Sustained hyperglycaemia increases muscle blood flow but does not affect sympathetic activity in resting humans

An increase in capillary blood flow and pressure in response to diabetes mellitus may lead to microangiopathy. We hypothesize that these haemodynamic changes are caused by a decreased activity of the sympathetic nervous system due to episodes of sustained hyperglycaemia. Twelve healthy volunteers consecutively underwent a hyperglycaemic experiment (HYPER), with the plasma glucose level maintained at 20 mmol.l^-1 for 6 h by combined infusion of somatostatin, insulin and glucose; and a normoglycaemic experiment (NORMO), with similar infusions but with the plasma glucose maintained at fasting level. During both experiments, sympathetic nervous system (SNS) activity was measured by assessing the plasma catecholamine levels, microneurography, power spectral analysis and forearm blood flow (FBF). In an age- and weight matched group, fasting and 6-h sympathetic activity was measured without infusion of somatostatin and insulin (CONTROL). During HYPER, forearm blood flow increased from 2.45 (0.21) to 3.10 (0.48) ml.dl^-1.min^-1 ( P <0.05), but did not change in NORMO or CONTROL. The HYPER conditions did not change the plasma noradrenaline levels or the muscle sympathetic nerve activity [42 (4), 50 (10) and 45 (5) bursts/100 beats, HYPER, NORMO and CONTROL respectively]. Also, the power spectral analysis was similar under all experimental conditions. All results are expressed as the mean (SEM). In conclusion, sustained hyperglycaemia in normal subjects induces moderate vasodilation in skeletal muscle, but this increased blood flow can not be attributed to a decreased sympathetic tone.     

Effects of hydralazine on renal sympathetic nerve activity in normal and congestive heart failure rats

We investigated the effects of hydralazine on renal sympathetic nerve activity in anaesthetized heart failure rats. Sham-operated rats (group 1) received 0.5 mg kg^?1 of hydralazine as bolus and were then infused with 0.3–0.5 mg kg^?1 h^?1 for 3 h intravenously. Heart failure rats received either the same regime (group 2) as group 1, or the same volume of vehicle (group 3). Heart failure rats exhibited lower mean blood pressure (P < 0.05) and elevated renal sympathetic nerve activity (P < 0.01) in the basal state. In group 2, the mean blood pressure decreased 26% after 30 min of hydralazine administration and remained lower for 3 h, with unchanged renal sympathetic nerve activity. In group 1, the mean blood pressure decreased 36%, and the heart rate and renal sympathetic nerve activity were significantly inhibited. Bilateral vagotomy did not alter renal sympathetic nerve response to hydralazine, but resulted in tachycardia. The results indicate that hydralazine, despite its profound hypotensive effect, did not activate renal sympathetic nerve activity in heart failure rats and inhibited renal sympathetic nerve activity in sham-operated rats. This inhibition was not mediated through the vagal nerve.     

Cardiovascular response to exercise in humans following acclimatization to extreme altitude

The purpose of this study was to assess the effects of acclimatization to extreme altitude on the cardiovascular system, using vagal and adrenergic blockade and acute restoration of normoxia during exercise to maximum with one and two legs. Fourteen climbers on an expedition to the Himalayas were studied at a lower base camp (5250 m) following 56–81 days at altitudes between 5250 and 8700 m. After acclimatization, peak heart rate (HR_peak), oxygen uptake (o_2k) and noradrenaline (NA) were similar during maximal one- and two-legged cycling, whereas peak plasma lactate was higher during the one-legged protocol. HR_peak (range 113–168 beats min“¹) was lowest when subjects returned from the higher camps. The degree of partial restoration of HR_peak to more normal values within seconds of 60% 0₂ inhalation (range 5–35 beats min?^l HR_peak increase) was greatest in subjects with low HR_peak. HR responses to /?-l blockade increased as a function of HR_peak and the HR responses to atropine were the least in subjects with high HRpeak- These findings suggest that (a) the reduction in HR_peak is linked to the duration and severity of the hypoxaemia, (b) the degree of restoration of HR_peak with acute normoxia is dependent on the level of attenuation or down-regulation of cardiac sympathetic activation (SNA), (c) cardiac vagal drive is masked to a lesser extent in chronic hypoxia because of attenuated SNA and lower HR_peak values, and (d) the lower blood lactate levels at altitude is a function of muscle mass involvement rather than adrenergic activation, as normal peak values were reached during exercise with a small muscle mass.     

Time-courses in renin and blood pressure during sleep in humans

We previously described a strong concordance between nocturnal oscillations in plasma renin activity (PRA) and the rapid eye movement (REM) and non-REM (NREM) sleep cycles, but the mechanisms inducing PRA oscillations remain to be identified. This study was designed to examine whether they are linked to sleep stage-related changes in arterial blood pressure (ABP). Analysis of sleep electroencephalographic (EEG) activity in the delta frequency band, intra-arterial pressure, and PRA measured every 10 min was performed in eight healthy subjects. Simultaneously, the ratio of low frequency power to low frequency power + high frequency power [LF/(LF + HF)] was calculated using spectral analysis of R--R intervals. The cascade of physiological events that led to increased renin release during NREM sleep could be characterized. First, the LF/(LF + HF) ratio significantly (P < 10(-4) decreased, indicating a reduction in sympathetic tone, concomitantly to a significant (P < 10(- 3) decrease in mean arterial pressure (MAP). Delta wave activity increased (P < 10(-4) 10-20 min later and was associated with a lag of 0-10 min with a significant rise in PRA (P < 10(-4) . Rapid eye movement sleep was characterized by a significant increase (P < 10(-4) in the LF/(LF + HF) ratio and a decrease (P < 10(-4) in delta wave activity and PRA, whereas MAP levels were highly variable. Overnight cross-correlation analysis revealed that MAP was inversely correlated with delta wave activity and with PRA (P < 0.01 in all subjects but one). These results suggest that pressure-dependent mechanisms elicit the nocturnal PRA oscillations rather than common central processes controlling both the generation of slow waves and the release of renin from the kidney.     

In oculo transplants of myometrium from postpartum guinea pigs fail to support sympathetic reinnervation

Sympathetic nerves to the enlarged fetus-containing region of the uterus undergo degenerative changes during late pregnancy and show slow regrowth after parturition. It is not known whether this unusual response of sympathetic nerves to smooth muscle hypertrophy is due to the sensitivity of short adrenergic neurons to hormonal changes, or whether the nerves respond to changes in the neurotrophic capacity of the target. We have investigated this question using in oculo transplantation. Small pieces of myometrium from the uterine horn of virgin guinea pigs, or from the region previously occupied by the placenta and fetus in postpartum guinea pigs, were transplanted into the anterior eye chamber. After 3 wk in oculo, the pattern of reinnervation of the transplants was assessed on whole mount stretch preparations stained for tyrosine hydroxylase. The histology of the transplants was examined in toluidine blue-stained semithin sections. Myometrial transplants from virgin donors and uterine artery transplants from both virgin and postpartum donors became organotypically reinnervated by sympathetic fibres from the host iris. In contrast, sympathetic nerves did not reinnervate myometrial transplants from postpartum donors, although they approached the transplants and became distributed in the surrounding connective tissue. All transplanted tissues showed a normal histological appearance. Both the myometrium and uterine artery from postpartum donors retained a hypertrophic appearance after 3 wk in oculo. We interpret these results to indicate that the degeneration of sympathetic nerves in late pregnancy, as well as their slow regrowth to the uterus after delivery, may be due to changes in uterine smooth muscle rather than a particular sensitivity of short adrenergic neurons to hormonal changes.     

Reflex responses evoked in the adrenal sympathetic nerve to electrical stimulation of somatic afferent nerves in the rat

The present study was initiated to determine the role of somatic A (myelinated) and C (unmyelinated) afferent fibers in both responses of increases and decreases in adrenal sympathetic nerve activities during repetitive mechanical pinching and brushing stimulations of the skin in anesthetized rats with central nervous system (CNS) intact. Accordingly, changes in adrenal sympathetic nerve activity resulting from repetitive and single shock electrical stimulation of various spinal afferent nerves, especially the 13th thoracic (Th13) spinal nerve and the sural nerve, were examined in urethane/chloralose-anesthetized rats. Repetitive electrical stimulation of A afferent fibers in Th13 spinal or sural nerve decreased the adrenal nerve activity similarly as brushing stimulation of skin of the lower chest or hindlimb did, while repetitive stimulation of A plus C afferent fibers of those nerves increased the adrenal nerve activity as pinching stimulation of those skins did. Single shock stimulation of spinal afferent nerves evoked various reflex components in the adrenal nerve: an initial depression of spontaneous activity (the early depression); the following reflex discharge due to activation of A afferent fibers (the A-reflex); a subsequent reflex discharge due to activation of C afferent fibers (the C-reflex); and following post-excitatory depressions. These reflexes seem to be mediated mainly via supraspinal pathways since they were abolished by spinal transection at the C1-2 level. Although the supraspinal A- and C-reflexes could be elicited from stimulation of a wide variety of spinal segmental afferent levels, the early depression was more prominent when afferents at spinal segments closer to the level of adrenal nerve outflow were excited. It is suggested that the decreased responses of the adrenal nerve during repetitive electrical stimulation of A afferent nerve fibers are attributable to summation of both the early depression and post-excitatory depression evoked by single shock stimulation, while the increased responses during repetitive stimulation of A plus C afferent fibers are attributable to summation of the C-reflex after single shock stimulation. In spinalized rats, repetitive stimulation of Th13 always increased the adrenal nerve activities regardless of whether A fibers alone or A plus C fibers were stimulated, just as brushing and pinching of the lower chest skin always increased them. The increased responses in spinal animals seem to be related to the fact that single electrical stimuli of Th13 produced A- and C-reflexes of spinal origin without clear depressions.     

Participation of interleukin-1 and tumor necrosis factor in the responses of the sympathetic nervous system during lipopolysaccharide-induced fever

The regional sympathetic responses during fevers induced by an exogenous pyrogen, lipopolysaccharide, and by two endogenous pyrogens, interleukin-1 (IL-1) and tumor necrosis factor (TNF-), were compared in urethane-anesthetized rabbits. Rectal temperature (T_re), ear skin temperature (T_ear) as an index for cutaneous sympathetic activity, renal sympathetic nerve activity (RSNA) representing visceral efferents, arterial blood pressure, and heart rate were recorded during fever caused by intravenous injections of each of the three pyrogens. Lipopolysaccharide (1 g/kg i.v.) caused prolonged fever of more than 3 h duration with a tendency towards a biphasic course of temperature, whereas fevers induced by IL-1 (1 g/kg i.v.) and TNF- (10 g/kg i.v.) were monophasic with a maximum between the 45th and 60th min. Each of the three pyrogens typically induced a decrease in T_ear, indicative of cutaneous sympathetic activation, and simultaneous inhibition of RSNA during the first phase of rising T_re. RSNA tended to increase again approximately to its control level when the maximum T_re had been attained after the injection of each pyrogen. When the second rising phase of lipopolysaccharide fever started, T_ear decreased once more, but RSNA remained at its control level. Taken together with the enhancement of IL-1 and TNF production during lipopolysaccharide-induced fever, the present results suggest the participation of these endogenous pyrogens in the responses of the sympathetic nervous system during the early phase of the lipopolysaccharide induced fever.     

Effects on blood pressure and autonomic nervous system function of a 12-week exercise or exercise plus DASH-diet intervention in individuals with elevated blood pressure

Aim: Hypertension is related to abnormalities in autonomic nervous system (ANS) function, with increased sympathetic output and decreased parasympathetic tone. Lifestyle interventions are the first line of treatment in hypertension, and decreased blood pressure (BP) effects may be related to changes in ANS function. Using heart rate recovery (HRR) from exercise as an index of parasympathetic tone and plasma noradrenaline as an index of sympathetic tone, we investigated the effects of lifestyle interventions on ANS function in patients with elevated BP. Methods: Sedentary participants with elevated BP were randomly assigned to either an exercise only (N = 25), exercise plus dietary approaches to stop hypertension (DASH) diet (N = 12), or waitlist control (N = 15) 12‐week intervention. Plasma noradrenaline was measured at rest and participants performed a peak exercise test before and after the intervention. HRR was calculated as peak heart rate (HR) minus HR at 1 min post‐exercise. Results: Heart rate recovery showed a significant group by time interaction; both intervention groups showed increases in HRR from pre‐ to post‐intervention, while waitlist showed no change. Similarly, both exercise plus diet and exercise groups, but not waitlist, showed significant reductions in BP from pre‐ to post‐intervention. Linear regression revealed that BP post‐intervention was significantly predicted by change in HRR when controlling for pre‐BP, age, gender and BMI. Conclusions: Lifestyle interventions induced training‐reduced BP and altered autonomic tone, indexed by HRR. This study indicates the importance of behavioural modification in hypertension and that increased parasympathetic function is associated with success in reduction of BP.     

Efferent renal sympathetic nerve stimulation in vivo. Effects on regional renal haemodynamics in the Wistar rat,studied by laser-Doppler technique

Intrarenal blood flow regulation probably affects long-term blood pressure homeostasis. We have previously shown that 5 Hz renal sympathetic stimulation inhibits a humoral renal depressor mechanism, otherwise activated when increasing perfusion pressure to an isolated kidney in a cross-circulation set-up. This inhibition was suggested to occur as a result of a reduction of renomedullary blood flow. Little is known about nervous blood flow regulation within the medulla. Therefore in this study, total renal (RBF), cortical (CBF) and papillary (PBF) blood flows were separately measured by ultrasonic and laser-Doppler techniques in Wistar rats during graded renal sympathetic stimulations. Periods of 15 min stimulation at 0.5, 2 and 5 Hz were performed in random order. RBF decreased at 0.5 Hz by 1%, at 2 Hz by 16% (P < 0.001) and at 5 Hz by 49% (P < 0.001). In a similar fashion (r = 0.73, P < 0.001), CBF decreased by 1%, 10% (P < 0.001) and 37% (P < 0.001), respectively. By contrast, PBF increased by 2% at 0.5 Hz and 4% at 2 Hz, while it decreased at 5 Hz, by 4% (P < 0.05, compared with 2 Hz). It seems therefore, that superficial renocortical and total renal blood flows are closely regulated by renal sympathetic nerves with increasing vasoconstriction at higher frequencies, while medullary blood flow, on the other hand, seems to be under strong local control, tending to offset neurogenic flow restrictions.     

Studies on the innervation of human renal allografts

Kidneys are innervated by a plexus of nerves around the renal artery, which is disrupted by transplantation. This is a report of a comparison of the nerves in human renal allografts and normal kidneys. There were many sympathetic ganglia around normal renal arteries but none around transplanted vessels, although equal numbers of ganglia were present in hilar tissues of normal and transplanted kidneys. An immunohistological study with an antibody to synaptophysin showed that the number of synapses in transplanted ganglia was severely reduced. Immunohistological studies on allograft kidneys using antibodies to various neurofilament proteins and the Schwann cell marker S100 showed a marked reduction in neurofilament proteins shortly after transplantation with subsequent partial recovery, and a lesser reduction in S100. Renal allografts have structurally abnormal innervation but are not completely denervated. © 1998 John Wiley & Sons, Ltd.     

Effect of tissue phospholipid composition on synergistic interactions between sympathetic and parasympathetic systems

The content of phospholipids in various tissues was studied during synergistic interaction between two branches of the autonomic nervous system. We found higher myocardial content of choline-containing phospholipids and lower rigidity of erythrocyte membranes in rabbits with pronounced sympathetic potentiation of the cardioinhibitory effect of the vagus nerve compared to rabbits without such potentiation.     

Ageing reduces sympatho-suppressive response to head-out water immersion in humans

Muscle sympathetic nerve activity (MSNA) is suppressed during thermoneutral head-out water immersion (HOI) in humans. In this study, the effects of ageing on the suppressive response of MSNA to HOI were determined. MSNA was recorded microneurographically from the tibial nerve in 16 healthy men, 10 of whom were aged 19–30 years (young group) and six aged 45–67 years (older group). MSNA was suppressed in all the subjects during HOI. The suppressive response was significantly less prominent in the older group than in the young group. A significant negative correlation between age and the suppressive response of MSNA induced by HOI (r=-0.53, P<0.05) was found. We conclude that suppressive response of sympathetic nerve activity to HOI is reduced with age.     

Parasympathetic and sympathetic nervous systems interactively predict change in cognitive functioning in midlife adults

The two branches of the autonomic nervous system (ANS) have been individually linked to changes in cognitive functioning: The parasympathetic nervous system (PNS) has been associated with healthy cognitive aging, whereas excessive sympathetic nervous system (SNS) activity has been linked to heightened cognitive decline. Despite these separate findings and despite the integrative nature of the ANS, little work has examined the two branches simultaneously to better understand their interactive effects on changes in cognitive functioning in midlife adults. We examined cognitive change in two waves of the Midlife in the United States (MIDUS) study cognitive project and indexed PNS and SNS activity from heart rate variability and epinephrine levels, respectively, from the MIDUS biomarker project (minimum n = 843, 57.9% female, mean age at first wave = 53.8 years). Our findings indicate that greater PNS responsivity (i.e., greater withdrawal and greater recovery) in response to cognitive challenge is associated with attenuated cognitive decline, but only among individuals with low SNS levels; at higher SNS levels, the effects of the PNS on cognitive decline are attenuated. These results suggest that future research targeting the ANS and cognitive aging should consider both ANS branch's effects simultaneously.     

Effects of cortical stimulation on reciprocal inhibition in humans

We attempted to demonstrate convergence onto human spinal Ia inhibitory interneurons from Ia afferents and from fast conducting corticospinal axons. Stimulation of the common peroneal nerve at or below the threshold of the alpha motoneuron axons resulted in inhibition of the soleus H-reflex, attributed to reciprocal inhibition. Magnetic stimulation over the contralateral motor cortex resulted in complex modulations of the soleus H-reflex, including a short latency-inhibition. To test for convergence, the two stimuli were given together so that the two inhibitions coincided.When each stimulus alone produced clear inhibition, the inhibition produced by both stimuli was less than expected, implying an interaction between the two volleys, for example, occlusion occurring in interneurons or motoneurons.When the H-reflex was relatively unaffected by one or other conditioning volley, the inhibition produced by the combined stimulation was greater than expected, as might be expected with convergence onto a common pool of interneurons.     

Expression of tyrosine hydroxylase and neuropeptide tyrosine in mouse sympathetic airway-specific neurons under normal situation and allergic airway inflammation

BACKGROUND: The traditional neurotransmitter catecholamine and the neuropeptide tyrosine in sympathetic airway nerves have been proposed to be involved in the pathogenesis of airway diseases. OBJECTIVE: The aim of the present study was to investigate the effect of allergic airway inflammation on the expression of catecholamine enzyme tyrosine hydroxylase (TH), neuropeptide tyrosine (NPY) and tachykinins in mouse sympathetic airway ganglia. METHODS: Using neuronal tracing in combination with immunohistochemistry, the present study was designed to characterize TH, NPY and tachykinin profiles of superior cervical (SCG) and stellate ganglia after allergen challenge. RESULTS: The vast majority of fast blue-labelled SCG neurons (allergen: 97.5+/-1.22% (mean+/-SEM) vs. controls: 94.5+/-1.48%, P=0.18) and stellate neurons (allergen: 95.3+/-1.01% vs. controls: 93.6+/-1.33%, P=0.34) were immunoreactive for TH. Of the TH immunoreactive and fast blue-labelled SCG neurons, 52.0+/-1.01% allergen vs. 51.2+/-3.58% controls (P=0.83) and stellate neurons, 57.3%+/-0.97 allergen vs. 56.4+/-1.65% controls (P=0.64) were positive for TH only but not NPY, whereas 45.3+/-1.05% allergen vs. 43.3+/-1.18% controls (P=0.47) of fast blue-labelled SCG neurons and 37.9+/-0.86% allergen vs. 37.1+/-1.24% controls (P=0.62) of fast blue-labelled stellate neurons were immunoreactive for both TH and NPY immunoreactivities. There was a trend of an increase, but not significant one, in the percentage of TH-/NPY-immunoreactive and fast blue-labelled neurons in allergen-treated animals in comparison with the controls. Tachykinins, however, were not expressed by sympathetic neurons and were also not induced in sympathetic neurons after allergen challenge. CONCLUSION: The present study indicates that allergic airway inflammation does not alter the expression of noradrenalin and NPY in sympathetic ganglia and also shows that sympathetic neurons do not respond to allergic airway inflammation with tachykinins induction. However, a participation of catecholamine and NPY in the pathogenesis of allergic airway inflammation cannot be excluded in the present study as a higher neurotransmitter output per neuron following allergen challenge could be possible.     

Prostaglandins and nitric oxide in regional kidney blood flow responses to renal nerve stimulation

We examined the roles of cyclooxygenase products and of interactions between the cyclooxygenase and nitric oxide systems in the mechanisms underlying the relative insensitivity of medullary perfusion to renal nerve stimulation (RNS) in anaesthetized rabbits. To this end we examined the effects of ibuprofen and N^G-nitro-l-arginine (L-NNA), both alone and in combination, on the responses of regional kidney perfusion to RNS. Under control conditions, RNS produced frequency-dependent reductions in total renal blood flow (RBF; –82±3% at 6 Hz), cortical laser-Doppler flux (CLDF; –84±4% at 6 Hz) and, to a lesser extent, medullary laser-Doppler flux (MLDF; –46±7% at 6 Hz). Ibuprofen did not affect these responses significantly, suggesting that cyclooxygenase products have little net role in modulating renal vascular responses to RNS. L-NNA enhanced RBF (P=0.002), CLDF (P=0.03) and MLDF (P=0.03) responses to RNS. As we have shown previously, this effect of L-NNA was particularly prominent for MLDF at RNS frequencies 1.5 Hz. Subsequent administration of ibuprofen, in L-NNA-pretreated rabbits, did not affect responses to RNS significantly. We conclude that counter-regulatory actions of NO, but not of prostaglandins, partly underlie the relative insensitivity of medullary perfusion to renal nerve activation.