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 >>
A PDF version of this Autonomic News can be downloaded from the CAR website
To review the original abstract of these articles, click on the references below
Modulation of immunity by the sympathetic nervous
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
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
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.