Input-size dependence of the baroreflex neural arc transfer characteristics during Gaussian white noise inputs.

Although Gaussian white noise (GWN) inputs offer a theoretical framework for identifying higher-order nonlinearity, an actual application to the data of the neural arc of the carotid sinus baroreflex did not succeed in fully predicting the well-known sigmoidal nonlinearity. In the present study, we assumed that the neural arc can be approximated by a cascade of a linear dynamic (LD) component and a nonlinear static (NS) component. We analyzed the data obtained using GWN inputs with a mean of 120 mmHg and standard deviations (SDs) of 10, 20, and 30 mmHg for 15 min each in anesthetized rats (n = 7). We first estimated the linear transfer function from carotid sinus pressure to sympathetic nerve activity (SNA) and then plotted the measured SNA against the linearly predicted SNA. The predicted and measured data pairs exhibited an inverse sigmoidal distribution when grouped into 10 bins based on the size of the linearly predicted SNA. The sigmoidal nonlinearity estimated via the LD-NS model showed a midpoint pressure (104.1 ± 4.4 mmHg for SD of 30 mmHg) lower than that estimated by a conventional stepwise input (135.8 ± 3.9 mmHg, P < 0.001). This suggests that the NS component is more likely to reflect the nonlinearity observed during pulsatile inputs that are physiological to baroreceptors. Furthermore, the LD-NS model yielded higher R2 values compared with the linear model and the previously suggested second-order Uryson model in the testing dataset.NEW & NOTEWORTHY We examined the input-size dependence of the baroreflex neural arc transfer characteristics during Gaussian white noise inputs. A linear dynamic-static nonlinear model yielded higher R2 values compared with a linear model and captured the well-known sigmoidal nonlinearity of the neural arc, indicating that the nonlinear dynamics contributed to determining sympathetic nerve activity. Ignoring such nonlinear dynamics might reduce our ability to explain underlying physiology and significantly limit the interpretation of experimental data.

Chronic Metformin Administration Does Not Alter Carotid Sinus Nerve Activity in Control Rats.

Metformin is a glucose-lowering, insulin-sensitizing drug that is commonly used in the treatment of type 2 diabetes (T2D). In the last decade, the carotid body (CB) has been described as a metabolic sensor implicated in the regulation of glucose homeostasis, being CB dysfunction crucial for the development of metabolic diseases, such as T2D. Knowing that metformin could activate AMP-activated protein kinase (AMPK) and that AMPK has been described to have an important role in CB hypoxic chemotransduction, herein we have investigated the effect of chronic metformin administration on carotid sinus nerve (CSN) chemosensory activity in basal and hypoxic and hypercapnic conditions in control animals. Experiments were performed in male Wistar rats subjected to 3 weeks of metformin (200 mg/kg) administration in the drinking water. The effect of chronic metformin administration was tested in spontaneous and hypoxic (0% and 5% O2) and hypercapnic (10% CO2) evoked CSN chemosensory activity. Metformin administration for 3 weeks did not modify the basal CSN chemosensory activity in control animals. Moreover, the CSN chemosensory response to intense and moderate hypoxia and hypercapnia was not altered by the chronic metformin administration. In conclusion, chronic metformin administration did not modify chemosensory activity in control animals.

No Evidence for Long Term Blood Pressure Differences Between Eversion and Conventional Carotid Endarterectomy in Two Independent Study Cohorts.

OBJECTIVE: Blood pressure (BP) management is a vital aspect of stroke prevention and post-stroke care. Different surgical carotid endarterectomy (CEA) techniques may impact on BP control post-operatively. Specifically, the carotid sinus nerve, which innervates the carotid baroreceptors and carotid body, is commonly left intact during conventional CEA but is routinely transected as part of eversion CEA. The aim of this study was to assess long term BP control after eversion and conventional CEA. METHODS: Patients from the International Carotid Stenting Study (ICSS cohort) and a personal series of patients from the Stroke Clinical Trials Unit at University College London (UCL cohort) were separately analysed and divided into eversion and conventional CEA groups. Mixed effect linear models were fitted and adjusted for baseline demographic data and antihypertensive treatment to test for changes in BP from baseline over a three year follow up period after the respective procedures. RESULTS: There were no differences in changes in baseline BP readings and follow up readings between eversion and conventional CEA in the ICSS or UCL cohorts. In the ICSS cohort a mild but significant systolic (-8.6 mmHg; 95% confidence interval [CI] -10.6 - -6.6) and diastolic (-4.9 mmHg; 95% CI -6.0 - -3.8) BP lowering effect was evident at discharge in the conventional group but not in the eversion CEA group. BP monitoring during follow up did not reveal any consistent BP changes with either conventional or eversion CEA vs. baseline levels. CONCLUSION: Neither conventional nor eversion CEA seem to result in clinically significant long term BP changes. Potential concerns related to either short or long term alterations in BP levels with transection of the carotid sinus nerve during eversion CEA could not be substantiated.

Quantitative Prediction of the Location of Carotid Bifurcation and Neurovascular Structures in the Carotid Region: A Cross-Sectional Cadaveric Study.

INTRODUCTION: The carotid region is encountered in vascular and neurological surgery and carries a potential for vascular and cranial nerve trauma. The carotid bifurcation is an especially important landmark and difficult to predict based on currently established landmarks. This study is a detailed analysis of the carotid region and proposes a novel methodology to predict the height of the bifurcation. MATERIALS AND METHODS: Superficial and deep dissections were performed on the anterior triangle of the neck to expose the carotid region in twenty-one formalin-fixed donor cadavers. Musculoskeletal and neurovascular structures were assessed in relation to the carotid bifurcation and the medial border of the clavicle (MBC). RESULTS: The carotid bifurcation occurred, on average, 11.4 mm higher on the left (p < 0.001; 95% CI: 9.28, 13.54). The superior thyroid artery (p < 0.001), facial vein (p < 0.001), and cranial nerve XII (p < 0.001) were all more distal on the left side when measured from the MBC while the angle of the mandible and stylohyoid muscle remained symmetric. Left- and right-sided vascular structures were symmetric when measured from the carotid bifurcation. CONCLUSIONS: Neurovascular structures within the carotid region are likely to be anatomically superior on the left side while vessels are likely to remain symmetric in relation to the carotid bifurcation. When measured from the MBC, the bifurcation height can be predicted by multiplying the distance between the MBC and mastoid process by 0.65 (right side) or 0.74 (left side). This novel methodological estimation may be easily learned and directly implemented in clinical practice.

Efficacy of Carotid Artery Stenting Performed under General Anesthesia with Somatosensory Evoked Potential Monitoring.

OBJECTIVES: During carotid artery stenting (CAS), hemodynamics may be affected by the carotid sinus reflex in some cases. Although general anesthesia has been reported to stabilize intraoperative hemodynamics, the patient's neurological condition must be assessed indirectly. Therefore, we investigated the changes in intraoperative hemodynamics and perioperative complications of CAS under general anesthesia and evaluated the efficacy of somatosensory evoked potential (SEP) monitoring in detecting a reduction in perfusion during CAS. MATERIALS AND METHODS: From April 2011 to August 2016,57 consecutive patients who underwent CAS under general anesthesia were evaluated. The follow-up period ranged from 3 to 8 years. During CAS, anesthesiologists monitored and managed the hemodynamics. SEP monitoring was performed during the CAS procedure in all patients. RESULTS: Intraoperative hypotension (systolic blood pressure ≤ 100 mmHg) was evident in 16 patients (28.1%), and 13 patients (22.8%) experienced intraoperative bradycardia; however, all of these cases were promptly managed under general anesthesia. None of the patients showed systolic blood pressure < 50 mmHg from baseline. Regarding perioperative complications, none of the patients exhibited myocardial infarction or postoperative hyperperfusion symptoms, and there was no mortality. Among 21 patients (36.8%) with a decrease in the intraoperative SEP, 3 (5.3%) exhibited transient ischemic symptoms and 1 (1.8%) had postoperative infarction. CONCLUSIONS: CAS under general anesthesia is a safe and effective management option in terms of intraoperative hemodynamic stability. In addition, our findings indicate that SEP monitoring could be helpful in evaluating transient postoperative cerebral ischemia or cerebral infarction after CAS.

Electrostimulation of the carotid sinus nerve in mice attenuates inflammation via glucocorticoid receptor on myeloid immune cells.

BACKGROUND: The carotid bodies and baroreceptors are sensors capable of detecting various physiological parameters that signal to the brain via the afferent carotid sinus nerve for physiological adjustment by efferent pathways. Because receptors for inflammatory mediators are expressed by these sensors, we and others have hypothesised they could detect changes in pro-inflammatory cytokine blood levels and eventually trigger an anti-inflammatory reflex. METHODS: To test this hypothesis, we surgically isolated the carotid sinus nerve and implanted an electrode, which could deliver an electrical stimulation package prior and following a lipopolysaccharide injection. Subsequently, 90 min later, blood was extracted, and cytokine levels were analysed. RESULTS: Here, we found that carotid sinus nerve electrical stimulation inhibited lipopolysaccharide-induced tumour necrosis factor production in both anaesthetised and non-anaesthetised conscious mice. The anti-inflammatory effect of carotid sinus nerve electrical stimulation was so potent that it protected conscious mice from endotoxaemic shock-induced death. In contrast to the mechanisms underlying the well-described vagal anti-inflammatory reflex, this phenomenon does not depend on signalling through the autonomic nervous system. Rather, the inhibition of lipopolysaccharide-induced tumour necrosis factor production by carotid sinus nerve electrical stimulation is abolished by surgical removal of the adrenal glands, by treatment with the glucocorticoid receptor antagonist mifepristone or by genetic inactivation of the glucocorticoid gene in myeloid cells. Further, carotid sinus nerve electrical stimulation increases the spontaneous discharge activity of the hypothalamic paraventricular nucleus leading to enhanced production of corticosterone. CONCLUSION: Carotid sinus nerve electrostimulation attenuates inflammation and protects against lipopolysaccharide-induced endotoxaemic shock via increased corticosterone acting on the glucocorticoid receptor of myeloid immune cells. These results provide a rationale for the use of carotid sinus nerve electrostimulation as a therapeutic approach for immune-mediated inflammatory diseases.

Carotid sinus nerve stimulation attenuates alveolar bone loss and inflammation in experimental periodontitis.

Baroreceptor and chemoreceptor reflexes modulate inflammatory responses. However, whether these reflexes attenuate periodontal diseases has been poorly examined. Thus, the present study determined the effects of electrical activation of the carotid sinus nerve (CSN) in rats with periodontitis. We hypothesized that activation of the baro and chemoreflexes attenuates alveolar bone loss and the associated inflammatory processes. Electrodes were implanted around the CSN, and bilateral ligation of the first mandibular molar was performed to, respectively, stimulate the CNS and induce periodontitis. The CSN was stimulated daily for 10 min, during nine days, in unanesthetized animals. On the eighth day, a catheter was inserted into the left femoral artery and, in the next day, the arterial pressure was recorded. Effectiveness of the CNS electrical stimulation was confirmed by hypotensive responses, which was followed by the collection of a blood sample, gingival tissue, and jaw. Long-term (9 days) electrical stimulation of the CSN attenuated bone loss and the histological damage around the first molar. In addition, the CSN stimulation also reduced the gingival and plasma pro-inflammatory cytokines induced by periodontitis. Thus, CSN stimulation has a protective effect on the development of periodontal disease mitigating alveolar bone loss and inflammatory processes.

Endogenous hydrogen sulfide maintains eupnea in an in situ arterially perfused preparation of rats.

Hydrogen sulfide (H2S) is constitutively generated in the human body and works as a gasotransmitter in synaptic transmission. In this study, we aimed to evaluate the roles of endogenous H2S in generating eupnea at the respiratory center. We employed an in situ arterially perfused preparation of decerebrated rats and recorded the central respiratory outputs. When the H2S-producing enzyme cystathionine ß-synthase (CBS) was inhibited, respiration switched from the 3-phase eupneic pattern, which consists of inspiration, postinspiration, and expiration, to gasping-like respiration, which consists of inspiration only. On the other hand, when H2S synthesis was inhibited via cystathionine γ-lyase (CSE) or when H2S synthesis was activated via CBS, eupnea remained unchanged. These results suggest that H2S produced by CBS has crucial roles in maintaining the neuronal network to generate eupnea. The mechanism of respiratory pattern generation might be switched from a network-based system to a pacemaker cell-based system in low H2S conditions.

TRPC6 participates in the development of blood pressure variability increase in sino-aortic denervated rats.

Increased blood pressure variability (BPV) has been proved to be associated with cardiovascular morbidity and mortality. It is of great significance to elucidate the mechanism of BPV increase. The cation channel transient receptor potential canonical 6 (TRPC6) is involved in a series of cardiovascular disease. Our experiment aimed to explore the role of TRPC6 in the development of BPV increase. Sino-aortic denervation (SAD) operation was applied to establish the model of BPV increase in rats. The BPV was presented as the standard deviation to the mean of systolic or diastolic blood pressure every 1 h during 12 h of the light period. SAD was performed in male Sprague Dawley (SD) rats at the age of 10 weeks. At 8 weeks after SAD operation, the hemodynamic parameters were determined non-invasively via a Rodent Blood Pressure Analysis System. The TRPC6 expressions in myocardial and thoracic aortic tissue was determined utilizing Western Blot, immunofluorescence and quantitative RT-PCR. The expression of TRPC3 was detected as well. To investigate whether TRPC6 was a causative factor of BPV increase in SAD rats, TRPC6 activator and inhibitor with three progressively increasing doses were intraperitoneally injected to the SAD rats. We found that SAD rats presented significant augmentation of systolic and diastolic BPV with no change of BP level and heart rate. The mRNA and protein expression levels of TRPC6 in myocardial and thoracic aortic tissue in SAD rats were substantially increased, but there was no obvious change in TRPC3 expression. The systolic and diastolic BPV increase were dose-dependently exacerbated after TRPC6 activation with GSK1702934A but were dose-dependently attenuated after TRPC6 inhibition with SAR7334. In Conclusion, the TRPC6 (but not TRPC3) expressions in myocardial and thoracic aortic tissue were substantially increased in SAD rats, and TRPC6 probably played an important role in the development of BPV elevation.

The potential role of the carotid body in COVID-19.

The carotid body (CB) plays a contributory role in the pathogenesis of various respiratory, cardiovascular, renal, and metabolic diseases through reflex changes in ventilation and sympathetic output. On the basis of available data about peripheral arterial chemoreception and severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), a potential involvement in the coronavirus disease 2019 (COVID-19) may be hypothesized through different mechanisms. The CB could be a site of SARS-CoV-2 invasion, due to local expression of its receptor [angiotensin-converting enzyme (ACE) 2] and an alternative route of nervous system invasion, through retrograde transport along the carotid sinus nerve. The CB function could be affected by COVID-19-induced inflammatory/immune reactions and/or ACE1/ACE2 imbalance, both at local or systemic level. Increased peripheral arterial chemosensitivity and reflex sympatho-activation may contribute to the increased morbidity and mortality in COVID-19 patients with respiratory, cardiovascular, renal, or metabolic comorbidities.

The carotid sinus acts as a mechanotransducer of shear oscillation rather than a baroreceptor.

The carotid sinus is a dilated area at the base of the internal carotid artery of humans and is located immediately superior to the bifurcation of the internal and external carotid arteries. It is widely accepted, in the fields of medicine and physiology, to function as a baroreceptor in its central control role. This paper presents a hypothesis challenging this paradigm - that the carotid sinus functions by detecting oscillations at the vessel wall which result from shear stress due to vortical flow. This is contrary to conventional thinking which presumes that the carotid sinus responds to blood pressure or wall pressure. Our hypothesis is based on anatomy, physiology and physical properties of fluid which make the sinus the area of highest vorticity. Utilizing magnetic resonance angiograms of undiseased carotid vessels, we computed the oscillatory shear index (OSI) via a computational fluid dynamics simulation of flow. This region of highest OSI coincides with the area where the nerve to the carotid sinus lies within the vessel wall. Accordingly, the hypothesis is that the carotid sinus acts as a mechanotransducer of wall shear stress oscillation and not as a baroreceptor.

Feasibility of kilohertz frequency alternating current neuromodulation of carotid sinus nerve activity in the pig.

Recent research supports that over-activation of the carotid body plays a key role in metabolic diseases like type 2 diabetes. Supressing carotid body signalling through carotid sinus nerve (CSN) modulation may offer a therapeutic approach for treating such diseases. Here we anatomically and histologically characterised the CSN in the farm pig as a recommended path to translational medicine. We developed an acute in vivo porcine model to assess the application of kilohertz frequency alternating current (KHFAC) to the CSN of evoked chemo-afferent CSN responses. Our results demonstrate the feasibility of this approach in an acute setting, as KHFAC modulation was able to successfully, yet variably, block evoked chemo-afferent responses. The observed variability in blocking response is believed to reflect the complex and diverse anatomy of the porcine CSN, which closely resembles human anatomy, as well as the need for optimisation of electrodes and parameters for a human-sized nerve. Overall, these results demonstrate the feasibility of neuromodulation of the CSN in an anesthetised large animal model, and represent the first steps in driving KHFAC modulation towards clinical translation. Chronic recovery disease models will be required to assess safety and efficacy of this potential therapeutic modality for application in diabetes treatment.

Carotid baroreceptor stimulation in obese rats affects white and brown adipose tissues differently in metabolic protection.

The sympathetic nervous system (SNS) regulates the functions of white adipose tissue (WAT) and brown adipose tissue (BAT) tightly. Carotid baroreceptor stimulation (CBS) efficiently inhibits SNS activation. We hypothesized that CBS would protect against obesity. We administered CBS to obese rats and measured sympathetic and AMP-activated protein kinase (AMPK)/ PPAR pathway responses as well as changes in perirenal WAT (PWAT), epididymal WAT (EWAT), and interscapular BAT (IBAT). CBS alleviated obesity-related metabolic changes, improving insulin resistance; reducing adipocyte hypertrophy, body weight, and adipose tissue weights; and decreasing norepinephrine but increasing acetylcholine in plasma, PWAT, EWAT, and IBAT. CBS also downregulated fatty acid translocase (CD36), fatty acid transport protein (FATP), phosphorylated and total hormone sensitive lipase, phosphorylated and total protein kinase A, and PPARγ in obese rats. Simultaneously, CBS upregulated phosphorylated adipose triglyceride lipase, phosphorylated and total AMPK, and PPARα in PWAT, EWAT, and IBAT. However, BAT and WAT responses differed; although many responses were more sensitive in IBAT, responses of CD36, FATP, and PPARγ were more sensitive in PWAT and EWAT. Overall, CBS decreased chronically activated SNS and ameliorated obesity-related metabolic disorders by regulating the AMPK/PPARα/γ pathway.

Carotid Sinus Nerve: A Comprehensive Review of Its Anatomy, Variations, Pathology, and Clinical Applications.

The carotid sinus nerve branches off the glossopharyngeal nerve just after its appearance from the jugular foramen, descends along the internal carotid artery, and enters the carotid sinus. There have been many studies of the pathway and the course of the carotid sinus nerve and its communications with surrounding nerves. The intercommunication is exceedingly complicated. Acknowledgment of its anatomic diversity can be important in specific operations dealing with this area. Herein we review the anatomy, variations, pathology, and clinical applications of the carotid sinus nerve.

The Carotid Sinus Nerve-Structure, Function, and Clinical Implications.

Interest has been renewed in the anatomy and physiology of the carotid sinus nerve (CSN) and its targets (carotid sinus and carotid body, CB), due to recent proposals of surgical procedures for a series of common pathologies, such as carotid sinus syndrome, hypertension, heart failure, and insulin resistance. The CSN originates from the glossopharyngeal nerve soon after its appearance from the jugular foramen. It shows frequent communications with the sympathetic trunk (usually at the level of the superior cervical ganglion) and the vagal nerve (main trunk, pharyngeal branches, or superior laryngeal nerve). It courses on the anterior aspect of the internal carotid artery to reach the carotid sinus, CB, and/or intercarotid plexus. In the carotid sinus, type I (dynamic) carotid baroreceptors have larger myelinated A-fibers; type II (tonic) baroreceptors show smaller A- and unmyelinated C-fibers. In the CB, afferent fibers are mainly stimulated by acetylcholine and ATP, released by type I cells. The neurons are located in the petrosal ganglion, and centripetal fibers project on to the solitary tract nucleus: chemosensory inputs to the commissural subnucleus, and baroreceptor inputs to the commissural, medial, dorsomedial, and dorsolateral subnuclei. The baroreceptor component of the CSN elicits sympatho-inhibition and the chemoreceptor component stimulates sympatho-activation. Thus, in refractory hypertension and heart failure (characterized by increased sympathetic activity), baroreceptor electrical stimulation, and CB removal have been proposed. Instead, denervation of the carotid sinus has been proposed for the "carotid sinus syndrome." Anat Rec, 302:575-587, 2019. © 2018 Wiley Periodicals, Inc.

Bilateral carotid sinus nerve transection exacerbates morphine-induced respiratory depression.

Opioid-induced respiratory depression (OIRD) involves decreased sensitivity of ventilatory control systems to decreased blood levels of oxygen (hypoxia) and elevated levels of carbon dioxide (hypercapnia). Understanding the sites and mechanisms by which opioids elicit respiratory depression is pivotal for finding novel therapeutics to prevent and/or reverse OIRD. To examine the contribution of carotid body chemoreceptors OIRD, we used whole-body plethysmography to evaluate hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses including changes in frequency of breathing, tidal volume, minute ventilation and inspiratory drive, after intravenous injection of morphine (10 mg/kg) in sham-operated (SHAM) and in bilateral carotid sinus nerve transected (CSNX) Sprague-Dawley rats. In SHAM rats, morphine produced sustained respiratory depression (e.g., decreases in tidal volume, minute ventilation and inspiratory drive) and reduced the HVR and HCVR responses. Unexpectedly, morphine-induced suppression of HVR and HCVR were substantially greater in CSNX rats than in SHAM rats. This suggests that morphine did not compromise the function of the carotid body-chemoafferent complex and indeed, that the carotid body acts to defend against morphine-induced respiratory depression. These data are the first in vivo evidence that carotid body chemoreceptor afferents defend against rather than participate in OIRD in conscious rats. As such, drugs that stimulate ventilation by targeting primary glomus cells and/or chemoafferent terminals in the carotid bodies may help to alleviate OIRD.

Derangement of open-loop static and dynamic characteristics of the carotid sinus baroreflex in streptozotocin-induced type 1 diabetic rats.

Although diabetes mellitus (DM) is a major risk factor for cardiovascular diseases, changes in open-loop static and dynamic characteristics of the arterial baroreflex in the early phase of DM remain to be clarified. We performed an open-loop systems analysis of the carotid sinus baroreflex in type 1 DM rats 4 to 5 wk after intraperitoneal streptozotocin injection ( n = 9) and we compared the results with control rats ( n = 9). The operating-point baroreflex gain was maintained in the DM rats compared with the control rats (2.07 ± 0.67 vs. 2.66 ± 0.22 mmHg/mmHg, P = 0.666). However, the range of arterial pressure (AP) control was narrower in the DM than in the control group (48.0 ± 5.0 vs. 77.1 ± 4.5 mmHg, P = 0.001), suggesting that the reserve for AP buffering is lost in DM. Although baroreflex dynamic characteristics were relatively preserved, coherences were lower in the DM than in the control group. The decreased coherence in the neural arc may be related to the narrowed quasi-linear range in the static relationship between carotid sinus pressure and sympathetic nerve activity in the DM group. Although the reason for the decreased coherences in the peripheral arc and the total reflex arc was inconclusive, the finding may indicate a loss of integrity of the baroreflex-mediated sympathetic AP control in the DM group. The derangement of the baroreflex dynamic characteristics is progressing occultly in this early stage of type 1 DM in a manner where dynamic gains are relatively preserved around the normal operating point.

Bioelectronic modulation of carotid sinus nerve activity in the rat: a potential therapeutic approach for type 2 diabetes.

AIMS/HYPOTHESIS: A new class of treatments termed bioelectronic medicines are now emerging that aim to target individual nerve fibres or specific brain circuits in pathological conditions to repair lost function and reinstate a healthy balance. Carotid sinus nerve (CSN) denervation has been shown to improve glucose homeostasis in insulin-resistant and glucose-intolerant rats; however, these positive effects from surgery appear to diminish over time and are heavily caveated by the severe adverse effects associated with permanent loss of chemosensory function. Herein we characterise the ability of a novel bioelectronic application, classified as kilohertz frequency alternating current (KHFAC) modulation, to suppress neural signals within the CSN of rodents. METHODS: Rats were fed either a chow or high-fat/high-sucrose (HFHSu) diet (60% lipid-rich diet plus 35% sucrose drinking water) over 14 weeks. Neural interfaces were bilaterally implanted in the CSNs and attached to an external pulse generator. The rats were then randomised to KHFAC or sham modulation groups. KHFAC modulation variables were defined acutely by respiratory and cardiac responses to hypoxia (10% O2 + 90% N2). Insulin sensitivity was evaluated periodically through an ITT and glucose tolerance by an OGTT. RESULTS: KHFAC modulation of the CSN, applied over 9 weeks, restored insulin sensitivity (constant of the insulin tolerance test [KITT] HFHSu sham, 2.56 ± 0.41% glucose/min; KITT HFHSu KHFAC, 5.01 ± 0.52% glucose/min) and glucose tolerance (AUC HFHSu sham, 1278 ± 20.36 mmol/l × min; AUC HFHSu KHFAC, 1054.15 ± 62.64 mmol/l × min) in rat models of type 2 diabetes. Upon cessation of KHFAC, insulin resistance and glucose intolerance returned to normal values within 5 weeks. CONCLUSIONS/INTERPRETATION: KHFAC modulation of the CSN improves metabolic control in rat models of type 2 diabetes. These positive outcomes have significant translational potential as a novel therapeutic modality for the purpose of treating metabolic diseases in humans.

Possible Breathing Influences on the Control of Arterial Pressure After Sino-aortic Denervation in Rats.

PURPOSE OF REVIEW: Surgical removal of the baroreceptor afferents [sino-aortic denervation (SAD)] leads to a lack of inhibitory feedback to sympathetic outflow, which in turn is expected to result in a large increase in mean arterial pressure (MAP). However, few days after surgery, the sympathetic nerve activity (SNA) and MAP of SAD rats return to a range similar to that observed in control rats. In this review, we present experimental evidence suggesting that breathing contributes to control of SNA and MAP following SAD.The purpose of this review was to discuss studies exploring SNA and MAP regulation in SAD rats, highlighting the possible role of breathing in the neural mechanisms of this modulation of SNA. RECENT FINDINGS: Recent studies show that baroreceptor afferent stimulation or removal (SAD) results in changes in the respiratory pattern. Changes in the neural respiratory network and in the respiratory pattern must be considered among mechanisms involved in the modulation of the MAP after SAD.