Sympathetic single axonal discharge after spinal cord injury in humans: activity at rest and after bladder stimulation.

STUDY DESIGN: Clinical experimental mechanistic study. OBJECTIVES: (1) To determine in three spinal cord-injured patients whether individual muscle sympathetic nerve fibres below the level of the spinal lesion display spontaneous activity. (2) To determine in these patients if individual sympathetic vasoconstrictor fibres show a prolonged discharge following a bladder stimulus. SETTING: University hospital in Gothenburg, Sweden. METHODS: Microneurographic recordings of action potentials from individual muscle nerve sympathetic fibres in a peroneal nerve. Recordings of skin blood flow and electrodermal responses in a foot. RESULTS: In all patients, there was sparse ongoing spontaneous impulse traffic in individual sympathetic fibres. Brisk mechanical pressure over the urinary bladder evoked a varying number of action potentials in individual fibres, but the activity was brief and did not continue after the end of the evoked multiunit burst. CONCLUSION: Prolonged discharges in individual sympathetic fibres are unlikely to contribute to a long duration of blood pressure increases induced by brief bladder stimuli.

Muscle sympathetic response to arousal predicts neurovascular reactivity during mental stress.

Mental stress often begins with a sudden sensory (or internal) stimulus causing a brief arousal reaction, and is followed by a more long lasting stress phase. Both arousal and stress regularly induce blood pressure (BP) increases whereas effects on muscle sympathetic nerve activity (MSNA) are variable. Here we have compared responses of MSNA and BP during arousal induced by an electrical skin stimulus and mental stress evoked by a 3 min paced auditory serial arithmetic test (PASAT) in 30 healthy males aged 33 ± 10 years. In addition, recordings were made of ECG, respiratory movements, electrodermal activity and perceived stress. We also monitored corresponding effects of a cold test (CT: 2 min immersion of a hand in ice water). The arousal stimulus evoked significant inhibition of one or two MSNA bursts in 16 subjects, who were classified as responders; the remaining 14 subjects were non-responders. During mental stress responders showed a significant decrease of MSNA and a lesser BP increase compared to non-responders. In non-responders MSNA was unchanged or increased. Perceived stress was higher in non-responders (P = 0.056), but other measures were similar in the two groups. In non-responders mental stress and the cold test induced increases of BP that lasted throughout the subsequent rest period. During the cold test MSNA and BP increased equally in responders and non-responders. In the whole group of subjects, there was a significant correlation (r = 0.80, P < 0.001) between MSNA responses induced by arousal and by mental stress but not between responses evoked by arousal and the cold test (r < 0.1, P > 0.6). Additionally arousal-induced MSNA change was positively correlated with blood pressure changes during MS (systolic BP: r = 0.48; P < 0.01; diastolic BP: r = 0.42; P < 0.05) but not with blood pressure changes during CT. We conclude that in males the MSNA response to arousal predicts the MSNA and BP responses to mental stress.

Fenofibrate-associated changes in renal function and relationship to clinical outcomes among individuals with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) experience.

AIMS/HYPOTHESIS: Fenofibrate has been noted to cause an elevation in serum creatinine in some individuals. Participants in the Action to Control Cardiovascular Risk in Diabetes Lipid Study were studied to better characterise who is at risk of an increase in creatinine level and to determine whether those with creatinine elevation have a differential risk of adverse renal or cardiovascular outcomes. METHODS: A fenofibrate-associated creatinine increase (FACI) was defined as an increase in serum creatinine of at least 20% from baseline to month 4 in participants assigned to fenofibrate. Baseline patient characteristics, and baseline and 4-month drug, clinical, laboratory characteristics and study outcomes were examined by FACI status. RESULTS: Of the sample, 48% of those randomised to receive fenofibrate had at least a 20% increase in serum creatinine within 4 months. In multivariable analysis, participants who were older, male, used an ACE inhibitor at baseline, used a thiazolidinedione (TZD) at 4 months post-randomisation, had baseline CVD, and had lower baseline serum creatinine and LDL-cholesterol levels were all more likely to meet the criteria for FACI. Participants in the FACI group were also more likely to have a decrease in their serum triacylglycerol level from baseline to 4 months. No differences in study outcomes were seen by FACI criteria. CONCLUSIONS/INTERPRETATION: Several characteristics predict a rapid rise in serum creatinine upon starting fenofibrate. Participants who met the criteria for FACI also had a greater change in triacylglycerol levels. In the setting of careful renal function surveillance and reduction of fenofibrate dose as indicated, no increase in renal disease or cardiovascular outcome was seen in those individuals demonstrating FACI. TRIAL REGISTRATION: ClincalTrials.gov: NCT00000620. FUNDING: The ACCORD Trial was supported by grants (N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035 and IAA-Y1-HC-1010) from the National Heart, Lung, and Blood Institute; by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute; by the Centers for Disease Control and Prevention; by General Clinical Research Centers and by the Clinical and Translational Science Awards. Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca Pharmaceuticals LP, Bayer HealthCare LLC, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis Pharmaceuticals, Novo Nordisk, Omron Healthcare, sanofi-aventis US and Takeda Pharmaceuticals provided study medications, equipment or supplies.

Autonomic innervation in multiple system atrophy and pure autonomic failure.

BACKGROUND: Pure autonomic failure (PAF) and multiple system atrophy (MSA) are both characterised by chronic dysautonomia although presenting different disability and prognosis. Skin autonomic function evaluation by indirect tests has revealed conflicting results in these disorders. Here, the authors report the first direct analysis of skin sympathetic fibres including structure and function in PAF and MSA to ascertain different underlying autonomic lesion sites which may help differentiate between the two conditions. METHODS: The authors studied eight patients with probable MSA (mean age 60±5 years) and nine patients fulfilling diagnostic criteria for PAF (64±8 years). They underwent head-up tilt test (HUTT), extensive microneurographic search for muscle and skin sympathetic nerve activities from peroneal nerve and punch skin biopsies from finger, thigh and leg to evaluate cholinergic and adrenergic autonomic dermal annexes innervation graded by a semiquantitative score presenting a high level of reliability. RESULTS: MSA and PAF patients presented a comparable neurogenic orthostatic hypotension during HUTT and high failure rate of microneurographic trials to record sympathetic nerve activity, suggesting a similar extent of chronic dysautonomia. In contrast, they presented different skin autonomic innervation in the immunofluorescence analysis. MSA patients showed a generally preserved skin autonomic innervation with a significantly higher score than PAF patients showing a marked postganglionic sympathetic denervation. In MSA patients with a long disease duration, morphological abnormalities and/or a slightly decreased autonomic score could be found in the leg reflecting a mild postganglionic involvement. CONCLUSION: Autonomic innervation study of skin annexes is a reliable method which may help differentiate MSA from PAF.

Tactile direction discrimination and vibration detection in diabetic neuropathy.

OBJECTIVE: To evaluate the clinical usefulness of quantitative testing of tactile direction discrimination (TDD) in patients with diabetic neuropathy. MATERIALS AND METHODS: TDD and vibration detection were examined on the dorsum of the feet in 43 patients with type 1 diabetes mellitus and clinical signs and symptoms indicating mild neuropathy, and abnormal results for neurography, temperature detection, or heart rate variability. Test-retest examination of TDD was performed in nine of the patients. RESULTS: Twenty-six of the patients had abnormal TDD (sensitivity 0.60) and 20 had abnormal vibration detection (sensitivity 0.46). Ten of the patients had abnormal TDD and normal vibration detection. Four of the patients had abnormal vibration detection and normal TDD. Test-retest examination of TDD showed a high degree of reproducibility (r = 0.87). CONCLUSION: TDD seems more useful than vibration detection in examination of diabetic neuropathy.

The right hemisphere fails to respond to temporal novelty in autism: evidence from an ERP study.

OBJECTIVE: This study aimed to investigate electrophysiological correlates of initial attention orienting to temporally novel sound in children with autism (CWA). METHODS: Twenty-one CWA (4-8 years) and 21 age-matched typically developing children (TDC) were presented with pairs of clicks separated by a 0.5s intra-pair interval, with longer (7-9s) intervals between pairs. Children watched a silent movie during click presentation. We assessed EEG perturbations and event-related potentials (ERP) in response to sounds of different temporal novelty - first (S1) and second (S2) clicks in the pair. RESULTS: In TDC, the early attention-modulated midtemporal N1c wave evoked by S1 and corresponding EEG phase locking and power increase were right-lateralized and were bilaterally higher than those evoked by S2. CWA demonstrated abnormal S1 responses, characterized by reduced N1c amplitude and EEG phase locking in the right midtemporal region, reversed leftward lateralization of the phase locking, and diminished later frontal N2 wave. Their brain responses to S2 were essentially normal. CONCLUSIONS: The impaired right hemispheric processing of temporary and contextually novel information and suboptimal lateralization of normally right-lateralized attention networks may be important features of autistic disorder. SIGNIFICANCE: Results of this study contribute to the understanding of autism neurobiology.

Laser-Doppler flowmetry reveals rapid perfusion changes in adipose tissue of lean and obese females.

The present study aimed to evaluate adipose tissue blood flow (ATBF) by means of laser-Doppler flowmetry (LDF) in humans. Lower body negative pressure (LBNP) and straining known to affect epidermal blood flow through the autonomic nervous system were performed in 11 lean and 11 obese female volunteers. ATBF changes were compared between both groups and also discriminated from skin blood flow (SBF) responses of the immediate vicinity. Additionally, LDF measurements were compared with flow measurements using (133)xenon washout in 10 lean subjects during whole body cooling. LDF estimations of SBF and ATBF showed a positive correlation to (133)Xe during cooling. SBF and ATBF were reduced to the same extent in both lean and obese subjects during LBNP. Straining induced divergent changes in SBF and ATBF: initially SBF decreased while ATBF increased, but toward the end of straining SBF increased above baseline and ATBF returned down to baseline level. Those changes were similar in both weight groups. Interestingly, only in obese subjects, both LBNP and straining were followed by ATBF augmentation, while SBF levels remained stable. In conclusion, LDF compares with (133)Xe washout in monitoring ATBF during tonic perfusion changes. Its strength, however, lies in the detection of rapid flow alterations within the subcutaneous tissue, allowing the evaluation of reflex responses of the subcutaneous microcirculation. Interestingly, those rapid changes in SBF and ATBF can be both concordant and discordant. With regard to ATBF, vasoconstrictor components of the reflex responses were similar in lean and obese subjects, whereas vasodilatory responses were more pronounced in obese volunteers.

EEG theta rhythm in infants and preschool children.

OBJECTIVE: To study behavioral correlates of theta oscillations in infants and preschool children. METHODS: EEG was recorded during baseline (visual attention) and two test conditions--exploration of toys and attention to 'social' stimulation. Age specific frequency boundaries of theta and mu rhythms were assessed using narrow bin analysis of EEG spectra. RESULTS: Theta spectral power increased whereas mu power decreased under test conditions in both age groups. In preschoolers theta rhythm increased predominantly over anterior regions during exploratory behavior and over posterior regions during attention to social stimulation. Theta frequency range changed with age from 3.6 to 5.6 Hz in infants to 4-8 Hz in children, and mu range from 6.4-8.4 Hz to 8.4-10.4 Hz. CONCLUSIONS: In early life, theta oscillations are strongly related to behavioral states with substantial attentional and emotional load. The scalp distribution of theta spectral power depends on age and behavioral condition and may reflect engagement of different brain networks in control of behavior. SIGNIFICANCE: The findings contribute to the scanty knowledge about the developmental course of theta rhythm. Data on behavioral correlates of theta rhythm in early life may improve our understanding of cognitive and mental processes in healthy and neuropsychiatrically diseased children.

No compensatory sweating after botulinum toxin treatment of palmar hyperhidrosis.

BACKGROUND: Primary focal hyperhidrosis is caused by excessive secretion by eccrine sweat glands, usually at the palms, soles and axillae. The underlying mechanism is unclear. In recent years botulinum toxin A has emerged as a useful treatment. Compensatory sweating, which is a major problem in many patients who have undergone transthoracic endoscopic sympathectomy for hyperhidrosis, has only rarely been reported after botulinum toxin. However, this potential side-effect of botulinum toxin treatment has not been systematically examined. OBJECTIVES: To investigate if treatment with botulinum toxin A in hyperhidrotic hands may cause compensatory sweating at other skin locations. METHODS: In 17 patients with a history of palmar hyperhidrosis repeated measurements of evaporation were made before and up to 6 months after treatment of the hands with botulinum toxin A. Recordings were made at 16 skin areas and compared with subjective estimates of sweating. RESULTS: Following treatment, palmar evaporation decreased markedly and then returned slowly towards pretreatment values, but was still significantly reduced 6 months after treatment. No significant increase of sweating was found after treatment in any nontreated skin area. CONCLUSIONS: Successful treatment of palmar hyperhidrosis with botulinum toxin does not evoke compensatory hyperhidrosis in nontreated skin territories.

Sumatriptan (5-HT1B/1D-agonist) causes a transient allodynia.

Unpleasant sensory symptoms are commonly reported in association with the use of 5-HT1B/1D-agonists, i.e. triptans. In particular, pain/pressure symptoms from the chest and neck have restricted the use of triptans in the acute treatment of migraine. The cause of these triptan induced side-effects is still unidentified. We have now tested the hypothesis that sumatriptan influences the perception of tactile and thermal stimuli in humans in a randomized, double-blind, placebo-controlled cross-over study. Two groups were tested; one consisted of 12 (mean age 41.2 years, 10 women) subjects with migraine and a history of cutaneous allodynia in association with sumatriptan treatment. Twelve healthy subjects (mean age 38.7 years, 10 women) without migraine served as control group. During pain- and medication-free intervals tactile directional sensibility, perception of dynamic touch (brush) and thermal sensory and pain thresholds were studied on the dorsal side of the left hand. Measurements were performed before, 20, and 40 min after injection of 6 mg sumatriptan or saline. Twenty minutes after injection, sumatriptan caused a significant placebo-subtracted increase in brush-evoked feeling of unpleasantness in both groups (P < 0.01), an increase in brush-evoked pain in migraineurs only (P = 0.021), a reduction of heat pain threshold in all participants pooled (P = 0.031), and a reduction of cold pain threshold in controls only (P = 0.013). At 40 min after injection, no differences remained significant. There were no changes in ratings of brush intensity, tactile directional sensibility or cold or warm sensation thresholds. Thus, sumatriptan may cause a short-lasting allodynia in response to light dynamic touch and a reduction of heat and cold pain thresholds. This could explain at least some of the temporary sensory side-effects of triptans and warrants consideration in the interpretation of studies on migraine-induced allodynia.

Regulation and counterregulation of lipolysis in vivo: different roles of sympathetic activation and insulin.

To obtain further information on the regulation of lipolysis in vivo, the effect of increasing sympathetic nerve activity via lower body negative pressure (LBNP, -20 mm Hg) was studied in 11 healthy human subjects. Subcutaneous and muscle microdialysis as well as blood flow measurements were performed in the postabsorptive state and during an euglycemic hyperinsulinemic clamp. LBNP for 30 min in the postabsorptive phase resulted in an approximately 50% increase (P < 0.005) in the interstitial-arterial concentration difference for glycerol in adipose tissue, whereas no such effect was registered in muscle. Blood flow in adipose tissue and the forearm remained unaltered. During euglycemic hyperinsulinemic conditions (p-insulin 645 +/- 62 pmol/liter), both interstitial adipose tissue and arterial concentrations of glycerol were reduced. LBNP resulted in an increase in interstitial-arterial concentration difference in glycerol similar to that seen in the postabsorptive state (approximately 50%, P < 0.05). Muscle glycerol was not changed by either insulin or LBNP. Glucose infusion rate during the clamp was significantly decreased during LBNP (7.82 +/- 0.88 vs. 8.67 +/- 1.1 ml/kg.min, P < 0.05). We conclude that the sympathetic nervous activation by LBNP results in an increased lipolysis rate in adipose tissue both in the postabsorptive phase and during insulin infusion. On the other hand, muscle glycerol output was not affected by either LBNP or insulin. The data suggest that 1) lipolysis is regulated differently in muscle and adipose tissue, 2) postabsorptive lipolysis is mainly regulated by insulin, and 3) sympathetic nervous activation effectively inhibits the antilipolytic action of insulin by inducing insulin resistance.

Why do human postganglionic neurones primarily only fire once during a sympathetic burst?

AIM: Single-unit recordings from muscle vasoconstrictor, cutaneous vasoconstrictor and sudomotor neurones in awake human subjects have shown that they tend to fire only once per sympathetic burst. We review the firing properties of human sympathetic neurones and examine the idea that the short duration of a sympathetic burst may limit the number of times a neurone can fire, using the human skeletomotor system as a model for the sympathetic nervous system. RESULTS: It is known that human alpha motor neurones usually fire in long trains during voluntary contractions, but what of their pattern when constrained by a brief burst? We recorded from single motor units in the tibialis anterior muscle while subjects generated brief electromyogram bursts in the intervals between heart beats, with a duration similar to that of muscle sympathetic bursts. Eight motor units fired mostly one spike per burst, with a pattern identical to that of sympathetic neurones. CONCLUSION: These results suggests that were it not for the constraint of the bursting pattern, individual sympathetic neurones would--like alpha motor neurones--tend to fire in long trains.

Arousal increases baroreflex inhibition of muscle sympathetic activity.

AIM: Surprising sensory stimuli causing arousal are known to evoke short-lasting activation of human sympathetic activity in skin but not in muscle nerves. In fact, anecdotal observations suggest that muscle sympathetic activity may be inhibited. To test this hypothesis, the effects of surprising somatosensory (electrical skin pulses) or visual (flash) stimuli on multiunit muscle sympathetic activity were studied in 36 healthy subjects, aged 19-71 years. METHODS: The stimuli were given either 200 or 400 ms after the R-wave of the electrocardiogram. Dummy stimuli, consisting of trigger pulses without sensory stimuli, served as controls. RESULTS: On a group basis, a single sensory stimulus of either type attenuated the amplitude of one or two sympathetic bursts, while no such effects occurred after dummy stimuli. Individually, the inhibition was evoked by at least one stimulus modality or delay in 16 subjects, whereas in three subjects no significant inhibition occurred. Electrodermal signs of skin sympathetic activation were present in all subjects. Compared with one, five repeated electrical skin pulses induced only minor additional inhibition of muscle sympathetic activity, indicating marked habituation of the neural response. In nine subjects, the experiments were repeated once and in three subjects twice (with intervals of 2-3 months); in 11 of the 12 subjects, the sympathetic effects were reproducible. In the group of subjects without significant sympathetic inhibition the stimuli induced a small, transient increase of mean blood pressure, which was not present in the group with sympathetic inhibition. CONCLUSION: The finding that different sensory stimuli induce similar effects that habituate markedly on repetition suggests that the inhibition of muscle sympathetic activity is because of arousal. The interindividual differences in sympathetic and blood pressure effects may be part of interindividual differences in behavioural responses to stress.

Sympathetic control of white adipose tissue in lean and obese humans.

AIM: To induce lipolysis, catecholamines could reach the adipocyte via the blood stream after being released from the adrenal medulla or, alternatively, via neuronal release in the vicinity of the fat cell. Sympatho-neuronal effects on fat tissue lipolysis have been demonstrated in experimental animal models. However, the role of sympathetic nerves in the control of lipolysis in human white adipose tissue, which is sparsely innervated, has not been clarified. CONCLUSION: The present review summarizes evidence for a direct neuronal influence on lipolysis in humans.

Pathological sympathoexcitation: how is it achieved?

AIM: Congestive heart failure (CHF) and obstructive sleep apnoea syndrome (OSAS) are both associated with an intense sympathoexcitation, including an increased muscle sympathetic nerve activity (MSNA). We have studied the firing characteristics of single vasoconstrictor fibres to the muscle vascular bed in CHF and OSAS patients, at rest and during transient sympathoexcitatory stimuli, to elucidate the mechanisms by which vasoconstrictor output is augmented in these conditions. RESULTS: The main alternatives for augmenting sympathetic output are an increased firing frequency of individual nerve fibres and an increased recruitment of nerve fibres. Starting with the frequency alternative, the inherent bursting character of MSNA provides two possibilities to increase the firing of individual fibres: (1) by increasing the proportion of neural bursts in which the fibre is active (increased firing probability) and (2) by increasing the number of spikes a fibre generates per burst (increased multiple within-burst firing). At rest and in cardiac sinus rhythm, an increased firing probability is seen in both CHF and OSAS patients, whereas increased multiple within-burst firing is found in OSAS but not in CHF. In response to transient sympathoexcitatory stimuli (such as pre-mature heart beats), both patient groups show marked shifts towards multiple within-burst firing. Thus, both mechanisms for augmenting discharge frequency are operating in these two pathological conditions, but the firing characteristics at rest differ significantly. During recording sessions in sympathoexcited patients, we have encountered vasoconstrictor fibres that are active almost exclusively during periods of transient sympathoexcitation, while being virtually silent at rest. This suggests that recruitment of previously inactive vasoconstrictor fibres, the second main alternative for increasing vasoconstrictor output, contributes to transient sympathoexcitatory responses in these patients. Although it seems reasonable to assume that recruitment may also contribute to the resting level of MSNA in CHF and OSAS, this issue is difficult to resolve in microneurographic studies. CONCLUSION: In conclusion, pathological sympathoexcitation appears to depend on both recruitment and increased firing frequency. A shift towards multiple within-burst firing, at rest or in response to transient stimuli, may constitute a risk factor per se as it entails neural volleys with high instantaneous firing frequencies and consequently higher release of neurotransmitters.

Increased hepatic VLDL secretion, lipogenesis, and SREBP-1 expression in the corpulent JCR:LA-cp rat.

The corpulent JCR:LA-cp rat (cp/cp) is a useful model for study of the metabolic consequences of obesity and hyperinsulinemia. To assess the effect of hyperinsulinemia on VLDL secretion in this model, we measured rates of secretion of VLDL in perfused livers derived from cp/cp rats and their lean littermates. Livers of cp/cp rats secreted significantly greater amounts of VLDL triglyceride and apolipoprotein, compared with lean littermates. The content of apoB, apoE, and apoCs in both perfusate and plasma VLDL was greater in the cp/cp rat, as was the apolipoprotein (apo)C, apoA-I, and apoA-IV content of plasma HDL. Triglyceride content was also greater in cp/cp livers, as was hepatic lipogenesis and expression of lipogenic enzymes and sterol regulatory element binding protein-1 (SREBP-1). Hepatic mRNAs for apoE, and apoA-I were higher in livers of cp/cp rats. In contrast, the steady state levels of apoC-II, apoC-III, and apoB mRNAs were unchanged. Thus, livers of obese hyperinsulinemic cp/cp JCR:LA-cp rats secrete a greater number of VLDL particles that are enriched in triglyceride, apoE, and apoC. Greater secretion of VLDL in the cp/cp rat in part results from higher endogenous fatty acid synthesis, which in turn may occur in response to increased expression of the lipogenic enzyme regulator SREBP-1c.

Is the somatotropic axis related to sympathetic nerve activity in healthy ageing men?

OBJECTIVE: The mechanisms underlying the age-related increase in blood pressure and sympathetic nerve activity remain largely unknown. The decline in growth hormone (GH) secretion and insulin-like growth factor-I (IGF-I) with age has been related to several cardiovascular risk factors. Low serum IGF-I levels in severe adult GH deficiency is associated with markedly increased sympathetic nerve activity. This study evaluates whether a relationship between serum IGF-I and sympathetic nerve traffic exists in healthy aging men. DESIGN AND METHODS: Sympathetic nerve activity to the muscle vascular bed (MSA) was recorded in 56 healthy normotensive males, and related to age (range 21-71 years), body mass index (BMI, range 18.4-32.2), serum IGF-I and plasma nitrate levels. Blood pressure, BMI and MSA increased with age, whereas IGF-I and plasma nitrate decreased. In a forward stepwise multiple regression analysis, age explained 40% of the variability in MSA and excluded other variables. Omitting age, IGF-I became the strongest independent predictor, explaining 23% of the variability in MSA. MSA was an independent predictor of diastolic blood pressure, but its influence (10%) was less than that of BMI (28%). BMI was not related to MSA or IGF-I. CONCLUSIONS: Decreased serum IGF-I levels are coupled to increased MSA during ageing, an effect independent from the impact of increased body weight. Although MSA is a weak predictor of rising blood pressure with age, it constitutes one possible pathway for the somatotropic axis to affect cardiovascular function in ageing.

Multiple firing of single muscle vasoconstrictor neurons during cardiac dysrhythmias in human heart failure.

Single vasoconstrictor nerve fibers in humans normally fire only once but have the capacity to fire as many as eight times, per cardiac interval. Our laboratory recently demonstrated that the mean firing frequency of individual vasoconstrictor fibers is more than doubled in the sympathoexcitation associated with congestive heart failure (Macefield VG, Rundqvist B, Sverrisdottir YB, Wallin BG, and Elam M. Circulation 100: 1708--1713, 1999). However, the propensity to fire only once per cardiac interval was retained. In the present retrospective study, we tested the hypothesis that vasoconstrictor fibers fire more than once per cardiac interval in response to transient sympathoexcitatory stimuli, providing one mechanism for further increase of an already augmented sympathetic discharge. Six patients with congestive heart failure (New York Heart Association functional class II--IV; left ventricular ejection range 13--37%, average 22%) were studied at rest and during premature ectopic heartbeats. Analyzed for a total of 60 premature beats, the average firing probability of 10 vasoconstrictor fibers increased from 61 to 80% in the prolonged cardiac interval (i.e., reduced diastolic pressure) after premature beats. The incidence of multiple within-burst firing increased markedly, with two spikes being more common than one. Our results illustrate two different mechanisms (increases in firing probability and multiple within-burst firing), and indirectly indicate a third mechanism (recruitment of previously silent fibers), for acute sympathoexcitatory responses.

Cardiovascular reflex testing contributes to clinical evaluation and differential diagnosis of Parkinsonian syndromes.

The differentiation between Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA) may be difficult but is important for prognostic and therapeutic purposes. Varying degrees of autonomic failure have been described in PD and MSA, whereas its involvement in PSP remains controversial. The aim of this study was to investigate autonomic function in patients fulfilling strict clinical diagnostic criteria for the disorders above, to evaluate the diagnostic capacity of laboratory autonomic tests. The study group was consecutively recruited among patients referred to a movement disorder unit. Thirty-four patients with PD, 15 patients with PSP, and 47 patients with MSA were compared with 18 healthy age-matched controls. Autonomic tests included analysis of heart rate variability (HRV) in temporal domain, at rest and during forced respiration, as well as blood pressure (BP) changes during 75 degrees head-up tilt. HRV did not differ between groups during quiet breathing but was significantly reduced during forced respiration in MSA (P < 0.01), while PD and PSP groups did not differ from controls. Hypotensive responses during orthostatic provocation were seen in PD (P < 0.01) and MSA (P < 0.001), whereas BP remained stable in most PSP patients, not differing from the healthy control group. On an individual basis, decreased HRV and severe hypotensive responses were seen in MSA patients regardless of age and disease duration, whereas PD patients showed this combination only at high age and long duration. In PSP, only a few cases with decreased HRV and limited hypotensive responses were found. We conclude that cardiovascular reflex tests can supplement the clinical differentiation of Parkinsonian syndromes.

Postmenopausal estrogen administration suppresses muscle sympathetic nerve activity.

The activity of the sympathetic nervous system shows gender-specific differences with lower sympathoneural activity to the muscle vascular bed in women compared with men, with this difference vanishing after menopause. The present study tested the hypothesis that estrogen exerts regulatory influence on the autonomic nervous system in postmenopausal women. Eleven healthy postmenopausal women (age, 58.5 +/- 1.0 yr; mean +/- SEM) were studied in a randomized double-blind crossover protocol with transdermal administration of 100 microgram/day estradiol (E(2)) or placebo (P) for 2 days. Muscle sympathetic activity (MSA), blood pressure, and heart rate were recorded at rest and during sympathoexcitatory maneuvers (apnea, cold pressor test). E(2) administration significantly increased serum E(2) to physiological levels (E(2), 469.5 +/- 51.5; P, 34.8 +/- 2.2 pmol/L; P < 0.05) and significantly lowered MSA (E(2), 30.1 +/- 3.0 vs. P 37.7 +/- 3.1 bursts/min; P < 0.05). At the same time, blood pressure and heart rate were not affected. MSA was significantly enhanced during apnea and the cold pressure test, and this physiological response to the maneuvers was not changed after estrogen supplementation. In conclusion, elevation of low postmenopausal estrogen levels to physiological premenopausal levels by transdermal E(2) administration supresses MSA. This effect is most likely the consequence of a direct E(2) effect on central nervous autonomic centers, which could explain the gender-specific differences in sympathetic outflow to the muscle vascular bed. The sympathoinhibitory estrogen effects could be important for beneficial cardiovascular effects of estrogen replacement therapy in postmenopausal women.