Hypothalamic pituitary adrenocortical and sympathetic nervous system responses to the cold pressor test in Alzheimer's disease.

BACKGROUND: Increased basal activity of the hypothalamic-pituitary-adrenocortical (HPA) axis has been repeatedly demonstrated in Alzheimer's disease (AD), and some studies suggest increased basal activity of the sympathetic nervous system (SNS) in this disorder; however, the effects of AD on HPA axis or SNS responses to a standardized aversive stressor have not been examined. The neuroendocrine response to aversive stress may be relevant to the pathophysiology of AD. METHODS: Plasma adrenocorticotropic hormone (ACTH), cortisol, norepinephrine (NE), and epinephrine responses to a 1-min cold pressor test (CPT) were measured in nine medically healthy AD outpatients (age 76 +/- 2 years) and nine age- and gender-matched medically healthy cognitively normal older subjects (age 76 +/- 1 year). RESULTS: The cortisol response to CPT was increased in the AD group but the ACTH response did not differ between groups. Basal NE concentrations were higher in the AD group. Although NE responses to CPT did not differ between groups, the blood pressure response to CPT was higher in the AD subjects. CONCLUSIONS: These results suggest increased HPA axis responsiveness to CPT at the level of the adrenal cortex in AD. The results also suggest increased basal sympathoneural activity and increased cardiovascular responsiveness to sympathoneural stimulation in AD under the conditions of this experimental protocol. Increased SNS stimulatory modulation of the adrenal cortex is a possible mechanism contributing to the observed enhanced cortisol response to CPT in these AD subjects.     

Beta-receptor sensitivity in autonomic failure.

We examined the cardiovascular, plasma norepinephrine (NE), and plasma renin (PRA) responses to isoproterenol infusion in patients with autonomic failure and in normal subjects. Slopes of the blood pressure response/dose relationships were more negative in patients with multiple system atrophy and pure autonomic failure (PAF) than in normal subjects, consistent with impaired baroreflex modulation. A shift to the left in patients with PAF suggests beta-adrenergic receptor supersensitivity. In normal subjects, the increase in plasma NE and PRA was proportional to the log of the plasma isoproterenol level. Isoproterenol infusion did not increase plasma NE or PRA in either patient group despite a reduction in mean blood pressure. Reflexive cardiovascular and renal mechanisms appear to play a role in eliciting the plasma NE and PRA responses to isoproterenol infusion in normal subjects.     

Noradrenergic responses to clonidine in acute and remitted depressed male patients.

To investigate noradrenergic function in depression, plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), plasma norepinephrine (NE), mean arterial pressure (MAP), and heart rate responses to intravenous clonidine (2 micrograms/kg), an alpha 2-adrenergic agonist, were measured in 27 acutely depressed patients, 18 remitted depressed patients, and 27 normal control subjects; a placebo infusion was administered to a subgroup. Clonidine compared with placebo, over a 150-minute time course, decreased plasma NE, MAP, and heart rate, but not plasma MHPG, in the control subjects. Plasma MHPG, plasma NE, MAP, and heart rate at baseline or in response to clonidine and placebo over 150 minutes did not indicate any group differences. The only significant plasma MHPG response to clonidine in the normal control subjects occurred 60 minutes after the infusion. A significantly diminished plasma MHPG response to clonidine at 60 minutes was found in the acutely depressed group compared with the normal control subjects. These results suggest that peripheral inhibitory noradrenergic responses to clonidine are normal in depressed patients, while plasma MHPG responses to clonidine, which have a limited central contribution, appear to be a weak reflection of central noradrenergic function and appear insufficiently robust for a meaningful evaluation of hypothetical group differences in central inhibitory alpha 2-adrenergic activity in this population.     

Orthostatic heart rate variability analysis in idiopathic Parkinson's disease

Objectives –  We evaluated time and spectral analyses of 24-h heart rate variability (HRV) and the heart rate responses to passive tilt in patients with idiopathic Parkinson's disease (IPD) in order to investigate cardiovascular autonomic functions.
Material and methods –  Twenty-three subjects with IPD without autonomic symptoms and 15 age-matched healthy controls were enrolled. Frequency- and time-domain HRV parameters were studied during resting and passive head-up tilt (HUT) test.
Results –  All time-domain parameters were found to be low in patients with IPD. In patients with IPD, both low frequency (LF) and high frequency (HF) decreased during HUT period and no significant change in LF to HF ratio was noted. Both time- and frequency-domain HRV indices showed no correlation with age, disease severity and duration, and with l -dopa medication.
Conclusion –  The results indicate that impairment of autonomic nervous system function in IPD without autonomic symptoms is frequent, and does not show clear association with clinical stage and the age of the patients.     

Estrogen-dependent effects of norepinephrine on hypothalamic gonadotropin-releasing hormone release in the rabbit

In the rabbit, either coitus or intraventricular administration of norepinephrine (NE) induces gonadotropin release and ovulation. It is hypothesized that ovulation induced with these manipulations involves activation of neuronal pathways that include catecholaminergic and peptidergic neurons. The aim of this study was to examine if perfusion of NE directly through the mediobasal hypothalamus (MBH) stimulates gonadotropin-releasing hormone (GnRH) release from the MBH in ovariectomized (OVEX) and estradiol-treated OVEX does (OVEX/E₂). All does were fitted with push-pull (PP) cannulae directed to the MBH and subsequently subjected to PP perfusion at a flow rate of 20 μl/min for 6 h to measure hypothalamic GnRH release. Five OVEX/E₂ and 7 OVEX does received NE that was added to the PP system (intrahypothalamic NE perfusion) at the rate of 2.5 μg/min for 2 h during 6 h of PP perfusion. In addition, 6 OVEX/E₂ does were given intrahypothalamic perfusion of homovanillic acid (HVA), a metabolite of the adrenergic system, to serve as controls. All PP samples were collected on ice at 10-min intervals, and jugular vein blood samples were obtained at 20-min intervals. The GnRH, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured by specific radioimmunoassays. In OVEX/E₂ does, intrahypothalamic perfusion of NE, but not HVA, stimulated a 10-fold increase in peak values of hypothalamic GnRH within 30 min, and a 3-fold increase in peak values of plasma LH within 40 min. Thereafter, both GnRH and LH levels returned to basal values by the end of the NE perfusion. In contrast, the same NE treatment failed to stimulate GnRH and LH release in OVEX does. Changes in plasma FSH after NE were not observed in any of the 3 groups of animals. These results demonstrate that the NE-stimulated neuronal discharge of GnRH, that is accompanied by an increase in plasma LH, is estrogen dependent. The results further support the hypothesis that GnRH is the final common pathway that mediates the effect of brain NE on pituitary gonadotropes.     

Plasma catecholamine and cardiovascular responses to physostigmine in Alzheimer's disease and aging

Stimulation of brain cholinergic systems increases activity of both the sympathoneural (SN) and sympathoadrenomedullary (SAM) components of the peripheral sympathetic nervous system. Because presynaptic cholinergic neuron numbers are substantially reduced in Alzheimer's disease (AD), we predicted decreased responsiveness in AD of plasma norepinephrine (NE), an estimate of SN activity, and of epinephrine (EPI), an estimate of SAM activity, to central cholinergic stimulation by the cholinesterase inhibitor physostigmine (0.0125 mg/kg i.v.). Because previous studies have demonstrated that normal human aging increases SN activity but not SAM activity, we specifically hypothesized: (1) a smaller NE response to physostigmine in subjects with mild to moderate AD (n=11; age 72+/-2 yrs; mini-mental state exam [MMSE] scores of 19+/-2) than in healthy older subjects (n=20; age 71+/-1 yrs); and (2) a smaller EPI response in AD subjects than in either healthy older or healthy young subjects (n=9; age 27+/-2 yrs). Unexpectedly, the plasma NE increase following physostigmine only achieved significance in AD subjects and plasma EPI responses were greater in both AD and older subjects than in young subjects. Blood pressure responses to physostigmine were consistent with the catecholamine responses. These data suggest that the presence of mild to moderate AD increases the SN response to cholinergic stimulation and that both AD and normal aging increase the SAM response to cholinergic stimulation. As a result, plasma catecholamine responses to physostigmine do not appear to be useful peripheral neuroendocrine estimates of the severity of brain cholinergic deficits in mild to moderate AD.     

Cardiovascular and neuroendocrine responses to behavioral stress after central or peripheral barodenervation in rats

The cardiovascular and neuroendocrine responses to acute behavioral stress were evaluated in rats after disruption of the baro reflexes by electrolytic lesions of the nucleus tractus solitarii (NTS) or sinoaortic denervation (SAD). Rats with NTS lesions or SAD showed significantly greater increases in mean arterial pressure (MAP) and plasma norepinephrine (NE) concentrations than control rats during a single 30-min escape-avoidance test. In addition, the increases in MAP and plasma NE concentration of NTS lesion rats were significantly greater than those of SAD rats. However, NTS lesion raats showed no increase in plasma renin activity (PRA), as observed in the other groups. Thus, disruption of the baroreflexes by NTS lesions oraugments the arterial pressure and plasma NE responses to stress. Additionally, NTS lesions appeared to eliminate the neurons or fibers of passage participating in the sympathetically mediated increase in PRA.     

Balance between sympathetic response to head-up tilt and cardiac vagal factors in healthy humans

We evaluated the association between cardio-vagal baroreflex sensitivity (BRS; assessed with modified Oxford technique) and catecholamine response to 5 min 60° head-up tilt (HUT) in 46 young healthy adults. HUT increased HR, mean arterial pressure, and NE (P < 0.05 for all). BRS was negatively correlated with NE response to HUT (r = −0.36, P < 0.05), suggesting that subjects with high vagal modulation (high BRS) require less sympathetic response (NE) to maintain normotension during orthostatic stress.     

Platelet alpha 2-adrenergic receptor function in psychiatric disorders

The inhibitory effects of norepinephrine (NE) on the cyclic adenosine-3',5'-monophosphate (cAMP) response to prostaglandin E1 (PGE1), a measure of alpha 2-adrenergic receptor function, have been compared in platelets from drug-free schizophrenic patients, depressive patients, and normal controls. The absolute value of the inhibition by NE of the cAMP response to PGE1 was smaller in platelets from schizophrenic and depressive patients than in controls. However, this result was secondary to the smaller baseline platelet cAMP response to PGE1 in patients with these disorders. Effects of NE on cAMP production did not discriminate between actively ill and remitted patients with either schizophrenia or depression. Platelet alpha 2-receptor sensitivity, as measured by the effects of NE on cAMP production, does not appear to be altered in these psychiatric disorders.     

Influence of age and cold stress on plasma catecholamine levels in rats

We measured arteria plasma concentrations of norepinephrine (NE) and epinephrine (E) in pentobarbital-anesthetized 3- and 24-month-old male F344 rats in basal (control) conditions and following acute cold exposure (6 h at 4 degrees C). Basal levels of circulating NE and E were also determined in 3- and 24-month-old Sprague-Dawley animals. Basal NE did not change between 3 and 24 months of age in either strain of rat, whereas older animals of both strains had significantly higher basal plasma E concentrations compared to younger counterparts. Cold exposure increased plasma NE approximately 100 pg . ml-1 above respective basal levels in 3- and 24-month-old F344 rats, suggesting no age-related differences in sympathetic nervous system reactivity to cold stress. Plasma E in young cold-stressed F344 animals was elevated approximately 336 pg . ml-1 (287%) over basal levels, and approximately 370 pg . ml-1 (155%) over basal levels in older animals, resulting in cold-induced circulating E concentrations of 515 +/- 90 pg . ml-1, and 1040 +/- 122 pg . ml-1 in 3- and 24-month-old animals, respectively. Thus, arterial plasma E concentration in older rats is significantly elevated, both in basal conditions and in response to acute cold stress, suggesting enhanced adrenal medullary activity with advancing age.     

Interrelationships among measures of autonomic activity and cardiovascular risk factors during orthostasis and the oral glucose tolerance test

Overstimulation of sympathetic nervous system activity is related to atherosclerotic cardiovascular disease risk, but the role of parasympathetic activity in this association is not clear. This study evaluated sympathetic and parasympathetic function by spectral analysis of heart rate variability and plasma levels of norepinephrine (NE) epinephrine (EPI), dihydroxyphenylglycol (DHPG), dihydroxyphenylalanine (DOPA) and dihydroxyphenylacetic acid (DOPAC). It also examined the interrelationships among these parameters and established atherosclerotic cardiovascular disease risk factors in 53 men (mean age 59.5 years). During supine rest, low-frequency power correlated positively with high-frequency power (r = 0.58, p < 0.001), plasma NE correlated with plasma DHPG (r = 0.41, p < 0.001) and plasma DOPA with DOPAC (r = 0.47, p < 0.001) but neither low- nor high-frequency power was correlated with plasma levels of any catechol. Among risk factors, plasma NE correlated with fasting insulin and mean arterial blood pressure, and urine NE correlated with body mass index. Both low- and high-frequency power correlated positively with insulin levels. Orthostasis decreased high-frequency power and increased low-frequency power and plasma NE levels. During the oral glucose tolerance test, both high- and low-frequency power increased, plasma NE levels were unchanged, and plasma EPI levels decreased [88.5 ± 18 (SEM) versus 52.5 ± 12 pM,p = 0.001]. The results suggest that orthostasis decreases and the oral glucose tolerance test increases parasympathetic outflows, whereas both stimuli increase sympathetic outflows. Among all atherosclerotic cardiovascular disease risk factors, hyperinsulinaemia showed the strongest association with autonomic nervous system activity, especially parasympathetic activity. Estimates of sympathetic responses obtained from power spectral analysis of heart rate variability agree poorly with those from plasma levels of catechols, possibly because of a parasympathetic contribution to low-frequency power and independence of sympathoneural outflows to the arm and heart.     

Heart rate variability in children with neurocardiogenic syncope

Abstract. In order to characterize the autonomic profile of syncopal children, we have studied heart rate variability (HRV) of 73 children, ages 11–18, with neurocardiogenic syncope and a positive outcome of head-up tilt testing (HUT).HRV was calculated over a 24-hour period for the time-domain indices (SDNN, SDANNi, SDNN, rMSSD, pNN50), and over 5-minute segments from night and day for frequency-domain indices (LF, HF, LF/HF). The obtained results were compared to reference values calculated for Polish children. 55% of the children had mixed response to HUT, 41% vasodepressor and 4% cardioinhibitory. Patients with syncope had significantly lower values of rMSSD and pNN50 in comparison to healthy children. Moreover, in the frequency-domain analysis they exhibited significantly higher LF and lower HF values. The day-night rhythm of HRV and the age-related changes of HRV were, however, similar in syncopal and healthy children. In addition to this, we found a significantly lower SDNN value in children with cardioinhibitory response during HUT in comparison to children with mixed response. We concluded that 1) based on HRV analysis children with neurocardiogenic syncope had alterations in basal autonomic balance, which indicated an increased sympathetic modulation in these patients, 2) syncopal children had adequate circadian rhythm of autonomic activity, 3) the changes of HRV indices with age in these groups are not altered in comparison to healthy children, 4) syncopal children may exhibit differences in HRV indices values depending on the kind of vasovagal response observed during HUT.     

Long-Term Dynamic in vitro System for Investigating Rat Pineal Melatonin Secretion

Several details regarding the control of melatonin (MT) secretion from the pinealocytes are still to be clarified. To obtain more data on the mechanism and kinetics of MT secretion and on the interactions between bioactive materials affecting MT production, a perifusion system has been developed in our laboratory. In this dynamic in vitro system the surviving pinealocytes maintain their full responsiveness for at least 5 days. In order to determine the MT contents of large numbers of samples collected in the perifusion system, a sensitive MT radioimmunoassay was set up utilizing our specific MT antibody. In our perifusion system the basal MT release does not change significantly during the 5-day experiments. Norepinephrine (NE) was used at 1 μM concentration for 30 min as a marker of the responsiveness of pinealocytes, given at the beginning and at the end of the same experiments. No significant difference was found in the MT responses to NE stimulation over 5 days. The kinetics of MT response and the dose-response relationship were investigated after NE exposure at various concentrations (100 nM to 10 mM). NE at 100 nM was found to be ineffective. Between 1 μM and 1 mM concentrations NE increased the MT release in a dose-dependent manner. No significant difference was found between the responses above 1 mM concentration. NE seems to be a specific stimulator of pineal MT production. The MT production reached the maximum value after a relatively long lag (2 to 3 h) when NE application had been stopped, and returned to basal values after 5 to 6 h. This prolonged time-course of MT secretion, in contrast with the fast responses of pituitary cells to releasing hormones, suggests that NE stimulated the synthesis of MT rather than the release of stored hormone. The modulatory effects of light-dark cycle on basal and stimulated MT release of perifused pineals was also investigated: Neither basal nor NE-stimulated (100 nM to 10μM) MT release was influenced significantly by light-dark conditions showing that the light-dark cycle does not have a direct modulatory effect on MT secretion under in vitro circumstances. Based on our observations, this perifusion system should be a useful tool for investigating: 1) hormone interactions on the regulation of pineal MT release, and 2) accurate kinetics of MT response.     

Interactions of amphetamine, pimozide, and lithium on plasma norepineophrine and dopamine-beta-hydroxylase in schizophrenic patients.

The peripheral interactions of amphetamine with antipsychotic agents may elucidate some central mechanisms by which these drugs affect the behavioral responses to amphetamine. The authors studied the effects of intravenous amphetamine on plasma levels of norepinephrine (NE), dopamine-beta-hydroxylase (DBH), pulse rate, and blood pressure in schizophrenic patients. Amphetamine increased plasma NE, pulse rate, and blood pressure without significantly changing plasma DBH. DBH activity was similar in drug-free schizophrenic and normal subjects. Neither pimozide nor lithium altered these amphetamine effects nor changed any of the cardiovascular parameters measured in the drug-free subjects. Pimozide and lithium alter behavior and the behavioral effects of amphetamine, but neurotransmitters other than NE may be involved.     

Effects of naloxone and morphine on cerebral ischemia in gerbils

A therapeutic role for naloxone during stroke has been suggested, but a neurochemical site of action remains to be determined. Previous work with the gerbil cerebral cortex has shown that either bilateral secondary ischemia (60-min occlusion of the carotid arteries followed by 40-min reflow) or unilateral primary ischemia (permanent ligation of one carotid artery for 6 hr in symptomatic animals) produced deficits in both Na+, K+-ATPase (EC 3.6.1.3) activity and various parameters of activation of adenylate cyclase (EC 4.6.1.1). Pretreatment of gerbils with either naloxone or morphine failed to ameliorate or exacerbate, respectively, the neurological signs of ischemia; however, morphine did reduce mortality. Infusion of naloxone prior to ischemia afforded varying degrees of protection to forskolin, GTP analogs, and NE (norepinephrine) activation of adenylate cyclase, as well as to Na+, K+-ATPase (bilateral ischemia only). Similarly, morphine inhibited damage to basal activity of adenylate cyclase and to stimulation by NE, forskolin, and Gpp (NH)p (5'-guanylyl imidodiphosphate). Under in vitro conditions morphine increased the basal activity of adenylate cyclase but reduced responses to NE and forskolin. Furthermore, morphine injected into control gerbils elevated basal- and forskolin-elicited activities but reduced the activation of adenylate cyclase by NE.     

The middle cerebral artery flow velocities during head-up tilt testing in diabetic patients with autonomic nervous system dysfunction

BACKGROUND: The goal of this study was to examine the effects of diabetes mellitus on the trend of mean arterial velocity (v(m)) in both middle cerebral arteries during head-up tilt (HUT). METHODS: The study was performed in 20 patients, 9 females and 11 males (mean age 51 +/- 12 years) with an average 17-year history of insulin-dependent diabetes mellitus type I or II and a dysfunction of the autonomic nervous system confirmed by cardiocirculatory tests [Valsalva maneuver, deep breathing test, handgrip test, orthostatic test and spectral analysis of heart rate (HR) variability], and 19 age-matched healthy volunteers, 9 females and 10 males (mean age 48 +/- 6.8 years). v(m) was measured by a transcranial Doppler monitoring system during a 5-min baseline period, followed by a 5-min HUT in the upright position (90 degrees ). Mean arterial blood pressure (MAP), HR and end-tidal CO(2) (Et-CO(2)) were monitored concomitantly. RESULTS: In healthy volunteers, v(m) decreased stepwise during the first minute of HUT, reaching a minimum during the last 2 min of the test (v(m): basal 63.0 +/- 11.7 cm/s, 1st min 57.6 +/- 12.2 cm/s, 2nd min 55.9 +/- 12.6 cm/s, 3rd min 53.4 +/- 12.6 cm/s, 4th min 52.1 +/- 12.7 cm/s, 5th min 51.3 +/- 13.5 cm/s). In the supine position, v(m) recovered and reached the resting v(m) values. It declined gradually during HUT and less steeply in diabetic (v(m): basal 54.4 +/- 10.1 cm/s, 1st min 51.96 +/- 9.3 cm/s, 2nd min 50.7 +/- 11.6 cm/s, 3rd min 50.5 +/- 11.4 cm/s, 4th min 49.5 +/- 10.7 cm/s, 5th min 48.8 +/- 11.5 cm/s) than in healthy subjects. v(m) differed significantly (p = 0.00) between rest and HUT in both groups. The differences in MAP, HR and Et-CO(2) during rest and HUT between the groups were not statistically significant (p DeltaMAP = 0.36, p DeltaHR = 0.86, p DeltaEt-CO(2) = 0.97). The results of the analysis of variance of v(m) for repeated measurements between the two groups of subjects were highly significant (p = 0.00). The model of linear regression analysis was significant (p = 0.007). Diabetes was significant in the model (p = 0.00), while DeltaMAP, DeltaHR and DeltaEt-CO(2) were not. CONCLUSIONS: These findings may indicate that vasomotor responses during HUT testing are decreased in diabetic patients.     

β-1 and β-2 adrenergic receptor polymorphism and association with cardiovascular response to orthostatic screening

Variation in the beta-1 and beta-2 adrenergic receptor genes (ADRB1 and ADRB2, respectively) may influence cardiovascular reactivity including orthostatic stress. We tested this hypothesis in a head-up tilt (HUT) screening protocol in healthy young adults without history of syncope. Following brachial arterial catheter insertion, 120 subjects (age 18-40, 72 females, Caucasian) underwent 5min 60° HUT. Polymorphisms tested were: Ser49/Gly and Arg389/Gly in ADRB1; and Arg16/Gly, Gln27/Glu, and Thr164/Ile in ADRB2. Three statistical models (recessive, dominant, additive) were evaluated using general linear models with analysis for each physiologic variable. A recessive model demonstrated a significant association between Arg16/Gly and: absolute supine and upright HR; HUT-induced change in cardiac index (CI), stroke index (SI) and systemic vascular resistance (SVR); and supine and upright norepinephrine values. Blood pressure was not influenced by genotype. Fewer associations were present for other polymorphisms: Ser49/Gly and the change in SI (dominant model), and Arg389/Gly and supine and HUT norepinephrine (additive model). We conclude that in this population, there is a robust association between Arg16/Gly and HUT responses, such that 2 copies of Arg16 increase supine and upright HR, and greater HUT-induced decreases in CI and SI, with greater increases in SVR and norepinephrine. ADRB1 gene variation appears to impact SI and plasma NE levels but not HR. Whether ADRB2 gene variation is ultimately disease-causing or disease-modifying, this study suggests an association between Arg16/Gly and postural hemodynamics, with sympathetic noradrenergic activity affected in a similar direction. This may have implications in the development of orthostatic disorders.     

Role of endogenous adenosine in vasovagal syncope

Adenosine may be a potential mediator in the pathogenesis of vasovagal syncope. Intravenous adenosine increases sympathetic discharge and provokes vasovagal syncope in sensitive subjects. No data are available for endogenous adenosine. The authors compared the results of head-up tilt-table testing (HUT) (45 minutes at 60°) of three arbitrary groups of subjects: sensitive (n=25, age 34 y, vasovagal syncope, positive HUT), moderately sensitive (n=28, age 34 y, vasovagal syncope, negative HUT), and nonsensitive (n=19, age 30 y). A positive test result produced syncopal symptoms with hypotension and/or bradycardia. Single-lead electrocardiogram (ECG) was recorded, and arterial pressure was measured noninvasively. Fourier transform was used for power-spectral heart rate variability (HRV) analysis of 5-minute ECG data. In the nonsensitive and moderately sensitive groups, HUT was repeated with intravenous dipyridamole, and adenosine transport blocker. In the sensitive group, HUT was repeated with oral theophylline, an adenosine receptor blocker, or placebo. In the moderately sensitive group, a third HUT was performed with dipyridamole and oral theophylline. If adenosine plays a role in vasovagal syncope, then dipyridamole would induce more positive HUT responses, a positive HUT response would be prevented by theophylline, and hemodynamic and HRV data in positive HUT responses induced by dipyridamole should reproduce those observed during spontaneous positive HUT responses. Dipyridamole induced positive HUT responses in 57% of the moderately sensitive group and 21% of the nonsensitive group (p<0.05). Theophylline treatment was not efficient in preventing HUT-induced syncope in sensitive subjects; however, it prevented dipyridamole-induced syncope in 75% of the moderately sensitive group. Dipyridamole immediately increased arterial pressure, heart rate, and total HRV in all (p<0.05). In sensitive subjects, these responses were different: small for arterial pressure and for total and low-frequency HRV, and large for heart rate. It is concluded that endogenous adenosine, like exogenous adenosine, may induce vasovagal syncope. However, the mechanism of adenosine-induced syncope is probably different from that of HUT-induced vasovagal syncope. This study complies with the Declaration of Helsinki. The state ethics committee (No. 171/94) approved the research protocol; informed consent was obtained from the subjects.     

Decreased sympathetic neuronal uptake in idiopathic orthostatic hypotension

The disappearance rates from plasma of intravenously administered levo-norepinephrine (l-NE), dextro-norepinephrine (d-NE), and isoproterenol (ISO) were measured in normal subjects and in patients with either multiple-system atrophy (MSA) or idiopathic orthostatic hypotension (IOH). The two isomers, l-NE and d-NE, were removed at similar rates in all groups. In normal subjects, the d and l isomers of norepinephrine were cleared more rapidly than ISO. In patients with IOH, the initial rates of disappearance of the NE isomers from plasma were slower than normal and similar to the rate for ISO disappearance. Plasma NE levels, NE clearance, and the apparent release rate of NE into plasma from sympathetic neurons were significantly lower in patients with IOH than in normal subjects. Only the apparent NE secretion rate was related to the baseline plasma NE level. Sympathetic neuronal dysfunction in IOH is attended by a reduction in the clearance of NE. The very low plasma NE levels, in association with the striking reduction in NE clearance, suggest that in IOH there is a marked decrease in NE release. NE clearance and apparent NE secretion rate are normal in MSA, consistent with a central nervous system dysfunction in regulating the sympathetic nervous system. Neuronal uptake of NE in humans does not appear to be stereoselective.     

Blunted heart rate response to vagal withdrawal in persons with tetraplegia

Cardiovascular autonomic mechanisms control heart rate (HR) and determination of heart rate variability (HRV) permits the quantitative assessment of relative shifts in autonomic cardiac control during head-up tilt (HUT). The study herein used HRV techniques to determine the vagal and sympathetic contribution to the change in HR during HUT in persons with tetraplegia (T; n = 7) paraplegia (P; n = 7) and a non-spinal cord injured (non-SCI; n = 8) control group. Heart rate (HR) was continuously monitored and cardiovascular autonomic responses were assessed for 5-minutes at supine and at 45° HUT. Change associated with tilt from supine to 45° HUT was calculated for HR (deltaHR), high & low frequency HRV (HF & LF) and the LF/HF ratio. HR and LF power were lower in the T compared to the P and non-SCI groups at 45° HUT, whereas there were no group differences for HF at 45° HUT. The LF/HF ratio was lower in the T compared to the non-SCI group at 45° HUT. The relationship between delta HR and delta HF response differed between groups (significant group × delta HF interaction) such that the slope of this relationship was reduced in the T (−1.026: 95% CI: −2.623 to 0.571) compared with the non-SCI (−6.985: 95% CI: −11.25 to 2.72) and P (−5.218: 95% CI: −8.197 to −2.239) groups. There was no significant interaction effect for the relationships between deltaHR and deltaLF or deltaLF/HF. In summary, although the magnitude of vagal withdrawal was comparable among the groups, the increase in HR was attenuated in the group with tetraplegia, which may reflect reduced sympathetic cardiac modulation or altered SA node responsiveness to vagal withdrawal.