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2003; Volume 13(4) from Clinical Autonomic Research                                           
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Molecular Pathogenesis of the Norepinephrine Transporter Gene Mutation Causing Orthostatic Intolerance
   
The norepinephrine transporter (NET) mediates reuptake of norepinephrine released from neurons into the synaptic cleft, contributing to the termination of its action.  Recently, a mutation in the human NET (hNET) gene A457P was identified in an individual suffering from orthostatic intolerance (OI) (New Engl J Med 2000;342:541-9). This mutation renders the transporter inactive in vitro.  The presence of the hNET-A457P allele tracked with elevated heart rates and plasma NE levels in the proband and family members, even though all were heterozygous for the defect and the normal allele should provide normal NET function. Hahn et al. studied this phenomenon in vitro and found that transfection of the hNET-A457P exerted a dominant-negative effect on hNET-wt uptake activity.   Furthermore, hNET-A457P oligomerized with, and decreased the surface expression of, the normal hNET-wild type (hNET-wt). These results reveal that hNET-A457P interferes with transporter biosynthetic progression and trafficking of both the mutant transporter and hNET-wt. This is likely the molecular mechanism explaining the disrupted NE homeostasis and cardiovascular function in OI patients heterozygous for the hNET-A457P mutation.
    Hahn MK, Robertson D, and Blakely RD
(2003) A Mutation in the Human Norepinephrine Transporter Gene (SLC6A2) Associated with Orthostatic Intolerance Disrupts Surface Expression of Mutant and Wild-Type Transporters. J Neurosci 23:4470-4478.

 Is Pure Autonomic Failure an Autoimmune Disorder?
    Subacute forms of autonomic failure usually follow a viral illness or are part of a paraneoplastic syndrome, and are thought to be autoimmune in nature.  Recently, many of these patients were found to have high titers of ganglionic acetylcholine receptor (AChR) autoantibodies. Kelin et al. now report the clinical characteristics of 18 patients having high titers of AChR autoantibodies.  As expected, ten patients had a subacute onset, six with an antecedent event. However, eight patients had chronic autonomic failure, characterized by insidious symptom onset, without an antecedent event, and gradual progression. This chronic autoimmune autonomic neuropathy (AAN) segregated into two subgroups. One subgroup (N = 4) had high antibody titer (mean ~12 nmol/L) and significant cholinergic failure (dry eyes, abnormal pupillary function neurogenic bladder and upper gastrointestinal dysfunction). The other subgroup (N = 4) had low antibody titer (mean ~0.1 nmol/L) and a paucity of cholinergic symptoms, and was clinically indistinguishable from pure autonomic failure. These observations expand the clinical spectrum of AAN to include chronic cases, some being indistinguishable from pure autonomic failure.  It remains possible, however, that the low titers found in patients resembling pure autonomic failure are an epiphenomenon of a primary neurodegenerative disease which exposes previously sequestered neuronal antigens.
   
Klein CM, Vernino S, Lennon VA et al. (2003) The spectrum of autoimmune autonomic neuropathies. Ann Neurol 53:752-758.

Nitric Oxide and Autonomic Cardiovascular Control
   
Nitric oxide interacts with the autonomic nervous system at multiple levels; it induces inhibition of central sympathetic outflow and postganglionic norepinephrine release, and modulates baroreflex function. To explore the latter interaction, Meyrelles et al. prepared adenoviral vectors encoding the endothelial type III NOS (eNOS) gene, and applied them topically to the adventitial surface of one of the carotid sinuses of rabbits. Transgene expression was restricted to the carotid sinus adventitia. Baroreceptor activity, studied 4-5 days later, was decreased significantly, and the pressure-activity curve was shifted to higher pressures in eNOS-transduced compared with beta-Gal-transduced carotid sinuses. Decreased baroreceptor activity was accompanied by a significant increase in carotid diameter in the eNOS-transduced carotid sinuses. The eNOS inhibitor l-NAME prevented the inhibition of baroreceptor activity and the increase in carotid diameter. Thus, local overexpression of eNOS in carotid sinus adventitia causes sustained inhibition of baroreceptor activity and resetting of the baroreceptor function curve to higher pressures.
    Meyrelles SS, Sharma RV, Mao HZ et al.
(2003) Modulation of baroreceptor activity by gene transfer of nitric oxide synthase to carotid sinus adventitia. Am J Physiol Regul Integr Comp Physiol 284:R1190-R1198.

 The Autonomic Actions of Statins May Explain Their Beneficial Cardiovascular Effects
   
HMG-CoA reductase inhibitors (“statins”) have been shown to reduce cardiovascular events and death in patients with congestive heart failure or hypertension.  Pelat et al. examined whether these beneficial effects may be related to actions other than to their cholesterol lowering effects.  They studied apolipoprotein E-/- mice that have increased blood pressure with loss of circadian rhythm, increased very low frequency (0.05-0.4 Hz) blood pressure variability and decreased high frequency (1.5-5.0 Hz) heart rate variability, an autonomic profile associated with poor cardiovascular outcomes in humans.  Rosuvastatin did not normalized plasma cholesterol levels, but completely normalized blood pressure and restored its circadian rhythm and normalized blood pressure and heart rate variabilities. 
    Pliquett et al. used a more direct approach to investigate the effect of simvastatin on central sympathetic outflow.  They measured renal sympathetic nerve activity (RNSA) in conscious normolipemic rabbits with congestive heart failure (CHF).  RSNA was increased in CHF rabbits, and this was normalized by simvastatin.  Similar data was obtained for plasma norepinephrine.  Simvastatin also improved the depressed baroreflex function of CHF rabbits.  Thus, the positive autonomic actions of statins may contribute to its overall beneficial cardiovascular effect, adding statins to the list of medications, such as angiotensin converting inhibitors and beta blockers, that reduce mortality in cardiovascular diseases in part through these mechanisms.
    Pelat M, Dessy C, Massion P et al.
(2003) Rosuvastatin decreases caveolin-1 and improves nitric oxide-dependent heart rate and blood pressure variability in apolipoprotein E-/- mice in vivo. Circulation 107:2480-2486.

    Pliquett RU, Cornish KG, Peuler JD et al.
(2003) Simvastatin normalizes autonomic neural control in experimental heart failure. Circulation 107:2493-2498.

Autonomic Biological Clocks
   
A main oscillator in the suprachiasmatic nucleus (SCN) conveys circadian information to the peripheral clock systems for the regulation of fundamental physiological functions. Terazono et al. investigated whether autonomic pathways are involved in this process.  Under a light-dark cycle, destruction of the SCN flattened the daily rhythms of not only the putative clock genes mPer1, mPer2 and mBmal1, but also noradrenaline content in mouse liver. Daily injection at a fixed time of adrenaline recovered oscillations of mPer2 and mBmal1 gene expression in the liver of SCN-lesioned mice. Sympathetic nerve denervation by 6-hydroxydopamine flattened the daily rhythm of mPer1 and mPer2 gene expression. Thus, the autonomic nervous system, through noradrenaline and/or adrenaline release, modulates peripheral biological clocks. 
    To study the sympathetic adrenergic signaling responsible for clock gene expression, Akiyama et al. constructed NIH3T3 cells that stably expressed each of three alpha(1)-adrenergic receptor subtypes (
α1A, α1B and α1D). They found that noradrenaline transiently induced the expression of mPer1, mPer2, and mE4bp4 via α1-receptor activation. Clock gene mRNA induction by PE was inhibited by U0126, a MEK inhibitor, suggesting involvement of the mitogen-activated protein kinase signaling pathway. Thus, sympathetic pathways relay biological clock information arising from the suprachiasmatic nucleus to peripheral organs.  This may involve α1 receptors.
    Terazono H, Mutoh T, Yamaguchi S et al. (2003) Adrenergic regulation of clock gene expression in mouse liver. Proc Natl Acad Sci U S A 100:6795-6800.

    Akiyama M, Minami Y, Kuriyama K et al. (2003) MAP kinase-dependent induction of clock gene expression by alpha 1-adrenergic receptor activation. FEBS Lett 542:109-114.

Paradoxical Vasodilation Produced by Tyramine
    Tyramine is often used as an investigational tool to mimic endogenous sympathetic activation by inducing norepinephrine release.  Indeed, intra-arterial infusion of tyramine increases local norepinephrine release and produces vasoconstriction.  When given systemically, however, sympathetically-mediated vasoconstriction has been equivocal in previous studies.  Meck et al. found that intravenous tyramine caused an increase in systolic blood pressure due to an increase in cardiac output, whereas total peripheral resistance decreased.  The mechanism of this paradoxical vasodilation was investigated by Jacob et al.  They found that intravenous tyramine, at doses that increased systolic blood pressure by 25 mmHg, also increased forearm norepinephrine spillover.  However, tyramine induced forearm vasodilation instead of the expected vasoconstriction.  By comparison, the cold pressor test produced a similar increase in blood pressure and forearm norepinephrine spillover, and induced forearm vasoconstriction.  Thus, systemic tyramine induced forearm norepinephrine release as anticipated, but this was not accompanied with the expected vasoconstriction.  The mechanism of this neurovascular dissociation is not known, but Jacob et al. found that intravenous tyramine significantly increased plasma dopamine.  Future studies would need to determine if tyramine-induced vasodilation is mediated by dopamine.  Tyramine can still be used to mimic sympathetically mediated activation if infused intra-arterially.  Intravenous tyramine measures cardiac, but not vascular sympathetic function.
    Meck JV, Martin DS, D'Aunno DS et al.
(2003) Pressor response to intravenous tyramine is a marker of cardiac, but not vascular, adrenergic function. J Cardiovasc Pharmacol 41:126-131.

    Jacob G, Costa F, Vincent S et al. (2003) Neurovascular Dissociation With Paradoxical Forearm Vasodilation During Systemic Tyramine Administration. Circulation 107:2475-2479.