in 8 male and 9 female adolescents aged 14-17 with originally high tone of the sympathetic system. Analysis of cardiointervalography and heart rate variability showed a significant decrease in sympathetic tone and an increase in parasympathetic tone due to the respiration with additional resistance, which can be regarded as a model for prediction of changes in neurogenic regulation of the heart function in children after a lengthy stay in a stuffy, enclosed area.

Prophylactic Ketamine for Prevention of Post-Spinal Shivering: Randomised Controlled Trial

Background: Post spinal anaesthesia shivering is a common complication and a leading cause of discomfort to patients under spinal anaesthesia. It follows a decrease in sympathetic tone which results in vasodilatation and redistribution of heat from core to peripheral part of the body. The physiological consequences of shivering include increase in cardiac and systemic energy expenditure, oxygen consumption and carbon dioxide production. Objective: The aim of this study was to compare prophylactic low dose intravenous ketamine with placebo for prevention of post spinal anaesthesia shivering. Methods: Following Institutional Ethical Review committee approval, this randomized, double blind study was conducted on eighty two patients aged ranged 16 to 50 years and ASA I and II who had repair of vesicio-vaginal fistula under spinal anaesthesia. Immediately after the spinal anaesthesia was established; Groups K and S received iv ketamine 0.25 mg/kg diluted to 5 mls and iv normal saline 5mls respectively. Incidence of shivering, haemodynamic parameters and side effects were assessed as primary outcome measures. Results: The incidence of shivering in groups S and K was 46.3% vs 7.3% in Group S compared to Group K respectively. Two (4.8%) patients had hallucination and 1 (2.4%) patient vomited among the group K patients. Similarly, mean arterial blood pressure, heart rates at 5 and 10 minutes after the spinal anaesthesia Group K were significantly higher. Conclusion: The use of prophylactic low dose ketamine significantly reduced spinal anaesthesia-induced shivering.

Effect of interscalene block on intraocular pressure and ocular perfusion pressure

BackgroundInterscalene block (ISB) is commonly associated with Horner’s syndrome due to spread of local anesthetic to the cervical sympathetic chain. Postganglionic neurons that originate from superior cervical ganglia form the sympathetic innervation of eye. Decrease in sympathetic tone may change intraocular pressure (IOP) and ocular perfusion pressure (OPP). The aim of the study was to investigate whether ISB affects IOP and/or OPP.MethodsThirty patients scheduled for ambulatory shoulder surgery under regional anesthesia with a single-shot ISB (15 mL 0.5% bupivacaine and 15 mL 2% lidocaine) were recruited. The IOP and OPP in both eyes, mean arterial pressure (MAP), heart rate (HR) and end-tidal CO2 (ETCO2) were measured before ISB and 5, 10, 20, 30 and 60 min after ISB in the beach-chair position.ResultsThe baseline IOP and OPP were similar in the blocked and unblocked sides (IOP 17.60 ± 1.69 and 17.40 ± 1.96 respectively p = 0.432; OPP 49.80 ± 8.20 and 50 ± 8.07 respectively p = 0.432). The IOP in the blocked side significantly decreased between 10th to 60th min following ISB, compared to the baseline values (p < 0.001). The OPP in the blocked side significantly increased from 10th to 60th min (p < 0.001) whereas, there were no significant changes in IOP and OPP throughout the measurement period in the unblocked side.ConclusionsISB decreased IOP in the blocked side. ISB could be considered as a safe regional technique of choice in elderly patients at high risk for developing glaucoma.

Increased Sympathetic Outflow Induces Adaptation to Acute Experimental Pain.

There are interrelationships between the autonomic nervous system and pain. This study aims to explore the effect of different autonomic manipulations on pain perception and modulation. Twenty healthy subjects (10 men and 10 women, mean age 25 ± 3 years) participated in this single-blinded, semi-randomized, controlled study, which included 2 study visits. Warm detection thresholds, heat pain thresholds, conditioned pain modulation (CPM), and pain adaptation were tested before and after administration of phenylephrine, clonidine, yohimbine, and saline. Changes in heart rate and blood pressure were found after all the pharmacological interventions. The only effect on pain measures was that yohimbine enhanced pain adaptation capacity while phenylephrine reduced it (P = 0.032). Several significant correlations were found between autonomic and pain parameters; greater decreases in heart rate after phenylephrine were associated with reduced pain ratings (r2 = 0.288, P = 0.018). In addition, enhanced pain adaptation was associated with higher total vascular resistance (r2 = 0.442, P = 0.01). Different effects of acute autonomic manipulations on experimental pain were found: an increase in sympathetic tone induced by yohimbine led to reduced pain sensitivity; a decrease in sympathetic tone with no effect on vagal-parasympathetic tone induced by phenylephrine led to reduction in pain adaptation capacity; and a decrease in sympathetic tone and increase in vagal parasympathetic tone by clonidine led to no change in pain adaptation capacity. While increased sympathetic outflow does facilitate pain adaptation, activation of either the sympathetic or parasympathetic limbs of the autonomic nervous system does not affect pain thresholds or CPM. Finally, a correlation exists between nociception and cardiovascular parameters only due to baroreflex activation.

Effect of interscalene anaesthesia on cerebral oxygen saturation.

Interscalene blockade (ISB) is commonly associated with Horner's syndrome, indicating spread of injectate to the cervical sympathetic chain. Cervical sympathetic nerve activity (SNA) is believed to influence cerebral autoregulation, and a decrease in sympathetic tone may alter cerebral blood flow (CBF). This study investigated whether ISB influenced CBF in patients undergoing shoulder surgery. Patients (n=30) scheduled for elective shoulder arthroscopy were recruited. Cerebral oxygen saturation (ScO(2)) of the left and right frontal cortices was continuously measured during ISB administration, sedation and anaesthetic induction. Baseline ScO(2) was similar in blocked and unblocked sides (74 ± 5% and 73 ± 5% respectively, P=0.70). ScO(2) decreased with sedation (-3 ± 3% and -4 ± 3%, P=0.93), and increased with pre-oxygenation and general anaesthesia (P <0.01). Following ISB there was no change in ScO(2) between blocked and unblocked sides (P=0.18), or any difference between right- or left-sided ISB. ISB is not associated with an increase in CBF as indicated by ScO(2), despite the presence of Horner's syndrome.

Gender differences in cardiovascular functions during exercise: a brief review

Exercise is a major challenge for the cardiovascular apparatus, since it has to provide adequate oxygen supply to exercising muscles and to guarantee arterial blood pressure regulation. Several adjustments, such as heart rate increase, contractility enhancement, and venous return modulation are made to accomplish this task. Furthermore, regular physical training induces several physiological adaptations due to an increase in parasympathetic and a decrease in sympathetic tone and to chronic increases in cardiac pre-load and after-load. There are gender-related physiological and morphological differences in the cardiovascular adjustments and adaptations to physical exercise in humans. In this review, we briefly summarize these differences. Moreover, differences in ECG pattern between sexes are discussed.

Evaluation of the influence of ayurvedic formulation (Ayushman-15) on psychopathology, heart rate variability and stress hormonal level in major depression (Vishada)

IntroductionAyurveda (Indian-complimentary and alternative medicine) is still most sought after in India and has promising potential in management of Vishada [major depressive disorder (MDD)]. But, systematic research is lacking. In this study we evaluated of influence of ayurvedic treatment (Panchakarma and Ayushman-15) on psychopathology, heart rate variability (HRV) and endocrinal parameters in patients with major depression. Methods81 drug naive patients diagnosed as Vishada by ayurvedic physician and MDD according to DSM IV-TR were given ayurvedic Virechana module (therapeutic purgation) and were randomized into two groups. Patients in group A (n=41) received Ayushman-15A while group B (n=40) received Ayushman-15B for two months and Shirodhara (forehead-oil pouring therapy). Patients were assessed with Hamilton Depression Rating Scale (HDRS), Montgomery Asberg Depression Rating Scale (MADRS), Heart Rate Variability (HRV). Cortisol and adrenocorticotropic hormone (ACTH) were estimated at baseline and after ayurvedic therapy. HRV and endocrinal parameters were compared with age and gender matched healthy volunteers. ResultsHRV parameters showed significant sympathetic dominance in patients compared to healthy volunteers. Two months of ayurvedic treatment significantly decreased psychopathology, showed increase in vagal tone, decrease in sympathetic tone and reduced cortisol levels. However, there was no significant difference between groups receiving Ayushman A and B. ConclusionThis study provides evidence for antidepressant, cardiac (HRV) and beneficial neuroendocrine modulatory influence of Ayurveda therapy in patients of Vishada (MDD). Further studies are needed to confirm these findings. Greater insight into the neurobiology behind this therapy might provide valuable information about newer drug target.

A new strategy for treating hypertension by blocking the activity of the brain renin–angiotensin system with aminopeptidase A inhibitors

Hypertension affects one-third of the adult population and is a growing problem due to the increasing incidence of obesity and diabetes. Brain RAS (renin-angiotensin system) hyperactivity has been implicated in the development and maintenance of hypertension in several types of experimental and genetic hypertension animal models. We have identified in the brain RAS that APA (aminopeptidase A) and APN (aminopeptidase N), two membrane-bound zinc metalloproteases, are involved in the metabolism of AngII (angiotensin II) and AngIII (angiotensin III) respectively. The present review summarizes the main findings suggesting that AngIII plays a predominant role in the brain RAS in the control of BP (blood pressure). We first explored the organization of the APA active site by site-directed mutagenesis and molecular modelling. The development and the use in vivo of specific and selective APA and APN inhibitors EC33 and PC18 respectively, has allowed the demonstration that brain AngIII generated by APA is one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control over BP in conscious hypertensive rats. This identified brain APA as a potential therapeutic target for the treatment of hypertension, which has led to the development of potent orally active APA inhibitors, such as RB150. RB150 administered orally in hypertensive DOCA (deoxycorticosteroneacetate)-salt rats or SHRs (spontaneously hypertensive rats) crosses the intestinal, hepatic and blood-brain barriers, enters the brain, generates two active molecules of EC33 which inhibit brain APA activity, block the formation of brain AngIII and normalize BP for several hours. The decrease in BP involves two different mechanisms: a decrease in vasopressin release into the bloodstream, which in turn increases diuresis resulting in a blood volume reduction that participates in the decrease in BP and/or a decrease in sympathetic tone, decreasing vascular resistance. RB150 constitutes the prototype of a new class of centrally acting antihypertensive agents and is currently being evaluated in a Phase Ib clinical trial.

Dissociation between blood pressure and heart rate response to hypoxia after bilateral carotid body removal in men with systolic heart failure

While the ventilatory response to hypoxia is known to be mediated by the carotid bodies, the origin of the haemodynamic alterations evoked by hypoxia is less certain. Bilateral carotid body removal (CBR) performed to treat congestive heart failure may serve as a model to improve our understanding of haemodynamic responses to hypoxia in humans. We studied six congestive heart failure patients before and 1month after CBR [median (interquartile range): age, 58.5(56-61)years old; and ejection fraction, 32(25-34)%]. Peripheral chemosensitivity (hypoxic ventilatory response) was equated to the slope relating lowest oxygen saturation to highest minute ventilation following exposures to hypoxia. Likewise, systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) slopes were calculated as slopes relating the lowest oxygen saturations to the highest SBP, DBP and HR responses. We found that CBR reduces the hypoxic ventilatory response (91%, P<0.05), SBP (71%, P<0.05) and DBP slopes (59%, P=0.07). In contrast, the HR slope remained unchanged. The dissociation between the blood pressure and HR responses after CBR shows involvement of a different chemoreceptive site(s) maintaining the response to acute hypoxia. We conclude that carotid bodies are responsible for ventilatory and blood pressure responses, while the HR response might be mediated by the aortic bodies. The significant reduction of the blood pressure response to hypoxia after CBR suggests a decrease in sympathetic tone, which is of particular clinical relevance in congestive heart failure.

Viewpoint: Is the resting bradycardia in athletes the result of remodeling of the sinoatrial node rather than high vagal tone?

it is well known that athletes have a low resting heart rate, i.e., a resting bradycardia and heart rates below 30 beats/min have been reported ([7][1]). For example, Wikipedia states that the Tour de France cyclist, Miguel Indurain, had a resting heart rate of 28 beats/min when race fit. The