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2004; Volume 14(2) from Clinical Autonomic Research    
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Prominent vagal impairment in idiopathic autonomic neuropathy caused by nicotinic ganglionic antibodies

Acute and subacute autonomic neuropathy often results from an autoimmune process following a viral illness.  A subset of these patients has high levels of ganglionic acetylcholine receptor (AChR) autoantibodies.   Sandroni et al reviewed the clinical characteristics of patients with idiopathic autonomic neuropathy who were seropositive (n = 19) and seronegative (n = 87) for ganglionic AChR antibodies. The seropositive group more frequently had abnormal pupillary responses (67% vs. 14%), sicca complex (60% vs. 23%), and lower gastrointestinal tract symptoms (84% vs. 56%). A subacute mode of onset was more common in the seropositive group (63% vs. 27%). Group differences in clinical characteristics remained present when the data was analyzed controlling for onset rate.  These observations support the concept that ganglionic AChR antibodies are diagnostically and pathophysiologically important in the development of a discrete disease entity characterized by orthostatic hypotension and prominent cholinergic dysautonomia.

Sandroni,P, Vernino,S, Klein,CM et al (2004)  Idiopathic autonomic neuropathy: comparison of cases seropositive and seronegative for ganglionic acetylcholine receptor antibody.  Arch Neurol 61:44-48.


Nitric oxide and central autonomic cardiovascular regulation.  From neuromodulator to neurotoxin.

Nitric oxide (NO) is can act as a neurotransmitter in the central nervous system and can modulate central autonomic cardiovascular control.  Chan et al evaluated the role of NO in the nucleus tractus solitarii (NTS), the terminal site of baroreflex afferents.  Baroreceptor activation induced by 30 min of sustained hypertension significantly and sequentially increased level of cyclic GMP-dependent protein kinase I (PKG-I), phosphorylated cyclic AMP response element-binding protein (pCREB), c-fos mRNA, and Fos protein in the NTS. The expression of these signaling factors was significantly attenuated in animals that were pretreated with bilateral microinjection into the NTS of a selective neuronal nitric-oxide synthase (nNOS) inhibitor, with an inhibitor of soluble guanylyl cyclase (sGC), or with an antagonist of cyclic GMP.  These results indicate that nNOS plays a role in the baroreflex modulation of blood pressure by the NTS, possibly by participating in c-fos expression via phosphorylation of CREB in a process that engages the sGC/cGMP/PKG-I signaling cascade.

Despite its role as a physiological neuromodulator, it is now evident that excess of NO can lead to oxidative stress and cell damage.  Experimental and clinical studies suggest that septic shock is associated with cardiovascular autonomic failure, and Sharshar et al examined the possibility that this is associated with ischemia or apoptosis within central nervous system centers involved in autonomic cardiovascular control.  They performed post-mortem examinations of supraoptic and paraventricular nuclei, cerebral amygdala, locus coeruleus, and medullary autonomic nuclei in 19 patients with septic shock, seven with non-septic shock and five who died suddenly from extracranial injury. Histological indices of ischemic, and neuronal and microglial apoptosis, were higher in patients with septic shock than in those with non-septic shock and non-shock related deaths. The scores for endothelial iNOS expression were also higher in septic shock than in the other groups.  Furthermore, vascular expression of iNOS correlated with the presence of apoptosis in autonomic neuronal centers.  The speculation is that increased iNOS expression contributes to the apoptosis of autonomic neural centers involved in autonomic cardiovascular control as the results of septic shock.  A causal relationship could be tested in mice lacking iNOS.

Chan,SH, Chang,KF, Ou,CC et al (2004)  Nitric oxide regulates c-fos expression in nucleus tractus solitarii induced by baroreceptor activation via cGMP-dependent protein kinase and cAMP response element-binding protein phosphorylation.  Mol Pharmacol 65:319-325.

Sharshar,T, Gray,F, Lorin,dlG et al (2003)  Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock.  Lancet 362:1799-1805.


Autonomic abnormalities precede essential hypertension?

Essential hypertension is known to be associated with sympathetic hyperactivity and/or vagal withdrawal. Davrath et al investigated the possibility that these abnormalities can be detected early in the development of essential hypertension.  They studied young adult normotensive offspring of one hypertensive parent (KHT; n = 12) and normotensive offspring of two normotensive parents (YN; n = 14), and examined HR and blood pressure spectral analysis using a continuous wavelet transform that allowed them to monitor HR variability during rapid transitions, such as an active change in posture. KHT had a significantly greater increase in the low-frequency fluctuations in HR than YN during standing, indicating enhanced sympathetic involvement in the HR response.  They also had a reduced alpha-index, indicating decreased baroreceptor sensitivity. These results indicate the early existence of malfunctions in autonomic control in individuals at increased risk of hypertension. 

Davrath,LR, Goren,Y, Pinhas,I et al (2003)  Early autonomic malfunction in normotensive individuals with a genetic predisposition to essential hypertension.  Am J Physiol Heart Circ Physiol 285:H1697-H1704.


Role of the adrenals in the sympathetic activation induced by hypoglycemia

Hypoglycemia causes significant sympathetic activation which contributes to the counterregulatory mechanisms required to restore plasma glucose.  Both components of the sympathoadrenal system, the peripheral sympathetic nervous system and the adrenal medullae, are activated by hypoglycemia, but their relative contributions to the manifestations of hypoglycemia are largely unknown. To examine this question, DeRosa et al compared the responses to hyperinsulinemic euglycemic and hypoglycemic clamps in 15 healthy control subjects and four bilaterally adrenalectomized patients (ADX).  As expected, plasma epinephrine responses to hypoglycemia were virtually absent in ADX. Nonetheless, neurogenic symptoms of hypoglycemia were induced in both controls and ADX. Plasma norepinephrine (NE) concentrations and systemic NE spillover increased during hypoglycemia in controls but not in ADX. Similarly, heart rate increased, diastolic blood pressure decreased and forearm blood flow increased during hypoglycemia in controls but not in ADX. These data indicate that the neurogenic symptoms of hypoglycemia do not require adrenomedullary, activation. They also suggest that the plasma norepinephrine and hemodynamic responses to hypoglycemia are largely the result of adrenomedullary, rather that sympathetic neural, activation.

DeRosa,MA and Cryer,PE (2004)  Hypoglycemia and the Sympathoadrenal System: Neurogenic Symptoms are Largely the Result of Sympathetic Neural, Rather than Adrenomedullary, Activation.  Am J Physiol Endocrinol Metab [Epub ahead of print]


Gender differences in autonomic cardiovascular control. 

Women have a greater incidence of orthostatic intolerance than men. Fu et al hypothesized that this was related to differences in cardiac filling rather than to a reduced responsiveness of vascular resistance during orthostatic stress. They constructed Frank-Starling curves from pulmonary capillary wedge pressure (PCWP) and stroke volume (SV) as well as stroke index during lower body negative pressure (LBNP) and rapid saline infusion in 10 healthy, sedentary women and 13 control men. Orthostatic tolerance, defined as time to presyncope induced by progressive LBNP, was significantly lower in females than males (627 vs. 928 mmHg x min). Women had a steeper maximal slope of their Frank-Starling curves than men whether expressed as SV or normalized as stroke index. At presyncope, SV was 35% and stroke index was 29% lower for the females compared with the males. Coincident with the smaller SV, females had higher heart rates, but similar mean arterial pressures compared with males at the onset of presyncope. Vascular resistance was similar and plasma norepinephrine concentration did not differ between the genders. These results suggest that lower orthostatic tolerance in women is associated with a decreased cardiac filling rather than a reduced responsiveness of vascular resistance during an orthostatic challenge. Thus, cardiac mechanics and the Frank-Starling relationship may be important mechanisms underlying the gender difference in orthostatic tolerance.  It will be of interest if similar findings underlie orthostatic intolerance in POTS.

            Norepinephrine transporter (NET) function regulates synaptic norepinephrine concentrations and actions. Clinical observations in orthostatic intolerance patients suggest a gender difference in NET function. Schroeder et al compared the cardiovascular response to selective NET inhibition with reboxetine between 12 healthy women and 12 age-matched men.  It should be noted that the effects of NET inhibition on autonomic cardiovascular control are complex, because it produces both central inhibition of sympathetic outflow and peripheral potentiation of norepinephrine actions. NET inhibition elicited a greater increase in supine blood pressure in men than women, due to an increase in cardiac output in both. NET inhibition produced a greater orthostatic heart rate increase in men compared to women (56 vs. 42 bpm). In contrast, NET inhibition resulted in a similar suppression in the cold pressor and handgrip response, low frequency blood pressure oscillations, and venous norepinephrine in the supine position, suggesting similar central sympatholytic effects of NET inhibition in males and females.  To examine potential gender differences in peripheral effects of NET inhibition, the authros applied incremental concentrations of tyramine through subcutaneous microdialysis catheters but found no gender differences in the lipolytic effect of tyramine. Thus, NET inhibition results in more pronounced changes in cardiac regulation in men than women, suggesting that the NET contribution to cardiac norepinephrine turnover is less important in women. The gender difference in NET function may not be expressed in tissues that are less NET-dependent than the heart.

Fu,Q, Arbab-Zadeh,A, Perhonen,MA et al (2004)  Hemodynamics of orthostatic intolerance: Implications for gender differences.  Am J Physiol Heart Circ Physiol 286:H449-H457.

Schroeder,C, Adams,F, Boschmann,M et al (2004)  Phenotypical evidence for a gender difference in cardiac norepinephrine transporter function.  Am J Physiol Regul Integr Comp Physiol [Epub ahead of print]