Neurocalcin-immunopositive nerve terminals in the muscle spindle, Golgi tendon organ and motor endplate

The present study revealed the immunohistochemical distribution of neurocalcin, a three EF-hand calcium-binding protein, in the rat muscles and tendons. In the muscle spindles, annulospiral endings, which made spirals around the intrafusal muscles, showed intense neurocalcin-immunoreactivity. In the Golgi tendon organs, immunopositive thick nerve fibers entered the collagenous fibers resulting in the projection of many swelling terminals. In all examined muscles, nerve terminals in the motor endplates showed neurocalcin-immunoreactivity associated with the membranes of synaptic vesicles and mitochondria. These findings suggest that neurocalcin is distributed and regulates calcium signaling in both afferent and efferent nerve terminals in the muscles and tendons.     

Brainstem interneurons necessary for vestibular influences on sympathetic outflow

The objective of this study was to determine which general brainstem regions contain interneurons that are critical for mediating vestibulo-sympathetic responses in decerebrate cats, as a prelude for future cell recording studies. Large injections of kainic acid into the lateral reticular formation at levels caudal to the obex abolished sympathetic nerve responses elicited by electrical stimulation of the vestibular nerve. The same lesions also diminished excitatory and some inhibitory components of somato-sympathetic responses elicited by stimulation of the sciatic nerve, raising the possibility that a common pool of interneurons integrates signals from muscle, skin and the vestibular system that reflect body position in space. Large lesions of other brainstem regions containing interneurons involved in regulation of sympathetic activity, including nucleus tractus solitarius, the lateral tegmental field rostral to the obex, and the parabrachial nucleus, had no appreciable effect on the amplitude of either vestibulo-sympathetic or somato-sympathetic responses. Thus, interneurons critical for relaying vestibular and other somatic signals to descending cardiovascular-regulatory pathways appear to be located in the caudal and lateral parts of the medulla.     

Assessment of sympathetic cardiovascular influences in man: Haemodynamic and humoral markers versus microneurography

Evaluation of sympathetic cardiovascular influences has important physiological, pathophysiological and clinical implications. This paper reviews some of the methods employed to measure these influences in man, along with their advantages and disadvantages. The most useful methods appear to be the measurement of plasma noradrenaline (particularly when modified to calculate spillover rate of noradrenaline) and direct recording of sympathetic nerve traffic. With the former, despite the technological advances in measurement, certain methodological problems remain, such as the separation of noradrenaline secretion from clearance. With the latter technique peripheral muscle and skin sympathetic activity can be measured separately but the question of regional vascular variability has still to be resolved. A combination of these two methods may represent the ideal approach. This review considers the complex problems associated with attempts to precisely quantify sympathetic cardiovascular influences in man.     

Emergence of lung-inflation-related sympathetic nerve activity in spinal cord transected neonatal swine

Sympathetic (SYMP) nerve activity in spinal intact neonatal swine is comprised of prominent bursts reflecting modulation by supraspinal structures involved in shaping central respiratory and baroreceptor activity. After spinal cord transection (SCT), we found no evidence of such modulation. SYMP activity was now related to the ventilatory cycle, exhibiting bursts only during lung inflation. Such activity suggests the emergence of latent spinal circuits which may have the capacity to regulate cardiovascular activity.     

Cardiac sympathetic nerve activity during kainic acid–induced limbic cortical seizures in rats

We sought to define changes in cardiac sympathetic nerve activity that occur during seizures. We studied kainic acid–induced limbic cortical seizures in urethane-anesthetized rats using cardiac sympathetic nerve, blood pressure, and electrocardiography (ECG) recordings. We studied changes in ventilation rate before and during seizures. Cardiac sympathetic nerve activity was increased during limbic cortical seizures. The modest increases were similar to changes induced by nitroprusside infusion. The normal relation of cardiac sympathetic nerve activity to ventilation rate was lost during seizure activity. Changes in cardiac sympathetic nerve activity caused by changes in ventilation rate became unpredictable, and could be extreme. We conclude that the modest changes in cardiac sympathetic nerve activity contribute to the predominantly parasympathetic effects on the heart during limbic cortical seizures and periods of asphyxia. Further, ventilation rate changes might be associated with large sudden increases or decreases in cardiac sympathetic outflow during seizures.     

Thermographic assessment of impaired sympathetic function in peripheral nerve injuries

Summary Twenty-three patients with focal, strictly unilateral lesions of the peripheral nervous system were examined by infrared-thermography. The Minor sweat test was used to determine if sympathetic outflow was disturbed.In fifteen patients without a concomitant sympathetic lesion (controls) thermosymmetry was not disturbed.Eight patients had evidence of abnormal sweat secretion. In these patients thermoregulation was severely disturbed. During the first 5 to 8 months, affected skin areas were hyperthermic, whereas later only hypothermia was observed. Cold stimuli increased temperature differences in patients with disturbed sympathetic function, but not in controls.Thermography is a reliable, non-invasive technique to detect a lesion of sympathetic outflow and permits an estimation of the time-course of the lesion.

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Zusammenfassung Dreiundzwanzig Patienten mit monotopen, streng einseitigen Schädigungen des peripheren Nervensystems wurden mittels der Infrarot-Thermographie untersucht. Durch den Schweißtest nach Minor wurde festgestellt, ob eine Sympathikusläsion vorlag.Bei fünfzehn Patienten (Kontrollpatienten) ohne eine begleitende Sympathikusschädigung war die Thermosymmetrie nicht gestört.Bei acht Patienten war die Schweißsekretion vermindert oder erloschen. Diese Patienten hatten eine schwere Störung der Thermoregulation. Während der ersten 5 bis 8 Monate waren die betroffenen Hautareale hypertherm, wohingegen später nur Hypothermien beobachtet wurden. Durch Kältereize vergrößerten sich die Temperaturdifferenzen bei Patienten mit einer Sympathikusschädigung, nicht jedoch bei den Kontrollpatienten.Die Thermographie ist eine verläßliche, nicht-invasive Methode zur Aufdeckung einer Sympathikusschädigung und erlaubt eine Abschätzung des Alters der Schädigung.

     

Spinal interneurons play a minor role in generating ongoing renal sympathetic nerve activity in spinally intact rats

The purpose of the present study was to determine whether spinal interneurons play a role in the regulation of sympathetic activity in spinally intact rats. In acutely spinally transected rats, we have described a population of spinal interneurons that, by virtue of correlations between their ongoing firing rates and the magnitude of ongoing renal sympathetic nerve activity (RSNA), are candidates for generators of sympathetic activity. Further evidence for a sympathetic role for these neurons comes from our observation that cervical spinal stimulation that reduces RSNA also reduces their discharge rates. In chloralose-anesthetized, spinally intact and spinally transected rats, we recorded ongoing RSNA and the ongoing activities of T₁₀ dorsal horn and intermediate zone interneurons, and we determined the incidence of sympathetically related neurons in these rats by cross-correlating their activities with RSNA. The incidence of correlated neurons was much smaller in spinally intact than in spinally transected rats. We stimulated the dorsolateral, C_2–3 spinal cord before and after acute C₁ spinal transection. Dorsolateral cervical stimulation in spinally transected rats reduced both RSNA and the activities of most T₁₀ interneurons, but stimulation in spinally intact rats increased RSNA while still reducing the activities of most T₁₀ interneurons. Both the low incidence of sympathetically correlated spinal neurons in intact rats and the dissociation between the effects of cervical stimulation on RSNA and the discharge rates of spinal interneurons argue against these neurons playing a major role in regulating sympathetic activity in intact rats.     

The structure and response properties of Golgi tendon organs in control and hypodynamia-hypokinesia rats

The Golgi tendon organs (GTOs) are encapsulated mechano-receptors that, in normal conditions, monitor via Ib afferent fibers the contractile force. A 14-day period of hypodynamia, absence of weight bearing and hypokinesia, and reduction of motor activity (HH) is known to induce changes in postural muscles such as the soleus. At present, there is no data available regarding the Ib afferent feedback in normal rats (CONT group) and in rats after a hypodynamia-hypokinesia (HH group) period. Consequently, the aim of our study was to determine the HH effects on the morphological (histochemistry on gross morphology) and electrophysiological properties of the GTOs in rat soleus muscle. In the histological study, nine CONT and nineteen HH GTOs of the soleus muscle were identified. The results demonstrated that HH GTOs were morphologically similar to the CONT GTOs. Regarding the electrophysiological study, a L2-L6 laminectomy was performed under deep anesthesia (sodium pentobarbital, 60 mg kg(-1)). Responses in single Ib fibers from the L5 dorsal root to the isometric twitch and tetanic fused contractions of "in-series" motor units (MUs) were recorded. Twenty-three and twenty-eight GTO/MU pairs were studied in the CONT and HH groups, respectively. In the HH group, the Ib afferent response exhibited a decrease in dynamic peak for the high stimulation frequencies and an increase in static sensitivity for all stimulation frequencies. Our results suggest that after an HH period, the GTOs continue to fulfil their mechano-sensory function to signal the contractile force but with a higher static sensitivity.     

Microneurographic analysis of muscle sympathetic nerve activity in amyotrophic lateral sclerosis

Muscle sympathetic nerve activity by (microneurograph) blood pressure and heart rate has been studied in patients with amyotrophic lateral sclerosis and in age-matched normal subjects (controls) at rest and during head-up tilt. Muscle sympathetic nerve activity in amyotrophic lateral sclerosis patients was significantly increased at rest unlike controls. There was no correlation between muscle sympathetic nerve activity and age in the patients with amyotrophic lateral sclerosis. Elevated muscle sympathetic nerve activity was present mainly in younger patients. There were no differences between blood pressure or heart rate in either group at rest or during head-up tilt in amyotrophic lateral sclerosis. The increase in muscle sympathetic nerve activity following tilt in the amyotrophic lateral sclerosis patients was less than in the controls, but they had no postural hypotension. The possible reasons for this observation of increased muscle sympathetic nerve activity at rest in amyotrophic lateral sclerosis are discussed.Corresponding Author     

High fat feeding is associated with increased blood pressure,sympathetic nerve activity and hypothalamic mu opioid receptors

Obesity and high fat diets are associated with an increased prevalence of diabetes, cardiovascular disease, and hypertension. However, the mechanism(s) linking obesity and high fat diet to these metabolic and cardiovascular disorders are not fully elucidated. Leptin stimulates the formation of pro-opiomelanocortin and its products. The stimulation of the central nervous system (CNS) opioids and their receptors is associated with an increase in cardiovascular dynamics. In this study we hypothesized that obesity changed the CNS opioids and their receptors that could play a role in altered cardiovascular and autonomic nervous regulation in obesity. Male Wistar rats were fed either a high fat (HF) or regular chow (control) diet. After 12 weeks, rats were anesthetized and instrumented to record mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). A blood sample was collected and plasma glucose, insulin, leptin, beta-endorphins were measured. The brains were subsequently processed for immunohistochemistry and in situ hybridization. The HF rats were larger and had a greater percentage of body fat. Leptin and insulin levels were also higher in the HF animals. Basal MAP and RSNA were significantly higher in HF rats. Additionally, immunohistochemistry and in situ hybridization demonstrated that HF rats had increased hypothalamus mu opioid receptors compared to controls. These studies suggest that HF feeding is associated with increased body fat, plasma leptin, insulin, and hypothalamic mu opioid receptors. The increased mu opioid receptors may contribute to the higher MAP and RSNA observed in HF animals.     

Time course of the attenuation of sympathetic nervous activity during active heat acclimation

The purpose of this study was to determine the time course of the attenuation in sympathetic nervous activity during active heat acclimation (HA) in healthy humans. Eight volunteers completed a maximal graded exercise test followed by 8 days of active HA. Heat acclimation consisted of 90 min of walking at 40% of maximal oxygen uptake in a heated environmental chamber at 35 °C. The mean (± SD) ending core temperature during exercise was significantly reduced during the 8 days of HA. Specifically, it decreased from 38.3 ± 0.4 °C on day 1 to 37.9 ± 0.3 °C on day 8. In addition, ending HR during exercise was also significantly reduced from 152 ± 18 bpm on day 1 to 135 ± 15 bpm on day 8 of HA. The most important new finding was that plasma norepinephrine concentration following the first day of exercise in the heat was 1.58 ± 0.22 ng/ml. It significantly decreased to 1.01 ± 0.20, 0.98 ± 0.15, and 0.89 ± 0.11 on days 3, 5, and 8, respectively. The results of the current study show that active HA causes a rapid and significant reduction in NE during exercise in the heat. Such a result suggests that SNA was likewise reduced during HA and may be partially responsible for the reductions in HR that occur with HA since end-exercise HR and NE were found to be highly correlated (r = 0.79).     

The period of latency before a muscle receptor generates an action potential as a response to a muscle stretch

Six primary (Ia) and seven secondary (II) muscle spindle afferents and eight Golgi tendon organ afferents (Ib) from the tibial anterior muscle of the cat, recorded at the dorsal roots, were subjected to a sinusoidal stretch of the host muscle, the frequency of which increased linearly from 2 to 80 Hz over four different lengths of time. Both the amplitude of the sinusoidal stretch and the prestretch of the muscle were varied. The phase of the action potentials was determined. The phase of the action potential, driven 1:1, increased linearly with frequency. From the gradient of the phase of this action potential the muscle-muscle receptor latency was determined, i.e., the period of latency between the stretch of the muscle and the occurrence of the action potential at the muscle nerve where it enters the muscle. The muscle-muscle receptor latency had values lying between 3 and 8 ms: it was dependent on the experimental parameters and became shorter as the conduction velocity of the afferent fiber increased. In three experiments the muscle latency was determined, i.e., the period of latency before the stretch was transferred from the tendon of the muscle to the proximal third of the muscle belly. The muscle was stretched sinusoidally under the same varying parameters as given above. The length changes occurring in the proximal third of the muscle were measured with a piezo element. The muscle latency was determined from the slope of the phase of the zero points of the sinusoidal piezo length changes; the phase increases linearly with frequency. The muscle latency had values lying between 6 and 15 ms: it was dependent on the experimental parameters. The muscle spindle latency, i.e., the period of latency between the stretch of the polar parts of the intrafusal muscle fibers and the recording of the action potentials from the spindle nerve near the spindle capsule, was determined from 5 Ia fibers and 1 II fiber of isolated muscle spindles. The isolated muscle spindle was stretched under the same varying parameters as given above. The muscle spindle latency was determined from the slope of the phase of the phase-locked action potential. The muscle spindle latency as measured by our method proved to be 0 ms. The latencies of the three elements and their dependence on the experimental parameters are discussed in the light of the transfer properties of the muscle and the muscle receptors.     

Long-term variability and reproducibility of resting human muscle nerve sympathetic activity at rest,as reassessed after a decade

Human muscle nerve sympathetic activity measured by microneurography during supine rest is known to vary considerably between healthy subjects, whereas in a given individual the level of muscle nerve sympathetic activity is stable over weeks and months. To further characterize long-term variability or reproducibility microneurographic recordings of muscle nerve sympathetic activity were performed in 15 healthy, normotensive subjects (mean age 51 years) who had undergone the same procedure between 10 and 14 years earlier (mean 12 years). The range of muscle nerve sympathetic activity was 9–59 in the first and 13–61 bursts/min in the second recording. Subjects maintained the level of muscle nerve sympathetic activity displayed previously, although with a slight but significant tendency to a higher outflow with increasing age.It is concluded that muscle nerve sympathetic activity is characterized by large inter-individual differences and strong intra-individual reproducibility over many years, with a tendency to increase with age. The age relationship is only in a minor part responsible for the variability, the cause of which remains unexplained. Because of the marked difference between individuals, strict normality criteria are difficult to define when comparing groups of subjects. There remains the risk of either obtaining spurious differences or obscuring a true abnormality. This is unlikely to apply when results in individual subjects are compared.     

Intraspinal amino acid neurotransmitter activities are involved in the generation of rhythmic sympathetic nerve discharge in newborn rat spinal cord

Endogenous neurotransmitter activities underlying the sympathetic nerve discharge (SND) generated by newborn rat spinal cord in vitro were investigated using glutamatergic, glycinergic, and GABAergic antagonists. Under control conditions, the SND power spectrum had two major frequency components: synchronous bursting SND (bSND) with power dominant at < 0.1 Hz and quasiperiodic SND (qSND) oscillating at 1-2 Hz. Using high Mg2+ solution (12-24 mM) to block Ca2+-dependent synaptic transmission reversibly abolished SND. An interruption of glutamatergic neurotransmission by CNQX (non-NMDA receptor blocker) or L-AP4 (reducing the synaptic release of glutamate) failed to affect qSND, but consistently reduced bSND. Application of kynurenate, a broad-spectrum ionotropic glutamate receptor blocker, only caused an unstable SND but did not reduce SND. In contrast, strychnine (Stry, glycine receptor antagonist) consistently reduced qSND in a dose-dependent manner. Bicuculline (Bic, GABA(A) receptor antagonist) induced a synchronous bSND of irregular rhythm, which could be further regularized by adding Stry. Bic-induced bSND was reversibly abolished by CNQX or L-AP4. In conclusion, intraspinal glycinergic, GABAergic, and glutamatergic activities are involved in the generation of the spinal cord-derived SND in newborn rats. Intraspinal GABAergic interneurons may tonically inhibit the glutamatergic bursting neurons that generate a synchronous bSND. Activities of these glutamatergic bursting neurons may also be modulated by intraspinal glycinergic interneurons.     

Cuneiform nucleus stimulation-induced sympathoexcitation: role of adrenoceptors, excitatory amino acid and serotonin receptors in rat spinal cord

Stimulation of the midbrain cuneiform nucleus has previously been shown to produce increases in arterial blood pressure and lumbar sympathetic nerve activity. While this sympathoexcitatory effect is, in part, due to excitation of premotor sympathoexcitatory neurons in the rostral ventrolateral medulla, the specific spinal neurotransmitter systems recruited by cuneiform nucleus stimulation remains to be elucidated. In this study, mean arterial pressure, resting and cuneiform nucleus stimulation-evoked lumbar sympathetic nerve activity were analysed following intrathecal injections of an excitatory amino acid antagonist (kynurenic acid), α₁-adrenoceptor antagonist (prazosin) and a serotonin receptor antagonist (methiothepin) in anesthetized, paralysed male Sprague-Dawley rats. Mean arterial pressure and resting sympathetic nerve discharge were decreased by all treatments (n=6/group) compared to the vehicle control group. Intermittent electrical stimulation of the cuneiform nucleus produced a bimodal sympathoexcitatory response, of which the short latency peak was significantly attenuated (43% reduction) by intrathecal kynurenate whereas the long latency peak was reduced by intrathecal prazosin (decrease of 21%) and methiothepin (38% attenuation). These results are consistent with the significant roles of excitatory amino acid, α₁-adrenergic and serotonin receptors in modulating the activity of sympathetic vasomotor preganglionic neurons supplying the lumbar sympathetic nerve trunk, and suggest the existence of at least three neuronal groups and/or pathways associated with the sympathoexcitatory response to cuneiform nucleus stimulation.     

Increase in muscle nerve sympathetic activity after glucose intake is blunted in the elderly

Muscle nerve sympathetic activity (MSA; involved in blood pressure regulation) was recorded by microneurography in the peroneal nerve for 90 min after ingestion of 100 gd-glucose in three groups of healthy subjects: young subjects (mean age 26 years) and 70-year-old men with normal and reduced insulin sensitivity as assessed by euglycaemic insulin clamp. Muscle nerve sympathetic activity at rest was lowest in the young and highest in the insulin-resistant subjects (burst frequencies 19.8±6.0, 47.7±7.0 and 55.1±11.5 bursts/min for the three groups, respectively). The young subjects responded to glucose intake with a pronounced increase in MSA, a response that was blunted in the elderly and weakest in the insulin-resistant subjects. A similar relationship was observed during a Valsalva manoeuvre, indicating that the blunted response in the elderly is a generalized phenomenon. Blood pressure remained stable in the young subjects but fell slightly and significantly in the elderly subjects. It is concluded that old subjects utilize their total capacity for MSA close to maximum at rest. Thus, the reserve for response to stimuli normally evoking a strong increase in MSA is restricted. This restriction may contribute to postprandial hypotension in the healthy elderly.     

Sympathetic neural control of integrated cardiovascular function: insights from measurement of human sympathetic nerve activity

Sympathetic neural control of cardiovascular function is essential for normal regulation of blood pressure and tissue perfusion. In the present review we discuss sympathetic neural mechanisms in human cardiovascular physiology and pathophysiology, with a focus on evidence from direct recordings of sympathetic nerve activity using microneurography. Measurements of sympathetic nerve activity to skeletal muscle have provided extensive information regarding reflex control of blood pressure and blood flow in conditions ranging from rest to postural changes, exercise, and mental stress in populations ranging from healthy controls to patients with hypertension and heart failure. Measurements of skin sympathetic nerve activity have also provided important insights into neural control, but are often more difficult to interpret since the activity contains several types of nerve impulses with different functions. Although most studies have focused on group mean differences, we provide evidence that individual variability in sympathetic nerve activity is important to the ultimate understanding of these integrated physiological mechanisms.     

Inhibition of muscle sympathetic nerve activity during yawning

Yawning is a complex event that depends largely on the autonomic nervous system. Microneurographic techniques were used to study the mechanism involved in yawning. A series of spontaneous yawns displayed by a healthy 39-year-old male offered us the opportunity to study the muscle sympathetic nerve activity (MSNA) during this phenomenon. It was found that 2 s of yawning inhibited the MSNA recorded at the right peroneal nerve in the lateral knee area, while 3 s of slow expiration succeeding a yawn provoked an MSNA discharge. Blood pressure decreased with each slow expiration by 5–6 mmHg, and increased again with the renewed MSNA discharge. We conclude that yawning is associated with a sympathetic suppression that favours a parasympathetic dominance, as indicated by the MSNA and the decrease in blood pressure. The slow expiration following a yawn is associated with a sympathetic activation marked by an MSNA discharge and an increase in blood pressure.     

The vertebral nerve: A comprehensive review of its form and function

The literature is littered with variable and scant reports of the vertebral nerve. The present paper reviews the literature regarding this nervous structure of the neck and attempts to clarify a number of issues surrounding its form, function, and implications of surgical manipulation. The nerve may arise from the stellate ganglion or the ansa subclavia, amongst a number of other structures. Additionally, the terminal insertion of the vertebral nerve varies in the reported literature, with authors observing various terminations. Animal models of the vertebral nerve have limited value, as variations between species and with species have been observed. This review also indicates that contradictory evidence exists regarding the clinical implications of vertebral nerve damage. Although irritation may result in ocular disturbance, hearing loss, headaches, and dizziness, a high degree of incongruity exists around whether or not any clinical findings will actually be observed. Based on our review of the available literature and recent cadaveric research, it appears it may be more logical to classify the vertebral nerve as a variable ramus communicans that connects the stellate or inferior cervical ganglia to the lower cervical spinal nerves and not a structure that ascends entirely with the vertebral artery to enter the cranium.     

Peripheral elimination of the sympathetic nervous system stimulates immunocyte retention in lymph nodes and ameliorates collagen type II arthritis

ObjectivesIn collagen type II-induced arthritis (CIA), early activation of the sympathetic nervous system (SNS) is proinflammatory. Here, we wanted to find new target organs contributing to proinflammatory SNS effects. In addition, we wanted to clarify the importance of SNS-modulated immunocyte migration.MethodsA new technique termed spatial energy expenditure configuration (SEEC) was developed to demonstrate bodily areas of high energy demand (to find new targets). We studied homing of labeled cells in vivo, lymphocyte expression of CCR7, supernatant concentration of CCL21, and serum levels of sphingosine-1-phosphate (S1P) in sympathectomized control/arthritic animals.ResultsDuring the course of arthritis, SEEC identified an early marked increase of energy expenditure in draining lymph nodes and spleen (nowhere else!). Although early sympathectomy ameliorated later disease, early sympathectomy increased energy consumption, organ weight, and cell numbers in arthritic secondary lymphoid organs, possibly a sign of lymphocyte retention (also in controls). Elimination of the SNS retained lymph node cells, elevated expression of CCR7 on lymph node cells, and increased CCL21. Serum levels of S1P, an important factor for lymphocyte egress, were higher in arthritic than control animals. Sympathectomy decreased S1P levels in arthritic animals to control levels. Transfer of retained immune cells from draining lymph nodes of sympathectomized donors to sympathectomized recipients markedly increased arthritis severity over weeks.ConclusionsBy using the SEEC technique, we identified draining lymph nodes and spleen as major target organs of the SNS. The data show that the SNS increases egress of lymphocytes from draining lymph nodes to stimulate arthritic inflammation.