The paraventricular nucleus: an important component of the central neurocircuitry regulating sympathetic nerve outflow

AIM: The sympathetic nervous system plays an important role in the regulation of physiological homeostasis under basal conditions and in response to acute and chronic stressors. It is known that multiple levels of the neuroaxis, including the paraventricular nucleus (PVN) of the hypothalamus, are involved in regulation of efferent sympathetic nerve discharge (SND). This review focuses on the role of the PVN in regulation of functional characteristics of efferent SND. RESULTS: The available experimental evidence indicates that the level of efferent sympathetic nerve activity is altered after microinjection of numerous substances into the PVN, including excitatory amino acids, gamma-aminobutyric acid (GABAA) receptor agonists and antagonists, and PVN nitric oxide synthase inhibitors. In addition, antagonism of PVN GABAA receptors changes the pattern of synchronized discharge bursts in efferent sympathetic nerves and enhances the frequency-domain coupling between low-frequency bursts in sympathetic nerve pairs. Finally, PVN microinjections of excitatory amino acids (L-glutamate, D,L-homocysteic acid) have been shown to produce non-uniform changes in the level of efferent sympathetic nerve activity. CONCLUSION: These findings support the concept that the PVN is an important component of the central neurocircuitry regulating functional characteristics (basal level of activity, bursting pattern, and relationships between discharges in nerves innervating different targets) of efferent sympathetic nerve outflow.     

Neuraxial modulation for treatment of VT storm

In the hyperadrenergic state of VT storm where shocks are psychologically and physiologically traumatizing, suppression of sympathetic outflow from the organ level of the heart up to higher braincenters plays a significant role in reducing the propensity for VT recurrence. The autonomic nervous system continuously receives input from the heart (afferent signaling), integrates them, and sends efferent signals to modify or maintain cardiac function and arrhythmogenesis. Spinal anesthesia with thoracic epidural infusion of bupivicaine and surgical removal of the sympathetic chain including the stellate ganglion has been shown to decrease recurrences of VT. Excess sympathetic outflow with catecholamine release can be modified with catheter-based renal denervation. The insights provided from animal experiments and in patients that are refractory to conventional therapy have significantly improved our working understanding of the heart as an end organ in the autonomic nervous system.     

Autonomous innervation in renal inflammatory disease—innocent bystander or active modulator?

Increasing evidence suggests a significant interrelation between the autonomic nervous system and the immune system. The kidney is innervated by efferent sympathetic nerves as well as by peptidergic sensory afferent nerve fibers. Inflammation in the kidney may be affected by both types of fibers. Peptidergic “sensory” neurons might play a particularly important role: These fibers can induce local neurogenic inflammation via paracrine effects of their transmitters and evoke increased efferent sympathetic nerve outflow via their projections to the central nervous system. Several reports support the notion that renal innervation does indeed contribute to inflammation and sclerosis in kidney diseases. Hence, receptor antagonists interfering with the interaction of innervation and the immune system may prove useful to mitigate inflammatory processes in the kidney.     

The modulation of visceral functions by somatic afferent activity

We began by briefly reviewing the historical background of neurophysiological studies of the somato-autonomic reflexes and then discussed recent studies on somatic-visceral reflexes in combination with autonomic efferent nerve activity and effector organ responses. Most of the studies that have advanced our knowledge in this area have been carried out on anesthetized animals, thus eliminating emotional factors. We would like to emphasize again that the functions of many, or perhaps all visceral organs can be modulated by somato-sympathetic or somato-parasympathetic reflex activity induced by a appropriate somatic afferent stimulation in anesthetized animals. As mentioned previously, some autonomic nervous outflow, e.g. the adrenal sympathetic nerve activity, is involved in the control of hormonal secretion. John F. Fulton wrote in his famous textbook "Physiology of the Nervous System" (1949) that the posterior pituitary neurosecretion system (i.e. for oxytocin and vasopressin) could be considered a part of the parasympathetic nervous system. In the study of body homeostasis and environmental adaptation it would seem very important to further analyze the contribution of somatic afferent input to the autonomic nervous and hormonal regulation of visceral organ activity. Also, some immunological functions have been found to be influenced by autonomic nerves or hormones (e.g. adrenal cortical hormone and catecholamines). Finally, we must take into account, as we have briefly discussed, that visceral functions can be modulated by somatic afferent input via various degrees of integration of autonomic nerves, hormones, and immunological processes. We trust that such research will be expanded to higher species of mammals, and that ultimately this knowledge of somato-visceral reflexes obtained in the physiological laboratory will become clinically useful in influencing visceral functions.     

Atrial natriuretic factor is a new neuromodulatory peptide

In this commentary, we will briefly discuss the potential regulatory role of atrial natriuretic factor in peripheral autonomic nervous system function. The focus will be on atrial natriuretic factor's involvement in cardiovascular homeostasis through its peripheral effect on sympathetic nervous activity, which may complement its humoral role. [Kuchel et al. (1987) Life Sci. 40, 1545-1551; Lang et al. (1985) Nature 314, 264-266]. We will attempt to support the hypothesis of its neuromodulatory action on efferent autonomic outflow. Specifically, the role of atrial natriuretic factor in the regulation of the synthesis and release of neurotransmitters and in synaptic transmission at the level of the sympathetic ganglia will be outlined. Its potential usefulness in neurobiological studies will also be indicated.     

Electrophysiological characteristics of the interoceptive reflex arc

Summary Acute experiments were performed on cats. The changes of the efferent impulsations were studied in the sympathetic fibers innervating various vascular areas in vesicular mechanoceptor stimulation of different intensity.Low intensity stimulation is required to produce changes in the impulsation of the nerves innervating the blood vessels of the urinary bladder proper (hypogastric nerve). With the rise of the intensity of stimulation these changes begin to spread to the more remote (in functional condition) vascular areas. At first the change of the efferent impulsation occurs to the renal vessels, then to the blood vessels of the skin of posterior extremity and, finally, to the vessels innervated by the cervical sympathetic nerve. With the rise of intensity of stimulation of the vesicular mechanoceptors these changes in the efferent impulsations in the hypogastric nerve undergo 3 phases: the first phase corresponds to the inhibition of the efferent impulsation, the second to its intensification and the third—to inhibition. Only the first two phases are observed in the renal nerve and only one in the skin and cervical sympathetic nerves. The intensification of the impulsation always leads to constriction while its inhibition—to the dilatation of the vessels.Presented by Active Member of the AMN SSSR V. N. Chernigovskii     

Left ventricular dysfunction and altered autonomic activity: a possible link to sudden cardiac death

There is now a growing body of clinical evidence that suggests a strong association between left ventricular dysfunction and sudden cardiac death in patients recovering from myocardial infarction. The mechanisms underlying this association remain to be determined. Alterations within the autonomic nervous system may represent one factor that links an impairment in cardiac function to an increased mortality. Since ventricular dysfunction would tend to reduce stroke volume, an increased sympathetic and/or decreased parasympathetic efferent activity may compensate for this fall in stroke volume by increasing heart rate and/or the force of contraction (inotropic state) in an attempt to maintain a more normal cardiac output. Similar changes in autonomic activity are, in fact, known to increase the vulnerability to ventricular fibrillation. Therefore, I propose that myocardial infarction induces changes in cardiac function which in turn elicits autonomic efferent changes. As a consequence of these compensatory reflex changes the heart becomes less electrically stable and thereby more prone to lethal arrhythmias.     

The autonomic nervous system is not a purely efferent system

The concept of the autonomic nervous system as purely efferent does not seem to describe satisfactorily the patterns of its actions and mobilizing mechanisms. It is herein suggested that the autonomic nervous system should be rather considered as composed of functional modules comprising the visceral afferents, the integrating centers and the visceral efferents (sympathetic and parasympathetic).     

Choline acetyltransferase (ChAT) immunoelectron microscopy distinguishes at least three types of efferent synapses in the organ of Corti

Summary Using anatomical criteria, the olivo-cochlear fibers ending in the organ of Corti (efferent fibers) have recently been separated into two systems: a lateral system innervating principally the inner hair cell (IHC) area and a medial system innervating mainly the outer hair cells (OHCs). Electrophysiological and biochemical experiments suggest that acetylcholine may be a neurotransmitter of these efferent fibers. However, efferent synapses that use acetylcholine as neurotransmitter have not yet been identified at the electron microscopic level. Using a pre-embedding immunoelectron microscopic technique with a monoclonal antibody against choline acetyltransferase (ChAT), we localized ChAT-immunostained fibers below both the IHCs and OHCs. In the inner spiral bundle, one type of ChAT-immunostained fibers was vesiculated and formed axo-dendritic synapses with the afferent auditory dendrites contacting the inner hair cells. A second type of ChAT-immunostained fibers seen in the inner spiral bundle was unvesiculated. Unstained vesiculated varicosities synapsing with the auditory dendrites were also seen in the inner spiral bundle. At the OHC level, ChAT immunostaining was found in nearly all the terminals synapsing with the OHCs. The finding of two types of ChAT-immunostained efferent synapses in the organ of Corti, i.e. axodendritic synapses in the inner spiral bundle and axosomatic synapses with the OHCs, supports the hypothesis that both the lateral and the medial olivocochlear systems use acetylcholine as a neurotransmitter. The finding of numerous unstained synapses in the inner spiral bundle, and some below OHCs, together with previous data about putative cochlear neurotransmitters, suggests the possibility of additional non-cholinergic olivo-cochlear systems. It might soon appear useful to reclassify efferents according to the nature of the different neurotrans-mitters/ co-transmitters found in the various efferent synapses of the organ of Corti.     

Varied effects of experimental diabetes on the autonomic nervous system of the rat

Disorders of the autonomic nervous system are a frequent late complication of human diabetes. They have been extensively studied clinically, yet their pathologic aspects are still poorly understood. Also, reports on the autonomic nervous system in animal models for diabetes are scanty. Therefore we have investigated sympathetic preganglionic and postganglionic nerve fibers, vagal fibers, as well as sympathetic and enteric neurons of male Wistar rats 1 year after streptozotocin or vehicle injection. By light and electron microscopic morphology we observed: various degenerative changes in sympathetic neurons and in Schwann cells of the sympathetic fibers; intraaxonal glycogen deposits in all fiber types; and a large amount of lipoid material in intraganglionic and endoneural mesenchymal cells. By morphometry, the cytoplasmic area and perimeter as well as the cytoplasmic to nuclear ratio were significantly reduced in the sympathetic neurons of diabetic rats. Further we found axonal dwindling, enlarged myelin-axons space and an increased number of Schwann cell pi-granules in the sympathetic preganglionic fibers of diabetic animals. Axonal glycogenosomes were absent in the vagus of control and were present in that of diabetic rats. By stereology, the mitochondria and smooth endoplasmic reticulum were reduced in the sympathetic neurons of diabetic rats, whereas in the same animals the volume density of the Golgi complex was increased in the sympathetic neurons and decreased in the enteric neurons. In conclusion, relevant changes occur in the sympathetic preganglionic nerve fibers which suggest a causal relationship between fiber and neuronal lesions. Further, the stereologic findings imply decreased cellular activity and imbalance between cellular synthesis and secretion in the sympathetic neurons.     

A novel online method to monitor autonomic nervous activity based on arterial wall impedance and heart rate variability

This paper proposes a new method of evaluating autonomic nervous activity using the mechanical impedance of arterial walls and heart rate variability. The cardiovascular system is indispensable to life maintenance functions, and homeostasis is maintained by the autonomic nervous system. Accordingly, it is very important to be able to make diagnosis based on autonomic nervous activity within the body’s circulation. The proposed method was evaluated in surgical operations; the mechanical impedance of the arterial wall was estimated from arterial blood pressure and a photoplethysmogram, and heart rate variability was estimated using electrocardiogram R–R interval spectral analysis. In this paper, we monitored autonomic nervous system activity using the proposed system during endoscopic transthoracic sympathetic block surgery in eight patients with hyperhidrosis. The experimental results indicated that the proposed system can be used to estimate autonomic nervous activity in response to events during operations.     

Autonomic innervation of the carotid body: role in efferent inhibition

The carotid body (CB) is a chemosensory organ that monitors blood chemicals and initiates compensatory reflex adjustments to maintain homeostasis. The 'afferent' sensory discharge induced by changes in blood chemicals, e.g. low PO(2) (hypoxia), is relayed by carotid sinus nerve (CSN) fibers and has been well studied. Much less is known, however, about a parallel autonomic (parasympathetic) 'efferent' pathway that is the source of CB inhibition. This pathway is the focus of this review which begins with a historical account of the early findings and links them to more recent data on the source of this innervation, and the role of endogenous neurotransmitters in efferent inhibition. We review evidence that these autonomic neurons are embedded in 'paraganglia' within the glossopharyngeal (GPN) and CSN nerves, and for the role of nitric oxide (NO) in mediating efferent inhibition. Finally, we discuss recent data linking the action of hypoxia and a key CB neurotransmitter, i.e. ATP, to potential mechanisms for activating this efferent pathway.     

Nervous control of photophores in luminescent fishes

Functional studies of the autonomic innervation in the photophores of luminescent fishes are scarce. The majority of studies have involved either the stimulation of isolated photophores or the modulatory effects of adrenaline-induced light emission. The fish skin is a highly complex organ that performs a wide variety of physiological processes and receives extensive nervous innervations. The latter includes autonomic nerve fibers of spinal sympathetic origin having a secretomotor function. More recent evidence indicates that neuropeptide-containing nerve fibers, such as those that express tachykinin and its NK1 receptor, neuropeptide Y, or nitric oxide, may also play an important role in the nervous control of photophores. There is no anatomical evidence that shows that nNOS positive (nitrergic) neurons form a population distinct from the secretomotor neurons with perikarya in the sympathetic ganglia. The distribution and function of the nitrergic nerves in the luminous cells, however, is less clear. It is likely that the chemical properties of the sympathetic postganglionic neurons in the ganglia of luminescent fishes are target-specific, such as observed in mammals.     

Internal jugular venous spillover of noradrenaline and metabolites and their association with sympathetic nervous activity

It is recognized that the brain plays a pivotal role in the maintenance of blood pressure and the control of myocardial function. By combining direct sampling of internal jugular venous blood with a noradrenaline isotope dilution method, for examining neuronal transmitter release, and microneurographic nerve recording, we were able to quantify the release of central nervous system noradrenaline and its metabolites and investigate their association with efferent sympathetic nervous outflow in healthy subjects and patients with pure autonomic failure. To further investigate the relationship between brain noradrenaline, sympathetic nervous activity and blood pressure regulation we examined brain catecholamine turnover, based on the internal jugular venous overflow of noradrenaline and its principal central nervous system metabolites, in response to a variety of pharmacological challenges. A substantial increase was seen in brain noradrenaline turnover following trimethaphan, presumably resulting from a compensatory response in sympathoexcitatory forebrain noradrenergic neurones in the face of interruption of sympathetic neural traffic and reduction in arterial blood pressure. In contrast, reduction in central nervous system noradrenaline turnover accompanied the blood pressure fall produced by intravenous clonidine administration, thus representing the blood pressure lowering action of the drug. Following vasodilatation elicited by intravenous adrenaline infusion, brain noradrenaline turnover increased in parallel with elevation in muscle sympathetic nervous activity. While it is difficult to assess the source of the noradrenaline and metabolites determined in our studies, available evidence implicates noradrenergic cell groups of the posterolateral hypothalamus, amygdala, the A5 region and the locus coeruleus as being involved in the regulation of sympathetic outflow and autonomic cardiovascular control.     

Peripheral autonomic nerves of human pineal organ terminate on vessels, their supposed role in the periodic secretion of pineal melatonin

Nonvisual pineal and retinal photoreceptors are synchronizing circadian and circannual periodicity to the environmental light periods in the function of various organs. Melatonin of the pineal organ is secreted at night and represents an important factor of this periodic regulation. Night illumination suppressing melatonin secretion may result in pathological events like breast and colorectal cancer. Experimental works demonstrated the role of autonomic nerves in the pineal melatonin secretion. It was supposed that mammalian pineals have lost their photoreceptor capacity that is present in submammalians, and sympathetic fibers would mediate light information from the retina to regulate melatonin secretion. Retinal afferentation may reach the organ by central nerve fibers via the pineal habenulae as well. In our earlier works we have found that the pineal organ developing from lobular evaginations of the epithalamus differs from peripheral endocrine glands and is composed of a retina-like central nervous tissue that is comprised of cone-like pinealocytes, secondary pineal neurons and glial cells. Their autonomic nerves in submammalians as well as in mammalian animals do not terminate on pineal cells, rather, they run in the meningeal septa among pineal lobules and form vasomotor nerve endings. Concerning the adult human pineal there are no detailed fine structural data about the termination of autonomic fibers, therefore, in the present work we investigated the ultrastructure of the human pineal peripheral autonomic nerve fibers. It was found, that similarly to other parts of the brain, autonomic nerves do not enter the human pineal nervous tissue itself but separated by glial limiting membranes take their course in the meningeal septa of the organ and terminate on vessels by vasomotor endings. We suppose that these autonomic vasomotor nerves serve the regulation of the pineal blood supply according to the circadian and circannual changes of the metabolic activity of the organ and support by this effect the secretion of pineal neurohormones including melatonin.     

Regulation of sympathetic nerve activity by L-carnosine in mammalian white adipose tissue

Previously, we showed that l-carnosine, a bioactive dipeptide, influences the sympathetic nerve activity innervating kidney and brown adipose tissue. Because the autonomic nervous system plays an important role in the regulation of lipid metabolism, we investigated the in vivo effects of L-carnosine on the sympathetic nerve activity innervating white adipose tissue (SNA-WAT) and lipolysis. We found that intraperitoneal (ip) administration of L-carnosine at doses of 100 ng/rat and 10 microg/rat elevated and suppressed SNA-WAT, respectively. The effect of lower dose of L-carnosine (100 ng/rat) was eliminated by pretreatment with diphenhydramine hydrochloride, a histamine H(1) receptor antagonist. In contrast, the effect of higher dose of L-carnosine (10 microg/rat) was suppressed by thioperamide maleate salt, a histamine H(3) receptor antagonist. Moreover, ip administration of 100 ng and 10 microg of L-carnosine increased and decreased the levels of plasma free fatty acids (FFAs), respectively. The changes of plasma FFAs resulting from the exposure to 100 ng and 10 microg of L-carnosine were diminished by the beta-adrenergic receptor blocker propranolol hydrochloride and the muscarinic receptor blocker atropine sulfate, respectively; and eliminated by the corresponding histamine receptor antagonists, which eliminated the changes in SNA-WAT. Our results suggest that low doses of L-carnosine may regulate the lipolytic processes in adipose tissue through facilitation of the sympathetic nervous system, which is driven by histamine neurons through the H(1) receptor, and that the beta(3)-receptor may be involved in this enhanced lipolytic response. High doses of L-carnosine, on the other hand, may lower lipolysis by suppressing sympathetic nerve activity via the H(3) receptor, and the muscarinic receptor may be related to this response.     

Effects of ageing on spinal motor and autonomic pain responses

The course of ageing leads to various changes in the nervous system, which can affect pain processing in the elderly. However, the affection of different components of the nociceptive system remains unclear. To investigate basic nocifensive responses, we compared age-related changes of autonomic and motor reflex responses to noxious electrical stimulation. In 39 healthy young subjects (mean +/- S.D.; 24.1 +/- 3.3 years) and 52 healthy elderly subjects (mean +/- S.D.; 71.9 +/- 5.3 years) the nociceptive flexion reflex (NFR) and the sympathetic skin response (SSR) were determined using noxious electrical stimulation of the sural nerve. Verbal pain ratings were assessed in addition. No ageing effects on the NFR and on verbal pain ratings were found, whereas the SSR amplitude declined significantly with ageing. Since both SSR and NFR share comparable primary afferent pathways and the motor as well as the subjective responses to noxious stimulation were preserved, our data seem to suggest that central or peripheral efferent sympathetic functions are altered by age.     

Body fat and the activity of the autonomic nervous system

The cause of most cases of human obesity is unknown. Specific alterations in the activity of the autonomic nervous system may mediate and perhaps cause obesity in animal models. We therefore looked for alterations in autonomic activity in human obesity. Fifty-six healthy men with various percentages of body fat underwent autonomic testing while at rest. Significant correlations were found between the percentage of body fat and the variation in the R-R interval after beta-adrenergic blockade (r = -0.30, P less than 0.03), the heart rate (r = 0.30, P less than 0.03), the plasma norepinephrine concentration (r = -0.30, P less than 0.05), the plasma epinephrine concentration (r = -0.49, P less than 0.001), and the pupillary latency period (r = 0.39, P less than 0.01). Each of these variables reflects the activity of the sympathetic nervous system or parasympathetic nervous system or both. Depressions in sympathetic and parasympathetic activity were significantly but weakly associated with increasing percentages of body fat. These associations indicate that in obese persons, autonomic changes, though not necessarily causal, involve several organ systems. We suggest that autonomic alterations are important in human obesity, as they are in animal obesity. A disordered homeostatic mechanism may promote excessive storage of energy by decreasing sympathetic activity, while defending against weight gain by decreasing parasympathetic activity. The use of autonomic profiles holds promise for classifying human obesity and identifying obese patients at increased risk for various disorders.     

Differential cardiovascular effects of pharmacological agents in chickens selected for high and low body weight.

This study was conducted to investigate whether there are differences in the autonomic nervous system function of chickens from lines selected for high (HWS) or low body weight (LWS). The cardiovascular response to various pharmacological agents was used as an indicator of autonomic nervous system response. Ten individuals from each line and sex were used in the study. Catheters were introduced into the left brachial artery and vein and connected to a MP100-BIOPAC system to record blood pressure and heart rate (HR). Chickens were injected with phenylephrine, atropine, propranolol, and tetraethylammonium chloride (TEAC). The LWS birds exhibited a greater increase in mean arterial blood pressure (MABP) and a lesser increase in HR than the HWS birds following atropine. The response to atropine showed a line and sex interaction in which male birds had a greater increase in HR than females and LWS females had a lower increase in HR than the HWS females. Injection of phenylephrine following pretreatment with atropine caused a baroreceptor reflex in which males showed a greater decrease in HR than females. In response to the beta-adrenergic receptor blocker propranolol, females displayed a greater decrease in MABP than males and LWS birds had a greater decrease in HR than HWS birds. In response to the autonomic ganglionic blocker TEAC, MABP and HR decreased equally in both lines. The percentage of adrenal and sympathetic impact on regulation of HR showed that LWS females required greater adrenal activity than those from the other subclasses. Although changes in HR and MABP ratios in response to phenylephrine were different between lines, these responses were not different when phenylephrine was given following atropine. This pattern of response suggested that HWS birds had greater parasympathetic nervous system activity in order to maintain cardiovascular function. These results demonstrate that selection for HWS or LWS has resulted in greater parasympathetic and sympathetic nervous system tone in birds from the HWS and LWS birds, respectively, and suggest that differences between the lines could be at the level of the chromaffin tissue in the adrenal gland.     

Adrenergic innervation in reactive human lymph nodes

Several experimental models have demonstrated that the central nervous system is functionally linked to the immune system by means of the autonomic nervous system. Samples of 36 lymph nodes of patients whose ages ranged from 16 to 69 y were studied. In order to demonstrate the existence and distribution of sympathetic nerve fibres, a polyclonal antibody antityrosine hydroxylase (TH), with the streptavidin-biotin system of detection, was used. TH-positive nerve fibres appeared in all reactive patterns of the lymph nodes studied. Thin nerve fascicles ramified at the hilar region and also in the connective tissue septae. Adventitial adrenergic nerve fibres were found following afferent, and to a lesser extent, efferent blood vessels. Another source of incoming nerve fibres was found at capsular level, accompanying blood vessels. On the arterial side, the innervation ceased before reaching the follicular arterioles. Our demonstration of innervation in postcapillary venules could support a regulatory role of adrenergic neurotransmitters in lymphocyte traffic. Occasional nerve fibres were also seen in T areas among parenchymatous cells. These findings confirm the existence of sympathetic innervation in human lymph nodes, and provide indirect evidence that the psychoneuroimmune axis could also exist in humans.