Modulation of immunity by the sympathetic nervous system >>
Regulation of metabolism by the sympathetic nervous system >>
Estrogen may explain the blunted sympathetic activation in response to hypoglycemia in women >>
Myocardial ischemia, sudden death and cardiac sympathetic innervation >>
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Modulation of immunity by the sympathetic nervous
system
Prass et al examined the modulation of immunity by the
sympathetic nervous system using an stroke-associated infection mice model. All
animals develop spontaneous septicemia and pneumonia after three days of focal
cerebral ischemia. This was associated with extensive apoptotic loss of
lymphocytes and a shift from T helper cells (Th1) to Th2 cytokine-producing
lymphocytes. Infection burden could be reduced by administration of interferon
gamma or transfusion of T cells from wild-type but not interferon
gamma-deficient mice. Blocking the sympathetic nervous system or administering
beta receptor antagonists drastically reduced infection-related mortality,
whereas blocking the hypothalamic-pituitary-adrenal axis had no effect. These
data suggest that a catecholamine-mediated modulation of lymphocyte function is
the key factor in the impaired antibacterial immune response after stroke.
Prass K, Meisel C, Hoflich C, et al (2003) Stroke-induced Immunodeficiency
Promotes Spontaneous Bacterial Infections and Is Mediated by Sympathetic
Activation Reversal by Poststroke T Helper Cell Type 1-like Immunostimulation. J
Exp Med 198:725-736.
Regulation of metabolism by the sympathetic nervous
system
Leptin, a hormone produced by fat cells, acts in the
central nervous system to reduce appetite and induce sympathetic activation (see
Autonomic News 2003; 13:168). Central melanocortin signaling pathways play an
important role in regulation of energy homeostasis by leptin and insulin.
Rahmouni et al explored if these pathways are also involved in the central
sympathoexcitatory effects of leptin. Intracerebroventrical administration of
leptin and a melanocortin agonist increased renal sympathetic nerve activity in
control mice, but not in db/db leptin-receptor deficient mice. In contrast, the
central sympathetic activation induced by corticotrophin-releasing factor (CRF)
and insulin were intact in db/db mice. Conversely, the central sympathetic
activation induced by leptin and insulin were abolished in melanocortin-4
receptor (MC-4R) knock-out mice, but sympathoexcitation by CRF was preserved.
These results suggest that central melanocortin pathways are important for the
central sympathetic activation by leptin.
Galanin-like peptide (GALP), a recently described
hypothalamic neuropeptide, is upregulated by leptin and has anorectic effects in
the mouse. Hansen et al found that central administration of GALP induced a
sustained decrease in body weight in leptin deficient ob/ob mouse but only a
transient decrease in food intake. The persistent weight loss may be related to
sympathetic activation because GALP induced a sustained increase in core body
temperature. The expression of pro-opiomelanocortin (POMC) mRNA in the arcuate
nucleus was decreased following chronic GALP treatment. These observations
suggest that upregulation of GALP can contribute to the sympathetic activation
thermogenesis induced by leptin, through a mechanism that does not require
activation of melanocortin pathways.
Polymorphic variations in adrenergic genes may play a role in
the pathogenesis of obesity (for review see Clinical Autonomic Research
2001;11:67-78). Sivenius et al investigated the impact of a three-amino acid
deletion (12Glu9) polymorphism in the alpha(2B)-adrenergic receptor gene on
obesity. No significant differences were found in the frequency of the 12Glu9
deletion polymorphism between 126 nondiabetic and 84 type 2 diabetic Finnish
subjects. The nondiabetic men with the Glu(9)/Glu(9) genotype, especially those
with abdominal obesity, had significantly lower total and low-frequency heart
rate variability when compared with other men. Furthermore, in a longitudinal
analysis of 10 years, the decrease in parasympathetic function was greater in
nondiabetic men with the Glu(9)/Glu(9) genotype than in the men with the
Glu(9)/Glu(12) or Glu(12)/Glu(12) genotypes. The results of the present study
suggest that the 12Glu9 polymorphism of the alpha(2B)-adrenergic receptor gene
modulates autonomic nervous function, with the Glu(9)/Glu(9) genotype being
associated with lower vagal activity and with central obesity.
An increase in sympathetic activity has been documented in
most causes of obesity, and may contribute to the "metabolic syndrome" leading
to hypertension. An exception is the obesity seen in Pima Indians. This
population has low sympathetic nervous system activity and this could contribute
to both their increased risk of obesity and reduced risk of hypertension.
Vozarova et al tested the hypothesis that this unexpected decrease in
sympathetic activity is due to an increased sensitivity to the central
inhibitory actions of cortisol on sympathetic tone. Compared to Caucasians, Pima
Indians had similar fasting plasma ACTH and cortisol, but a lower muscle
sympathetic nerve activity (MSNA) normalized for body fat. No correlation was
found between fasting cortisol and MSNA. Overnight partial adrenalectomy with
metyrapone had no effect on MSNA. Additional infusion of hydrocortisone to
restore glucocorticoid function resulted in a decrease in MSNA in Pima Indians
but not in Caucasians. These results indicate that tonic release of cortisol
does not account for the decreased baseline MSNA in Pima Indians, but suggest
that an acute release of cortisol may produce a greater restrain of
sympathoexcitation during stress in Pima Indians. It is possible that this
phenomenon contributes to the apparent cardiovascular protection observed in
this population.
Rahmouni K, Haynes WG, Morgan DA, et al (2003) Role of melanocortin-4
receptors in mediating renal sympathoactivation to leptin and insulin. J
Neurosci 23:5998-6004.
Hansen KR, Krasnow SM, Nolan MA, et al (2003) Sympathetic Nervous System
Activation by Galanin-like Peptide - A Possible Link between Leptin and
Metabolism. Endocrinology 144:4709-4717.
Sivenius K, Niskanen L, Laakso M, et al (2003) A deletion in the
alpha2B-adrenergic receptor gene and autonomic nervous function in central
obesity. Obes Res 11:962-970.
Vozarova B, Weyer C, Snitker S, et al (2003) Effect of cortisol on muscle
sympathetic nerve activity in Pima Indians and Caucasians. J Clin Endocrinol
Metab 88:3218-3226.
Estrogen may explain the blunted sympathetic
activation in response to hypoglycemia in women
Women have lower sympathetic activation in response to
hypoglycemia compared to men. Sandoval et al explored if this difference is due
to estrogen by comparing responses to hyperinsulinemic hypoglycemia in
postmenopausal women receiving estrogen replacement, postmenopausal women not
receiving estrogen, and age- and BMI-controlled males. In response to
hypoglycemia, women on estrogen replacement had a lower compensatory increase in
epinephrine, glucagon and muscle sympathetic nerve activity compared to
postmenopausal women on no estrogen replacement or male controls. Therefore,
estrogen appears to explain the sexual dimorphism found in counterregulatory
responses to hypoglycemia in healthy humans.
Sandoval DA, Ertl AC, Richardson MA, et al (2003) Estrogen blunts
neuroendocrine and metabolic responses to hypoglycemia. Diabetes 52:1749-1755.
Myocardial ischemia, sudden death and cardiac
sympathetic innervation
ATP is a co-transmitter released with norepinephrine (NE)
upon sympathetic activation. Sesti et al reported that ATP enhances NE
exocytosis, providing a positive feedback mechanism. Conversely, neuronal
ectonucleotidase (E-NTPDase) metabolizes extracellular ATP, restraining its
facilitatory actions on NE release. A relatively brief period of ischemia (10
minutes) induced release of NE by exocytosis in isolated guinea pig hearts. NE
release was linearly correlated with ATP release, and subjected to modulation by
E-NTPDase. NE release was reduced by solCD39, the recombinant equivalent of E-NTPDase.
More protracted ischemia induced NE release through reversal of NE transporter
rather than through exocytosis. This process was not modulated by ATP
mechanisms.
Ischemic heart disease is associated with sudden cardiac
death due to ventricular arrhythmias. Prevention of sudden death often requires
the use of implantable cardioverter defibrillators, but identification of
patients who most benefit from this device remains difficult. Arora et al used
iodine 123 metaiodobenzylguanidine (MIBG) imaging and heart rate variability (HRV)
analysis to determine if cardiac autonomic innervation correlated with episodes
of sudden death, as documented by defibrillator discharges. Seventeen patients
with previously implanted defibrillators were studied. Of these, 10 had at least
1 appropriate device discharge for ventricular tachyarrhythmias, whereas 7 had
no discharge. Patients with a discharge had a significantly lower I-123 MIBG
heart-mediastinal tracer uptake ratio, higher I-123 MIBG defect scores, more
extensive sympathetic denervation, and significantly reduced values for several
HRV parameters in the frequency domain. When combined, the I-123 MIBG heart-mediastinal
ratio and HRV 5-minute low-frequency variables were highly predictive of
defibrillator discharges. Cardiac autonomic assessment using a combination of
myocardial scintigraphic and neurophysiologic techniques may help select
patients who would most benefit from an implantable defibrillator by identifying
those at increased risk for potentially fatal arrhythmias. These results also
implicate abnormal autonomic function in the genesis of ventricular arrhythmias
associated with sudden death.
Sesti C, Koyama M, Broekman MJ, et al (2003) Ectonucleotidase in sympathetic
nerve endings modulates ATP and norepinephrine exocytosis in myocardial
ischemia. J Pharmacol Exp Ther 306:238-244.
Arora R, Ferrick KJ, Nakata T, et al (2003) I-123 MIBG imaging and heart
rate variability analysis to predict the need for an implantable cardioverter
defibrillator. J Nucl Cardiol 10:121-131.