Carotid Sinus Nerve Stimulation Research Articles

Abstract P388: Electrical Stimulation of the Porcine Carotid Sinus Nerve Reliably Decreases Blood Pressure and Heart Rate

Introduction: Neuromodulation of the baroafferent pathway via direct carotid sinus nerve (CSN) stimulation is recognized as a potential therapeutic modality for treating uncontrolled hypertension. Although proof of concept has been demonstrated acutely in humans, there are many questions that remain in both acute and chronic applications. A translational non-companion large animal model is vital for safe development of this modality. Here we present data on the effects of CSN and baroafferent stimulation in farm pigs. Hypothesis: We hypothesized that an effective CSN-bioelectode interface in the pig would demonstrate significant and reproducible reductions in blood pressure in tandem with pulse rate (PR). Methods: Acute CSN stimulation was investigated in 9 anesthetized Yorkshire pigs. Following general anesthesia, CSNs were exposed and an application-specific electrode was placed. A fixed current paradigm was employed at constant 100Hz and 100µs pulse width. Following contact mapping to identify the baroafferent neurointerface, electrical current was escalated to establish dose-response curves. The primary outcome was systolic blood pressure (SBP) and secondary outcomes were diastolic pressure (DBP) and PR. Data were analyzed in Matlab to extract the baseline BP and PR, during and following stimulation. Statistical calculations used a one-sample Wilcoxon signed rank test. Explanted electrodes with surrounding tissue were evaluated using micro-computed tomography (μCT) and histologically. Results: Six of 9 animals were responders (n=7, 2 sides were stimulated in one animal), CSN stimulation caused average (mean±SD, p<0.001) decreases in SBP (6.8±7.2mmHg) and DBP (3.9±3.7mmHg), which tracked closely with decreases in PR (6.2±5.7bpm). Average maximum decreases were: SBP, 9.3±9.9mmHg; DBP, 7.7±6.4mmHg; and PR, 9.7±8.3bpm. Upon stimulation withdrawal, there was near-immediate recovery of both BP and HR. μCT and histological analysis of tissue samples demonstrated inter-animal anatomic heterogeneity. Conclusions: CSN stimulation causes reproducible reduction in BP synchronous with PR drops followed by near immediate recovery of both with stimulation withdrawal. Variations in animal response may be due to anatomical variation in CSN anatomy that can be overcome with further anatomical study. Pigs provide a robust large-animal model for investigating CSN stimulation, offering a platform to better understand baroafferent stimulation as treatment for uncontrolled hypertension.

Electrical carotid sinus nerve stimulation attenuates experimental colitis induced by acetic acid in rats

AimsThe carotid bodies are sensors that detect physiological signals and convey them to the central nervous system, where the stimuli are processed inducing reflexes through efferent pathways. Recent studies have demonstrated that electrical stimulation of the carotid sinus nerve (CSN) triggers the anti-inflammatory reflex under different conditions. However, whether this electrical stimulation attenuates colitis was never examined. This study aimed to evaluate if the electrical CSN stimulation attenuates the experimental colitis induced by intrarectal administration of acetic acid in rats. MethodsElectrodes were implanted around the CSN to stimulate the CSN, and a catheter was inserted into the left femoral artery to record the arterial pressure. The observation of hypotensive responses confirmed the effectiveness of the electrical CNS stimulation. This maneuver was followed by a 4 % acetic acid or saline administered intrarectally. After 24 h, colons were segmented into distal and proximal parts for macroscopy, histological and biochemical assessment. Key findingsAs expected, the electrical CSN stimulation was effective in decreasing arterial pressure in saline and colitis rats. Moreover, electrical CSN stimulation effectively reduced colonic tissue lesions, colitis scores, and histopathologic parameters associated with colitis. In addition, the CSN stimulation also reduced the colonic mucosa pro-inflammatory cytokine interleukin-1 beta, and increased the anti-inflammatory interleukin-10, in rats submitted to colitis. SignificanceThese findings indicated that electrical CSN stimulation breaks the vicious cycle of local colon inflammation in colitis, which might contribute to its better outcome.

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.

Hypoxia-induced hypotension elicits adenosine-dependent phrenic long-term facilitation after carotid denervation

Moderate acute intermittent hypoxia (AIH) elicits a persistent, serotonin-dependent increase in phrenic amplitude, known as phrenic long-term facilitation (pLTF). Although pLTF was originally demonstrated by carotid sinus nerve stimulation, AIH still elicits residual pLTF in carotid denervated (CBX) rats via a distinct, but unknown mechanism. We hypothesized that exaggerated hypoxia-induced hypotension after carotid denervation leads to greater spinal tissue hypoxia and extracellular adenosine accumulation, thereby triggering adenosine 2A receptor (A2A)-dependent pLTF. Phrenic activity, arterial pressure and spinal tissue oxygen pressure were measured in anesthetized CBX rats. Exaggerated hypoxia-induced hypotension after CBX was prevented via intravenous phenylephrine; without the hypotension, spinal tissue hypoxia during AIH was normalized, and residual pLTF was no longer observed. Spinal A2A (MSX-3), but not serotonin 2 receptor (5-HT2) inhibition (ketanserin), abolished residual pLTF in CBX rats. Thus, pLTF regulation may be altered in conditions impairing sympathetic activity and arterial pressure regulation, such as spinal cord injury.

Circulatory control of phrenic motor plasticity

Acute intermittent hypoxia (AIH) elicits distinct mechanisms of phrenic motor plasticity initiated by brainstem neural network activation versus local (spinal) tissue hypoxia. With moderate AIH (mAIH), hypoxemia activates the carotid body chemoreceptors and (subsequently) brainstem neural networks associated with the peripheral chemoreflex, including medullary raphe serotonergic neurons. Serotonin release and receptor activation in the phrenic motor nucleus then elicits phrenic long-term facilitation (pLTF). This mechanism is independent of tissue hypoxia, since electrical carotid sinus nerve stimulation elicits similar serotonin-dependent pLTF. In striking contrast, severe AIH (sAIH) evokes a spinal adenosine-dependent, serotonin-independent mechanism of pLTF. Spinal tissue hypoxia per se is the likely cause of sAIH-induced pLTF, since local tissue hypoxia elicits extracellular adenosine accumulation. Thus, any physiological condition exacerbating spinal tissue hypoxia is expected to shift the balance towards adenosinergic pLTF. However, since these mechanisms compete for dominance due to mutual cross-talk inhibition, the transition from serotonin to adenosine dominant pLTF is rather abrupt. Any factor that compromises spinal cord circulation will limit oxygen availability in spinal cord tissue, favoring a shift in the balance towards adenosinergic mechanisms. Such shifts may arise experimentally from treatments such as carotid denervation, or spontaneous hypotension or anemia. Many neurological disorders, such as spinal cord injury or stroke compromise local circulatory control, potentially modulating tissue oxygen, adenosine levels and, thus, phrenic motor plasticity. In this brief review, we discuss the concept that local (spinal) circulatory control and/or oxygen delivery regulates the relative contributions of distinct pathways to phrenic motor plasticity.

Interaction between baroreflex and chemoreflex in the cardiorespiratory responses to stimulation of the carotid sinus/nerve in conscious rats.

Electrical stimulation of the carotid baroreflex has been thoroughly investigated for treating drug-resistant hypertension in humans. However, a previous study from our laboratory, performed in conscious rats, has demonstrated that electrical stimulation of the carotid sinus/nerve (CS) activated both the carotid baroreflex as well as the carotid chemoreflex, resulting in hypotension. Additionally, we also demonstrated that the carotid chemoreceptor deactivation potentiated this hypotensive response. Therefore, to further investigate this carotid baroreflex/chemoreflex interaction, besides the hemodynamic responses, we evaluated the respiratory responses to the electrical stimulation of the CS in both intact (CONT) and carotid chemoreceptors deactivated (CHEMO-X) conscious rats. CONT rats showed increased ventilation in response to electrical stimulation of the CS as measured by the respiratory frequency (fR), tidal volume (VT) and minute ventilation (VE), suggesting a carotid chemoreflex activation. The carotid chemoreceptor deactivation abolished all respiratory responses to the electrical stimulation of the CS. Regarding the hemodynamic responses, the electrical stimulation of the CS caused hypotensive responses in CONT rats, which were potentiated by the carotid chemoreceptors deactivation. Heart rate (HR) responses did not differ between groups. In conclusion, the present study showed that the electrical stimulation of the CS, in conscious rats, activates both the carotid baroreflex and the carotid chemoreflex driving an increase in ventilation and a decrease in AP. These findings further contribute to our understanding of the electrical stimulation of CS.

Abstract P285: Carotid Sinus Nerve Stimulation Attenuates Alveolar Bone Loss in Rats With Induced Periodontitis.

Introduction: Few studies have focused on the impact of the progression of periodontitis on hypertension. Baroreflex Activation Therapy (BAT) has been used to treat patients with resistant hypertension. Our laboratory has investigated the role of electrical carotid sinus nerve (CSN) stimulation in unanesthetized rats, on local and systemic inflammation. Since periodontitis is a chronic inflammatory disease, the aim of this study was to evaluate the role of the baro- and chemoreflex activation, by means of electrical stimulation of the CSN, on alveolar bone loss in rats with periodontitis. Methods and Results: Under ketamine/xylazine anesthesia Wistar Hannover rats were implanted with electrodes around the CSN and a catheter inserted into the abdominal aorta for blood pressure recording. After 48h periodontitis was induced by the ligation of the bilateral mandibular first molar, followed by the electrical stimulation of the CSN (1,5-4V, 1ms, 30Hz for 10 min); which was continued during the next eight days. At the 8 th day after the induction of periodontitis, the rats were euthanized and the jaws were resected; besides, microtomographic analysis was performed by bi and three-dimensional quantification using micro-computerized tomography. As compared to baseline results the electrical stimulation of the CSN (N=7) promoted a decrease in mean arterial pressure (108± 8 vs. 91± 5 mmHg; p<0.05) and heart rate (374±10 vs. 319±15 bpm; p<0.05). The CSN stimulated rats (N=7) with periodontitis showed greater bone volume and bone surface than the non-stimulated control rats (N=4) with periodontitis, evaluated by three-dimensional analysis (0.5±0.005 vs. 0.7±0.03 mm 3 ; 16.54±0.22 vs. 23.30±0.66 mm 2 , respectively; p<0.05). Moreover, the CSN stimulated rats with periodontitis presented a decrease of the furcation area and interproximal region as compared to the non-stimulated control rats (1.14±0.06 vs. 0.5±0.07 mm; 3.25±0.03 vs. 2,48±0,13 mm, respectively; p<0.05). Conclusions: Overall, these results demonstrate that stimulation of the CSNs promotes a protective effect on alveolar bone loss elicited by periodontitis involving the activation of the baro- and chemoreflex.

Carotid sinus nerve electrical stimulation in conscious rats attenuates systemic inflammation via chemoreceptor activation

Recent studies demonstrated a critical functional connection between the autonomic (sympathetic and parasympathetic) nervous and the immune systems. The carotid sinus nerve (CSN) conveys electrical signals from the chemoreceptors of the carotid bifurcation to the central nervous system where the stimuli are processed to activate sympathetic and parasympathetic efferent signals. Here, we reported that chemoreflex activation via electrical CSN stimulation, in conscious rats, controls the innate immune response to lipopolysaccharide attenuating the plasma levels of inflammatory cytokines such as tumor necrosis factor (TNF), interleukin 1β (IL-1β) and interleukin 6 (IL-6). By contrast, the chemoreflex stimulation increases the plasma levels of anti-inflammatory cytokine interleukin 10 (IL-10). This chemoreflex anti-inflammatory network was abrogated by carotid chemoreceptor denervation and by pharmacological blockade of either sympathetic - propranolol - or parasympathetic - methylatropine – signals. The chemoreflex stimulation as well as the surgical and pharmacological procedures were confirmed by real-time recording of hemodynamic parameters [pulsatile arterial pressure (PAP) and heart rate (HR)]. These results reveal, in conscious animals, a novel mechanism of neuromodulation mediated by the carotid chemoreceptors and involving both the sympathetic and parasympathetic systems.

Limitation of Infarct Size and the Open Artery Hypothesis: A Conversation With Eugene Braunwald, MD.

Eugene Braunwald received an MD from the New York University School of Medicine. He completed an internal medicine residency at Johns Hopkins Hospital and cardiology fellowships at Mount Sinai Hospital, Columbia University, and the National Heart Institute. He served as chief of cardiology and subsequently clinical director of the institute. From 1968 to 1972, he was the founding chair of medicine at the University of California, San Diego. From 1972 to 1996, he served as chair of medicine at the Brigham and Women’s Hospital. In 1975, he was elected to the National Academy of Sciences. He is now the Distinguished Hersey Professor of Medicine at Harvard Medical School and a senior investigator of the TIMI Study Group, which he founded in 1984. Dr Braunwald replies: I became aware of the importance of AMI in 1951 during an elective in cardiology during my senior year at the New York University School of Medicine. At the time, AMI was by far the most common cause of death in adults in the United States. Of the patients who survived to be admitted to hospitals (no one knew how many AMI patients failed to reach hospital emergency departments), about one third died before discharge, either suddenly, presumably from an arrhythmia, or secondary to pump failure. Of the patients who were discharged alive, about one quarter died within a year, most frequently as a consequence of heart failure or recurrent MI. Pathologists had taught that AMI was usually associated with coronary thrombosis. Indeed, during my cardiology elective, Herrick’s classic article describing AMI was required reading. Its title, “Clinical Features of Sudden Obstruction of the Coronary Arteries,” showed how these 2 conditions (coronary occlusion and AMI) were intertwined.1 My direct involvement in the care of several patients who did not survive the acute event left …

Invasive treatment of resistant hypertension: present and future.

The underlying pathophysiologic concept of diverse invasive devices to treat resistant hypertension (e.g., sympathetic denervation, carotid sinus nerve stimulation) is known for a long time. Since the pioneering work in the 1940s in humans, innovative techniques have been developed resulting in less invasive treatment procedures and, hence, overcoming serious side effects, which in turn improved safety and lead to more widespread use. Recently, new experimental technologies have been or are under evaluation in experiments and first-in-man studies have been conducted. Data with interventional techniques are rapidly expanding and have to be interpreted with caution. Additional data from randomized potentially sham-controlled studies are urgently needed. This article focuses on the increasing work of different invasive approaches for the treatment of resistant hypertension.

New devices in heart failure: an European Heart Rhythm Association report: Developed by the European Heart Rhythm Association; Endorsed by the Heart Failure Association

Several new devices for the treatment of heart failure (HF) patients have been introduced and are increasingly used in clinical practice or are under clinical evaluation in either observational and/or randomized clinical trials. These devices include cardiac contractility modulation, spinal cord stimulation, carotid sinus nerve stimulation, cervical vagal stimulation, intracardiac atrioventricular nodal vagal stimulation, and implantable hemodynamic monitoring devices. This task force believes that an overview on these technologies is important. Special focus is given to patients with HF New York Heart Association Classes III and IV and narrow QRS complex, who represent the largest group in HF compared with patients with wide QRS complex. An overview on potential device options in addition to optimal medical therapy will be helpful for all physicians treating HF patients.

Acute intermittent optogenetic stimulation of glutamatergic NTS neurons induces sympathetic long‐term facilitation

Acute intermittent hypoxia (AIH) induces phrenic and sympathetic long‐term facilitation (LTF). Phrenic LTF can be induced by carotid sinus nerve stimulation, suggesting that hypoxia is not necessary to generate phrenic LTF. To determine if hypoxia is necessary to generate sympathetic LTF, we investigated the effect of acute intermittent optogenetic stimulation (AIO) of glutamatergic NTS neurons on renal sympathetic nerve activity (RSNA) in isoflurane anesthetized, vagotomized and artificially ventilated Sprague‐Dawley rats. AIH was performed by ventilation with 10% oxygen for 1min every 6min for a total of 10 exposures to hypoxia. In a separate group of animals, AAV containing CaMKIIa ‐ hChR2(H134R) ‐ mCherry was injected into NTS to express channelrhodopsin2 in glutamatergic neurons and the same pattern of stimulation as in the AIH protocol was used to stimulate the NTS (20 Hz, 5ms duration and 600mA for 1min every 6min for a total of 10 stimuli). Arterial Pressure (AP), RSNA and heart rate (HR) were compared at baseline (before) and 60min after AIH (n=6) or AIO (n=2). AIH increased AP and HR (P<0.05). RSNA was increased by 85% measured 60min after AIH (P=0.02). AIO increased AP and HR. RSNA similarly increased by 60% measured 60min after AIO. These results suggest that acute intermittent direct stimulation of glutamatergic NTS neurons can induce sympathetic LTF in the absence of hypoxia. Supported by HL‐088052

Differential effect of central command on aortic and carotid sinus baroreceptor-heart rate reflexes at the onset of spontaneous, fictive motor activity

Our laboratory has reported that central command blunts the sensitivity of the aortic baroreceptor-heart rate (HR) reflex at the onset of voluntary static exercise in conscious cats and spontaneous contraction in decerebrate cats. The purpose of this study was to examine whether central command attenuates the sensitivity of the carotid sinus baroreceptor-HR reflex at the onset of spontaneous, fictive motor activity in paralyzed, decerebrate cats. We confirmed that aortic nerve (AN)-stimulation-induced bradycardia was markedly blunted to 26 ± 4.4% of the control (21 ± 1.3 beats/min) at the onset of spontaneous motor activity. Although the baroreflex bradycardia by electrical stimulation of the carotid sinus nerve (CSN) was suppressed (P < 0.05) to 86 ± 5.6% of the control (38 ± 1.2 beats/min), the inhibitory effect of spontaneous motor activity was much weaker (P < 0.05) with CSN stimulation than with AN stimulation. The baroreflex bradycardia elicited by brief occlusion of the abdominal aorta was blunted to 36% of the control (36 ± 1.6 beats/min) during spontaneous motor activity, suggesting that central command is able to inhibit the cardiomotor sensitivity of arterial baroreflexes as the net effect. Mechanical stretch of the triceps surae muscle never affected the baroreflex bradycardia elicited by AN or CSN stimulation and by aortic occlusion, suggesting that muscle mechanoreflex did not modify the cardiomotor sensitivity of aortic and carotid sinus baroreflex. Since the inhibitory effect of central command on the carotid baroreflex pathway, associated with spontaneous motor activity, was much weaker compared with the aortic baroreflex pathway, it is concluded that central command does not force a generalized modulation on the whole pathways of arterial baroreflexes but provides selective inhibition for the cardiomotor component of the aortic baroreflex.

Autocrine and paracrine actions of ATP in rat carotid body

Carotid bodies are peripheral chemoreceptors that detect lowering of arterial blood O(2) level. The carotid body comprises clusters of glomus (type I) cells surrounded by glial-like sustentacular (type II) cells. Hypoxia triggers depolarization and cytosolic [Ca(2+)] ([Ca(2+)](i)) elevation in glomus cells, resulting in the release of multiple transmitters, including ATP. While ATP has been shown to be an important excitatory transmitter in the stimulation of carotid sinus nerve, there is considerable evidence that ATP exerts autocrine and paracrine actions in carotid body. ATP acting via P2Y(1) receptors, causes hyperpolarization in glomus cells and inhibits the hypoxia-mediated [Ca(2+)](i) rise. In contrast, adenosine (an ATP metabolite) triggers depolarization and [Ca(2+)](i) rise in glomus cells via A(2A) receptors. We suggest that during prolonged hypoxia, the negative and positive feedback actions of ATP and adenosine may result in an oscillatory Ca(2+) signal in glomus cells. Such mechanisms may allow cyclic release of transmitters from glomus cells during prolonged hypoxia without causing cellular damage from a persistent [Ca(2+)](i) rise. ATP also stimulates intracellular Ca(2+) release in sustentacular cells via P2Y(2) receptors. The autocine and paracrine actions of ATP suggest that ATP has important roles in coordinating chemosensory transmission in the carotid body.

Carotid sinus nerve stimulation, but not intermittent hypoxia, induces respiratory LTF in adult rats exposed to neonatal intermittent hypoxia

We tested the hypothesis that exposure to neonatal intermittent hypoxia (n-IH) in rat pups alters central integrative processes following acute and intermittent peripheral chemoreceptor activation in adults. Newborn male rats were exposed to n-IH or normoxia for 10 consecutive days after birth. We then used both awake and anesthetized 3- to 4-mo-old rats to record ventilation, blood pressure, and phrenic and splanchnic nerve activities to assess responses to peripheral chemoreflex activation (acute hypoxic response) and long-term facilitation (LTF, long-term response after intermittent hypoxia). In anesthetized rats, phrenic and splanchnic nerve activities and hypoxic responses were also recorded with or without intact carotid body afferent signal (bilateral chemodenervation) or in response to electrical stimulations of the carotid sinus nerve. In awake rats, n-IH alters the respiratory pattern (higher frequency and lower tidal volume) and increased arterial blood pressure in normoxia, but the ventilatory response to repeated hypoxic cycles was not altered. In anesthetized rats, phrenic nerve responses to repeated hypoxic cycles or carotid sinus nerve stimulation were not altered by n-IH; however, the splanchnic nerve response was suppressed by n-IH compared with control. In control rats, respiratory LTF was apparent in anesthetized but not in awake animals. In n-IH rats, respiratory LTF was not apparent in awake and anesthetized animals. Following intermittent electrical stimulation, however, phrenic LTF was clearly present in n-IH rats, being similar in magnitude to controls. We conclude that, in adult n-IH rats: 1) arterial blood pressure is elevated, 2) peripheral chemoreceptor responses to hypoxia and its central integration are not altered, but splanchnic nerve response is suppressed, 3) LTF is suppressed, and 4) the mechanisms involved in the generation of LTF are still present but are masked most probably as the result of an augmented inhibitory response to hypoxia in the central nervous system.

Interactions of carotid sinus or aortic input with emetic signals from gastric afferents and vestibular system

This study investigated how baro- and chemoreceptor afferents interact with emetic signals from gastric afferents and the vestibular system, and how these interactions modulate emetic and prodromal responses. We performed splanchnic denervation and abdominal vagotomy in anesthetized shrews ( Suncus murinus), and then induced emetic responses by gastric distension. Next, we investigated the effects of these gastric afferent sections on cardiovascular and emetic responses induced by electrical stimulation of the aortic depressor nerve (ADN) and the carotid sinus nerve (CSN) with or without gastric distension. Splanchnic denervation abolished the prodromal response before retching and aortic baroreflex inhibition caused by gastric distension, but had no effects on the emetic response. In contrast, abdominal vagotomy abolished the emetic response induced by gastric distension with or without CSN stimulation, but without affecting gastric distension-induced or CSN stimulation-induced vascular and respiratory responses. In conscious animals, CSN denervation significantly suppressed veratrine- and motion-induced emetic responses, whereas ADN denervation had no significant effects. These results suggest that aortic baroreflex inhibition via the activation of splanchnic afferents contributes to the prodromal response before retching and circulatory homeostasis. In contrast, carotid sinus inputs, which are usually non-emetic signals, interact with vagal and vestibular inputs, and modulate the development of retching and vomiting.

Point:Counterpoint: Respiratory sinus arrhythmia is due to a central mechanism vs. respiratory sinus arrhythmia is due to the baroreflex mechanism

Blood pressure and heart periods fluctuate at respiratory frequencies in healthy humans. Some researchers ([8][1], [23][2]) explain this as a cause-and-effect relation: blood pressure changes trigger baroreflex-mediated R-R interval changes. Here I make the case that respiratory sinus arrhythmia is

Facilitation of phrenic motor output following sustained hypocapnia in rats

Phrenic motoneurons exhibit serotonin-dependent synaptic plasticity, particularly following intermittent hypoxia. Another means of altering synaptic strength in the central nervous system is synaptic scaling, a process whereby efficacy is increased in inverse proportion to activity. We hypothesized that phrenic motoneuron inactivity increases synaptic efficacy, resulting in a long-lasting increase in phrenic motor output. Phrenic nerve inactivity was induced by modest hypocapnia in anesthetized, paralyzed, vagotomized and ventilated rats (4 to 6 mmHg below CO2-apneic threshold, 25 min). After restoring normocapnic arterial CO2 levels, an early and lasting facilitation in phrenic nerve burst amplitude was observed (n = 8; 15 min: 87%±21%; 60 min: 110%±29% baseline; p<0.05), a response significantly different from control rats (n=6; 15 min: −1%±3%; 60 min: 7%±7%). To confirm that inactivity versus respiratory alkalosis per se caused the facilitation, we restored baseline phrenic activity during hypocapnia with steady carotid sinus nerve (CSN) stimulation (2–5 Hz). This combination attenuated, but did not eliminate the phrenic facilitation (n = 5; 15 min: 39%±11%; 60 min: 45%±18%, both p<0.05). The results are consistent with the hypothesis that inactivity induces synaptic plasticity in the phrenic motor system, but do not rule out independent effects of hypocapnia and/or CSN stimulation. Inactivity-induced phrenic facilitation may have important implications: it may play a role in progressive central sleep apnea, since central apneas are among the few instances of spontaneous respiratory motor inactivity; and it may contribute to patient recovery following prolonged ventilatory support. Supported by NIH 69064 and CIHR (Canada).

Zur Interaktion chemosensibler und vagaler Afferenzen auf die respiratorische Moto-Aktivität und die Atemarbeit

The central interaction of intracranial and arterial chemoreceptors plays an important role for the generation of respiratory motor activity. Whereas the inspiratory inhibitory effect of lung stretch receptors is largely described, relatively little is known about their influence on expiration and on the pathomechanisms of obstructive airway disease. In anaesthetised cats, electrical activity of inspiratory and expiratory muscles (IM, EM) has been studied along with tidal volume and the position of breathing in eupnoea and increased respiratory drive before and after bilateral vagotomy. In order to mimic slowly adapting lung stretch receptor activity (SAR), the distal ends of vagal nerves (VN) were stimulated electrically using a frequency modulated signal derived from the respiratory alterations in oesophageal pressure. With intact VN, electrical stimulation of carotid sinus nerves or inhalation of 5 % CO (2) in O (2) resulted in an increased activation of IM in inspiration and activation of EM in expiration. Elimination of lung stretch receptor activity during quiet breathing resulted in prolongation and increase in IM activity without much effecting EM, since expiration is passive in eupnoeic breathing. After bilateral vagotomy, the electrical activity of the expiratory muscles was effectively reduced and the activity of the inspiratory muscles was largely enhanced. The effects of vagotomy could be completely reversed by electrical VN stimulation. Simulating an increased tidal volume by increasing the end inspiratory stimulation frequency to more than 100 Hz resulted in a decrease in IM activity and tidal volume. On mimicking an increased end expiratory lung inflation by end expiratory frequencies up to 50 Hz, expiration was prolonged and expiratory muscles activated. In consequence the position of breathing shifted to below the functional residual capacity (FRC). The results of these acute investigations show, that besides terminating inspiration, lung stretch receptors cause a facilitation of expiration during increased respiratory drive and expiratory airflow limitation by activation of expiratory muscles.

Modulation of emetic response by carotid baro- and chemoreceptor activations

We hypothesized that baroreceptor or chemoreceptor activation might be involved in the emetic, and prodromal cardiovascular and respiratory responses. To test this hypothesis, we induced the emetic responses by gastric distension in anesthetized Suncus murinus (house musk shrew), that had intact and absent baroreceptor and chemoreceptor afferents. Secondly, we stimulated the aortic depressor nerve (ADN) and the carotid sinus nerve (CSN) with or without gastric distension. Internal carotid artery ligation in the bifurcation area, which abolished reflex bradycardia by baroreceptor activation, and abolition of chemoreceptor reflex bradycardia and hyperventilation, by carotid body denervation, suppressed the emetic response but did not abolish it. ADN denervation, which produced no significant effects on the baroreceptor or chemoreceptor reflex bradycardia, had no effect on the emetic response, including the prodromal phase. CSN stimulation with gastric distension elicited retching accompanied by reflex bradycardia and hypotension during or just after stimulation, whereas ADN stimulation with gastric distension did not induce the cardiovascular reflex, and had no effects on the emetic response. These results indicate that carotid, rather than aortic, baroreceptor or chemoreceptor activation plays an important role in the augmentation of cardiac parasympathetic activity and the development of emetic response. In conclusion, carotid baroreceptor or chemoreceptor activation, which is non-emetic stimulation, acts as a modulator in the central mechanisms of emesis.