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2004; Volume 14(4) from Clinical Autonomic Research    
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A novel treatment approach for synucleinopathies?     
     Convergent biochemical and genetic evidence suggests that the formation of alpha-synuclein (SYN) protein deposits is an important and, probably, seminal step in the development of Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Inhibiting and/or reversing SYN self-aggregation could, therefore, provide a novel approach to treating these diseases. El Agnaf et al synthesized short peptides that bound to the binding region thought to be responsible for SYN self-aggregation (residues 69-72).  These “alpha-synuclein inhibitors” (ASI), were found to interact with full-length SYN and block its assembly into both early oligomers and mature amyloid-like fibrils. ASI, introduced into cells using a polyarginine peptide delivery system, were able to inhibit DNA damage in neuronal cells transfected with SYN(A53T), a mutation associated with familial PD. These short peptides could lead to a novel therapeutic approach for PD and related disorders.
     Mutations of another gene, Parkin, can cause a recessive form of parkinsonism. Parkin has been recently shown to protect cells against alpha-synuclein toxicity, but the precise mechanisms are unclear.  
Pael-R has recently been identified as a substrate for Parkin, and Murakami et al examined its distribution in Parkinson's disease (PD) and multiple system atrophy (MSA). Pael-R was localized in the core of Lewy bodies (LBs) whereas Parkin and alpha-synuclein accumulated in the halo.  Neither Pael-R nor Parkin was found in glial cytoplasmic inclusions (GCIs) in MSA, implying a distinct pathway in the formation of SYN deposits in LBs and GCIs.

El Agnaf,OM, Paleologou,KE, Greer,B et al (2004)  A strategy for designing inhibitors of alpha-synuclein aggregation and toxicity as a novel treatment for Parkinson's disease and related disorders.  FASEB J (Publishised on line ahead of print)

Murakami,T, Shoji,M, Imai,Y et al (2004)  Pael-R is accumulated in Lewy bodies of Parkinson's disease.  Ann Neurol 55:439-442.


The autonomic nervous system in obesity
    Obesity is associated with increased sympathetic activity in Caucasians, in part due to increased leptin produced by fat cells that then acts in the central nervous system (CNS) to increase sympathetic tone.  Eikelis et al measured whole body and regional leptin release in 22 lean and 20 obese normotensive men.  Whole body leptin release was 5-fold greater in obese men. Total and renal norepinephrine spillover rates correlated directly with whole body leptin secretion rate. Extra-adipocyte release of leptin was examined using simultaneous arteriovenous blood sampling. Surprisingly, release of leptin by the brain was substantial, accounting for > 40% whole body leptin release, and was 5.8-fold greater in obese.  These results suggest that leptin is released within the brain, and that this release is greater in obesity.  Brain leptin, in addition to fat-derived leptin, may explain increased sympathetic activation in obesity.
    Not all obesity is associated with increased sympathetic activity.  Pima Indians, e.g., have a high incidence of obesity, but low sympathetic nerve activity.  They also have a high risk of type 2 diabetes and exhibit marked hyperinsulinemia and elevated plasma levels of pancreatic polypeptide (PP), a surrogate marker of parasympathetic nervous system (PNS) drive to the pancreas. To test if hyperinsulinemia in Pima Indians is due to increased vagal input to the beta-cell, Vozarova et al examined the effect of PNS blockade with atropine in 17 Caucasian and 17 Pima Indian males with normal glucose tolerance. Postprandial increases in insulin and PP were higher in Pima Indians than Caucasians.  Atropine attenuated the ethnic difference in PP but not in postprandial insulin secretion. These results confirm that, compared with Caucasians, Pima Indians have an exaggerated PNS drive to pancreatic F-cells that secrete PP. However, the hyperinsulinemia of this population does not appear to be due to increased vagal input to pancreatic beta-cells

Eikelis,N, Lambert,G, Wiesner,G et al (2004)  Extra-adipocyte leptin release in human obesity and its relation to sympathoadrenal function.  Am J Physiol Endocrinol Metab 286:E744-E752.

Vozarova de Court, Weyer,C, Stefan,N et al (2004)  Parasympathetic blockade attenuates augmented pancreatic polypeptide but not insulin secretion in Pima Indians.  Diabetes 53:663-671.

The autonomic nervous system and hypertension
There is growing evidence that essential hypertension is initiated and sustained by sympathetic nervous system overactivity. Schlaich et al investigated the potential mechanisms of this overactivity by measuring sympathetic nerve traffic with microneurography to assess central sympathetic outflow, and norepinephrine spillover to assess norepinephrine (NE) neuronal reuptake.  Hypertensive patients displayed increased muscle sympathetic nerve activity, elevated total systemic, cardiac and renal NE spillover, and decreased cardiac neuronal NE reuptake. Arterial baroreflex control of sympathetic nerve traffic was not impaired in hypertensive subjects.  The authors conclude that increased central sympathetic drive and reduced neuronal NE reuptake both contribute to sympathetic activation in hypertension.
    The cause of the increase in central sympathetic drive observed in essential hypertension is not known.  Observational studies have suggested an anatomical variant of the left posterior inferior cerebellar artery can produce a pulsatile compression of the rostral ventrolateral medulla (neurovascular compression, NVC) and increase sympathetic drive in patients with essential hypertension (EHT).  This potential mechanism, however, remains controversial.  Smith et al used magnetic resonance imaging to detect NVC, and peroneal microneurography to quantify muscle sympathetic nerve activity (MSNA) in subjects with normal (NT) (n = 24) or high-normal (HN) (n = 14) blood pressure and mild (EHT-1) (n = 26) or severe (EHT-2/3) (n = 19) EHT. A significantly greater sympathetic activity was found in 23 subjects with NVC, compared with 60 subjects without NVC. The prevalence of NVC and the magnitude of sympathetic hyperactivity were greater in the EHT-1 group (p < 0.05) than in the other three groups. These results, if validated, would support a role of neurovascular compression of the brainstem as a cause of central sympathetic activation contributing to hypertension.
    Increased salt intake acutely lowers sympathetic tone but, paradoxically, salt-induced hypertensive syndromes are associated also with sympathetic overactivity.  Luo et al tested the hypothesis that the increased sympathetic activity in DOCA-salt hypertensive rats is due to impaired function of alpha(2)-adrenergic autoreceptors with increased norepinephrine release from sympathetic nerves.  Nerve stimulation evoked a 1.5-fold increase in NE release in arteries isolated from control animals, whereas in DOCA-salt arteries there was a 3.9-fold increase in NE release. Similar differences were observed in veins (2.9-fold increase in control and 8.4-fold increase in DOCA-salt). The alpha(2)-adrenergic receptor antagonist yohimbine increased NE release in control but not in DOCA-salt arteries, suggesting that an impairment of alpha(2)-adrenergic autoreceptor function was present in DOCA-salt rats, resulting in augmented NE release.
    To determine the effect of increased salt intake during the perinatal period, Swenson et al gave an 8% NaCl diet (HS) to pregnant rats during the final one-third of gestation and their pups throughout age 30 days. Control groups received a normal-salt diet (NS). In HS rats, mean arterial pressure (MAP) was significantly higher (110±5 vs. 96±3 mmHg) compared with NS rats. Blockade of brain AT(1) receptors with intracerebroventricular losartan decreased MAP in HS but not NS rats. Blockade of alpha-adrenergic receptors with intravenous phentolamine or ganglionic transmission with intravenous chlorisondamine produced a greater decrease in MAP in HS rats.  AT(1) receptor binding was increased in the subfornical organ of the HS rats. Expression of AT(1a) receptor mRNA was greater in both subfornical organ and paraventricular nucleus of the HS rats. These data suggest that high-salt diet elevated blood pressure by augmented sympathetic nervous activity, resulting, in part, from greater brain AT(1) receptor activation.
    Angiotensin (Ang) II may also increase sympathetic nerve activity (SNA) via a direct action on sympathetic ganglia. Ma et al hypothesized that sympathetic ganglionic actions of endogenous Ang II contribute to SNA in transgenic mice overexpressing both renin and angiotensinogen (R+A+). Ganglionic blockade essentially abolished renal SNA in control mice, but only reduced it by half in R+A+ mice. The residual SNA remaining after ganglionic blockade in R+A+ mice was essentially abolished by Ang II blockade with losartan (P<0.05). The sympathoinhibitory response to losartan was accompanied by an enhanced decrease in arterial pressure in R+A+ mice compared with that observed in control mice. AT1 receptor expression in sympathetic ganglia, as measured by real-time reverse transcription-polymerase chain reaction, was increased approximately 3-fold in R+A+ versus control mice. The results indicate that Ang II-evoked ganglionic activity accounts for approximately half of total renal SNA in R+A+ mice. The significant contribution of the direct ganglionic action of Ang II in R+A+ mice likely reflects both increased levels of Ang II and upregulation of AT1 receptors in sympathetic ganglia.
    Given the evidence for increased sympathetic drive contributing to hypertension, central sympatholytics would be useful in the treatment of this condition, but current medications are limited by side effects.  Xu et al found that the superoxide dismutase mimetic Tempol produced a dose-dependent decrease in mean arterial blood pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) in DOCA-salt rats. Tempol (300 micromol/kg) decreased MAP from 140±5 to 83±4 mm Hg, HR from 435±15 to 390±12 bpm, and RSNA by 54±6%. However, Tempol did not reduce dihydroethidium-induced fluorescent signals in the aorta and vena cava, an index of oxidative stress.  Furthermore, other antioxidants did not alter MAP or HR in this model.  These results suggest that the central sympatholytic effects of Tempol are unrelated to its antioxidant activity. Even if its precise mechanism of action is not known, Tempol may represent a novel approach in the treatment of hypertension.

Schlaich,MP, Lambert,E, Kaye,DM et al (2004)  Sympathetic augmentation in hypertension: role of nerve firing, norepinephrine reuptake, and Angiotensin neuromodulation.  Hypertension 43:169-175.  (See also accompanying editorial by Grassi and Mancia, Hypertension 2004;43:154-5).

Smith,PA, Meaney,JF, Graham,LN et al (2004)  Relationship of neurovascular compression to central sympathetic discharge and essential hypertension.  J Am Coll Cardiol 43:1453-1458.

Luo,M, Fink,GD, Lookingland,KJ et al (2004)  Impaired function of alpha2-adrenergic autoreceptors on sympathetic nerves associated with mesenteric arteries and veins in DOCA-salt hypertension.  Am J Physiol Heart Circ Physiol 286:H1558-H1564.

Swenson,SJ, Speth,RC, and Porter,JP (2004)  Effect of a perinatal high-salt diet on blood pressure control mechanisms in young Sprague-Dawley rats.  Am J Physiol Regul Integr Comp Physiol 286:R764-R770.

Ma,X, Sigmund,CD, Hingtgen,SD et al (2004)  Ganglionic action of angiotensin contributes to sympathetic activity in renin-angiotensinogen transgenic mice.  Hypertension 43:312-316.

Xu,H, Fink,GD, and Galligan,JJ (2004)  Tempol lowers blood pressure and sympathetic nerve activity but not vascular O2- in DOCA-salt rats.  Hypertension 43:329-334.