Sympathetic nervous system behavior in human obesity

The sympathetic nervous system (SNS) plays an essential role in the regulation of metabolic and cardiovascular homeostasis. Low SNS activity has been suggested to be a risk factor for weight gain and obesity development. In contrast, SNS activation is characteristic of a number of metabolic and cardiovascular diseases that occur more frequently in obese individuals. Until recently, the relation between obesity and SNS behavior has been controversial because previous approaches for assessing SNS activity in humans have produced inconsistent findings. Beginning in the early 1990s, many studies using state of the art neurochemical and neurophysiological techniques have provided important insight. The purpose of the present review is to provide an overview of our current understanding of the region specific alterations in SNS behavior in human obesity. We will discuss findings from our own laboratory which implicate visceral fat as an important depot linking obesity with skeletal muscle SNS activation. The influence of weight change on SNS behavior and the potential mechanisms and consequences of region specific SNS activation in obesity will also be considered.     

Sympathetic nervous system activity in panic disorder

To assess sympathetic nervous system (SNS) activity in panic disorder, arterialized venous norepinephrine (NE) and epinephrine (EPI) were measured in 10 patients and 10 age- and weight-matched controls. In addition, arterialized plasma NE kinetics were determined using a tritiated NE isotope dilution technique. There were no significant differences between patients and controls for resting, supine plasma NE levels, plasma NE appearance rate, plasma NE clearance, or plasma cortisol. However, plasma EPI levels were significantly higher in panic patients (103 +/- 23 vs. 33 +/- 16 pg/ml). Furthermore, there was a significant correlation between anxiety ratings and plasma EPI levels in panic disorder patients. These findings suggest that during the resting state, panic disorder is associated with a selective activation of the adrenomedullary component of the SNS.     

Sympathetic nervous system function in XYY subjects

Initial reports of males with the XYY sex chromosome anomaly indicated that these individuals excessively exhibit impulsive, aggressive, and criminal behavior. Central nervous system (CNS) defects, including low intelligence, in certain XYY subjects may be associated with these antisocial behaviors. The sympathetic nervous system (SNS) is activated in stressful conditions of "fight or flight" upon standing up from a supine posture, with physical exercise, and with aggressive behavior. Norepinephrine (NE) is the principal neurotransmitter of the SNS, and plasma levels of NE and dopamine-beta-hydroxylase are indices of SNS function. We questioned the integrity of SNS function in XYY subjects for two reasons: (1) their inferred propensity for aggressive behavior and the association of this behavior with increased NE levels; and (2) their potential for CNS dysfunction, which could be reflected in abnormal SNS regulation by the CNS. In the current study plasma levels of NE in XYY subjects are nonsignificantly higher than in normal volunteers. Additionally, XYY patients have a normal NE half-life indicating normal SNS activity and metabolism. Thus, we are unable to document with confidence any abnormality in SNS function in these XYY subjects.     

Central nervous system circuitry and peripheral neural sympathetic activity responsible for essential hypertension

Both clinical and experimental studies dealing with patients affected by idiopathic or essential hypertension (EH) are devoted to the great deal of physiological, pharmacological and pathological as well as therapeutical issues of EH. However, most articles devoted to EH do not refer to the central nervous system mechanisms underlying this disease and the channels which allow that these mechanisms are funneled to the peripheral autonomic nervous system and trigger this cardiovascular disorder. In the present review article we attempted to reach this target devoted to the central nervous system circuitry involved in the cardiovascular pathophysiology. We postulated that EH depends on the predominance of the binomial A5 noradrenergic (NA) nucleus + median raphe serotonergic (5-HT) nucleus over the (A6)-NA + dorsal raphe-5HT nuclei. This hypothesis receives additional support from our results obtained throughout the neuropharmacological therapy of this type of neurophysiological disorder. Our therapeutical strategy is addressed to enhance the activity of the (A6)-NA + dorsal raphe-5HT binomial circuitry.     

Sympathetic nervous system activity in patients with subarachnoid hemorrhage

In patients with subarachnoid hemorrhage there were increased concentrations of plasma epinephrine and norepinephrine when compared with those concentrations in a group of patients admitted to hospital with other illness. Reassessment after a variable period showed that in patients whose eventual clinical result was poor the plasma epinephrine and norepinephrine concentrations increased further while in those with a good result those concentrations showed a decline. No such changes were evident in plasma dopamine-beta-hydroxylase activities which were within normal range. In a sub-group of patients who had neurosurgery after admission for clipping an aneurysm, the post-operative changes of plasma epinephrine and norepinephrine concentrations were related to the clinical condition of the patients.     

Sympathetic postganglionic unmyelinated axons in the rat peripheral nervous system

We determined the contribution made to the unmyelinated axon population of the rat peripheral nervous system by sympathetic paravertebral ganglion cells. Sympathectomy, achieved by administration of guanethidine to neonatal rats, led to atrophy of the sympathetic paravertebral ganglion chain, a 95% decrease in peripheral nerve norepinephrine, and loss of 20 to 26% of the unmyelinated axons in a cutaneous nerve (sural), a muscular nerve (nerve to soleus), and a mixed nerve (sciatic). These data indicate that up to a quarter of the total population of peripheral nerve unmyelinated axons are sympathetic ganglia-derived.     

Essential hypertension and the sympathetic nervous system

Cryptoccus neoformans meningitis (CNM) is an opportunistic infection that typically occurs in immunosuppressed patients. Subjects affected by sarcoidosis, a systemic granulomatous disease of unknown cause, are predisposed to CNM because of the impairment of cell-mediated immunity and because of the chronic corticosteroid therapy they frequently receive. Here we report the case of a 38-year-old man who developed CNM as the first clinical manifestation of sarcoidosis. The patient developed CNM even though he was apparently immunocompetent and was not on therapy with either corticosteroid or cytotoxic drugs.

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Sommario La meningite da Cryptoccus neoformans colpisce tipicamente soggetti immunodepressi tra cui i pazienti affetti da sarcoidosi. In particolare, si ritiene che questi ultimi siano predisposti a sviluppare una meningite criptococcica sia a causa della compromissione dell’immunità cellulo-mediata sia a causa della terapia corticosteroidea cui sono frequentemente e cronicamente sottoposti. Il caso che presentiamo riguarda un paziente di 38 anni che ha sviluppato una meningite criptococcica come prima manifestazione clinica della sarcoidosi. Ciò che, a nostro giudizio, rende meritevole di segnalazione questo caso, è il fatto che il paziente, oltre a non aver mai manifestato alcun segno clinico di sarcoidosi, era apparentemente immunocompetente e non era mai stato sottoposto ad alcun trattamento cronico con corticosteroidi.

     

Sympathetic nervous system and PC12 pheochromocytoma-derived factors suppress stimulation of lymphocytes

We have reported previously that ablation of the sympathetic nervous system augments immune responses in mice and rats. In the present study we show that a factor present in the sympathetic cervical ganglia of newborn rats suppresses Con A-induced stimulation of splenic T lymphocytes significantly whether added prior to, throughout, or following exposure to Con A. We also show that rat PC 12 pheochromocytoma cells secrete a factor which has the same inhibitory effect on T cell proliferation as the sympathetic ganglia-derived factor.     

Sympathetic nervous system modulation of tumor metastases and host defense mechanisms.

The sympathetic nervous system can signal cells of the immune system through release of norepinephrine (NE), and may thus modulate several aspects of immune reactivity. We have examined the consequences of chemical denervation using 6-hydroxydopamine (6-OHDA) on the response of BALB/c mice to tumor cell challenge. In this study, chemical axotomy prior to the intravenous (i.v.) injection of the alveolar carcinoma line 1 significantly increased the number of pulmonary metastases. In contrast, axotomy performed after i.v. injection of tumor cells had no effect on the number of lung metastases. Line 1 tumor cells have been reported to be susceptible to lysis by natural killer (NK) cells. To examine possible mechanisms through which prior axotomy leads to increased lung metastases, we tested the effects of axotomy on in vitro and in vivo NK cell activity. No differences in NK cell activity were found between 6-OHDA- and vehicle-treated mice. Line 1 tumor cell growth in vitro was unaffected by both 6-OHDA and NE, and the tumor cells do not express beta-adrenergic receptors. Priming mice with lethally irradiated line 1 cells significantly reduced the number of lung metastases following challenge with live tumor cells; axotomy did not alter this decrease in metastases associated with priming. In summary, chemical axotomy of mice prior to injection of alveolar carcinoma cells resulted in an increased number of pulmonary metastases that was not correlated with alterations in either NK cell cytotoxicity or the putative immunological consequences of in vivo priming.     

Sympathetic reactivity in hypertension

Summary In agreement with earlier studies reported in the literature it is found that the majority (about 80%) of hypertensives react to Mecholyl with a marked, prolonged and only partially reversible fall in blood pressure. This type of response seen in experimental subjects, mental patients, and experimental animals in which the central sympathetic reactivity is low, occurs also when the baroreceptors of the sino-aortic area have been eliminated. Since in experimental hypertension a weakening of the baroreceptor discharges and a resetting at a higher level occur it is suggested that the preponderance of Mecholyl Type III in hypertensives results from this diminution in baroreceptor function. It is further suggested that the virtual absence of the most common response to Mecholyl, the Type II, is due to the fact that hypertensives are sympathetic hyperreactors who respond to Mecholyl before failure of the baroreceptors with Type I and after failure with Type III. Studies on the Mecholyl test in an adequate number of recent and old cases are recommended to clarify this question.Finally, the possibility that the Mecholyl test III in chronic hypertension is due to a lessened central sympathetic reactivity is discussed.

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Zusammenfassung In Übereinstimmung mit der Literatur fand sich, daß die Majorität von Personen mit Hypertonie auf die Injektion von Mecholyl mit einer erheblichen, langdauernden Blutdrucksenkung reagiert. Diese Reaktion zeigt dieselben Merkmale, die sich mit der Mecholyl-Probe an Mensch und Tier finden, wenn diese an Fällen ausgeführt wird, in denen die zentrale sympathische Erregbarkeit gering ist, entweder spontan oder als das Ergebnis experimenteller Eingriffe. Ähnliche Resultate werden im Tierexperiment nach Beseitigung der Rezeptoren der Blutdruckzügler erhalten. Da die Annahme einer verminderten sympathischen Erregbarkeit in klinischer oder experimentaller Hypertonie vielen Tatsachen widerspricht, ist es mehr wahrscheinlich, daß die Mecholyl-Reaktion der Hypertonie auf eine Verminderung der Aktivität der Rezeptoren der Blutdruckzügler und ihr Resetting auf eine höhere Blutdrucklage zurückzuführen ist. Es ist außerdem anzunehmen, daß das Fehlen der beim Normalen häufigsten Gruppe (Mecholyl Typ II) dadurch bedingt ist, daß Hypertoniker in den Frühstadien zum Typ I gehören (sympathisch überreaktiv) und in dem Spätstadium aus den oben besprochenen Gründen den Typ III aufweisen. Die Richtigkeit dieser Deutung muß noch durch ausgedehnte Studien an alten und jungen Fällen von Hypertonie und den Veränderungen der Mecholyl-Reaktion bei diesen während jahrelanger Beobachtungen bewiesen werden.Die Möglichkeit, daß der Mecholyl-Test (Typ III) bei chronischer Hypertonie von einer verminderten zentralen sympathischen Erregbarkeit abhängig ist, wird erörtert.

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Résumé D'accord avec la littérature il fut constaté, que la majorité de personnes hypertoniques réagissent après une injection de la Mécholyle avec une assez durable diminution de la pression sanguine. Cette réaction montre les mêmes caractères qui se trouvent chez l'homme et l'animal avec le test de la Mécholyle, si celle-ci est appliquée en cas d'excitation soit spontanée soit comme résultat d'actions expérimentales. De résultats analogues sont obtenus expérimentalement chez l'animal après élimination des barorécepteurs. Comme la supposition d'une excitation modérée en cas d'hypertonies cliniques et expérimentales est contraire à beaucoup de faits, il est très probable que la réaction mécholylénique de la hypertonie est due à une diminution de l'activité des barorécepteurs et leur montée sur un plus haut degré de la pression sanguine. On peut de plus admettre que la manque du groupe le plus fréquent chez l'individu normal (Mécholyle type II) est la suite du fait que les personnes hypertoniques dans la phase initiale appartinement au type I (hyperactivité sympathique) et dans les phases tardives montrent le type III d'accord avec les motifs mentionnés plus haut. Le fait de cette interprétation doit être vérifié par des études approfondies en cas récents et chroniques d'hypertonie et les changements de la réaction mécholylénique chez ces cas pendant des longues années.La possibilité que le test mécholylénique (type III) soit le résultat d'une diminution centrale sympathique en cas d'hypertonies chroniques est discutée.

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Supported by a Grant from NIH MH 06552-01.