The effect of indomethacin on the circulatory and plasma noradrenaline responses to cold pressor testing in normal subjects

Prostaglandins may alter neuronal noradrenaline release or vascular responsiveness to sympathoexcitation. The purpose of this study was to determine if indomethacin, a prostaglandin synthesis inhibitor, influences the sympathetic and circulatory adjustments to a commonly utilized laboratory stressor in the clinical assessment of autonomic function, the cold pressor test. Venous plasma noradrenaline levels (n = 8), mean arterial pressure and heart rate (n = 10) were measured in healthy male subjects during immersion of the non-dominant hand in cold water (1°C) for 90 s. The subjects were given either placebo or indomethacin (100 mg) in a double-blind manner. The order of administration was counterbalanced and a 1 week period was given for systemic clearance of the drug. The absolute level of mean arterial pressure was elevated during the resting control period after indomethacin treatment (88 in placebo vs. 92 mmHg in indomethacin). Both heart rate and venous plasma noradrenaline levels were similar between trials during the resting control period. Mean arterial pressure and heart rate increased similarly during cold pressor testing in both indomethacin and placebo. Venous plasma noradrenaline levels increased during cold pressor testing 162 ± 39 vs. 200 ± 69 pg/ml in indomethacin vs. placebo (p > 0.05), respectively. In addition, perceived pain (peak level = 7 ± 1 vs. 6 ± 1 units; indomethacin vs. placebo, respectively) was not different between the trials. These results suggest that administration of indomethacin in a maximal single therapeutic dose, does not affect the sympathetic nervous system or circulatory responsiveness to cold pressor testing. It may not be necessary to discontinue indomethacin prior to autonomic function testing.     

Autonomic cardiovascular control and responses to experimental pain stimulation in fibromyalgia syndrome

Objective

This study involves a comprehensive investigation of autonomic cardiovascular regulation in fibromyalgia syndrome (FMS) at rest and during painful stimulation and its association with pain indices.

Methods

In 35 patients and 29 healthy controls, electrocardiography, impedance cardiography, and finger continuous blood pressure measurements were conducted. For the purpose of experimental pain induction, a cold pressor test was applied.

Results

FMS patients showed lower pain threshold and tolerance, as well as higher ratings of pain intensity and unpleasantness on visual analogue scales. Resting stroke volume, myocardial contractility, R-R interval, heart rate variability, and sensitivity of the cardiac baroreflex were reduced in the patients, and increases in stroke volume and myocardial contractility during cold pressor stimulation were less pronounced. In the whole sample as well as in the FMS group, baroreflex sensitivity was inversely associated with subjective pain intensity, and a higher number of baroreflex operations per unit of time predicted higher pain tolerance.

Conclusions

The data suggest impaired autonomic cardiovascular regulation in FMS in terms of reduced sympathetic and parasympathetic influences, as well as blunted sympathetic reactivity to acute stress. The association between baroreflex function and pain experience reflects the pain inhibition mediated by the baroreceptor system. Given the reduced baroreflex sensitivity in FMS, one may assume deficient ascending pain inhibition arising from the cardiovascular system, which may contribute to the exaggerated pain sensitivity of FMS.     

Effect of water immersion on renal sympathetic nerve activity and arterial baroreflex in conscious rabbits with heart failure

Several studies have indicated an interaction between cardiopulmonary mechanoreflex and arterial baroreflex. However, the contribution of cardiopulmonary mechanoreflex to an abnormal arterial baroreflex in chronic heart failure (CHF) has not been fully investigated. We examined the effect of the activation of cardiopulmonary mechanoreceptors induced by head-out water immersion (WI) on the arterial baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) in conscious rabbits with CHF induced by myocardial infarction. The arterial baroreflex sensitivity (BRS) of both HR and RSNA were decreased in CHF. WI induced a small decrease in RSNA in CHF compared to a sham-operated group (Sham), despite a similar increase in central venous pressure. WI did not affect BRS of HR or RSNA in either Sham or CHF. By averaging rectified RSNA recordings, we found that miniature RSNA in the control in CHF was higher than that in Sham. WI decreased the synchronized RSNA without changing miniature RSNA in either group. These results suggest that cardiopulmonary mechanoreflex control of RSNA is reduced in CHF, and that cardiopulmonary mechanoreflex has little effect on arterial baroreflex. An increase in miniature RSNA may reflect sympatho-excitation in CHF.     

Influence of cardiopulmonary reflex on the sympathetic activity during myocardial infarction

The time-course of changes in renal sympathetic nerve activity (RSNA), arterial and cardiopulmonary baroreflexes sensitivities was evaluated in conscious rats eight hours (8 h) and ten days (10 day) after myocardial infarction (MI), induced by coronary artery ligation. RSNA was recorded by a platinum electrode implanted in left renal nerve. Arterial and cardiopulmonary baroreflexes sensitivities were evaluated by changes in blood pressure and serotonin administration, respectively. Both 8 h and 10 day groups presented hypotension (103+/-4 vs. 102+/-2 vs. 115+/-4 mm Hg), but only 8 h showed tachycardia (422+/-22 vs. 378+/-11 vs. 384+/-9 bpm) when compared to Control rats. RSNA was depressed 8 h after MI and increased in 10 day group (12+/-2 vs. 39+/-8 vs. 22+/-2 mV/cycle). Although arterial baroreflex control of heart rate was similar in all groups, the arterial baroreflex control of RSNA in 8 h group was impaired during reductions (-0.35+/-0.10 vs. -1.66+/-0.23 vs. -0.09+/-0.14 mV/cycle/mm Hg) or increases (-0.77+/-0.17 vs. -1.63+/-0.58 vs. -1.66+/-0.17 mV/cycle/mm Hg) in blood pressure when compared to Control animals. Moreover, cardiopulmonary baroreflex bradycardic response was increased in 8 h rats and normalized in 10 day group. The results suggest that the increased cardiopulmonary baroreflex sensitivity in 8 h may contribute to the reduction in the tonic level of RSNA as well as in the impairment of the baroreflex control of RSNA in the presence of hypotension.     

The long-term reproducibility of clinical tests of autonomic cardiovascular function in normal man

Tests for the integrity of autonomic cardiovascular reflexes have been widely used in the clinic and in space physiology for decades. However, whereas some information on the short-term reproducibility of such tests are available, little is known about their long-term reproducibility. The work in this study was, therefore, directed towards assessing intra- and inter-subject variations in responses (heart rate, mean arterial blood pressure, forearm blood flow and forearm vascular conductance) to cortical arousal, cold face stimulation and lower body negative pressure (at 10, 30 and 50 mmHg) in eleven healthy male subjects (aged between 22 and 45 years). Subjects were studied repeatedly (each month) over a 6-month period. It was found that forearm vascular conductance responses to cold face stimulation were the most reproducible (mean coefficient of variation 10.9%), and with diminishing reproducibility curve responses to lower body negative pressure at 50 mmHg (mean coefficient of variation 12.4%), lower body negative pressure at 30 mmHg (mean coefficient of variation 18.9%), lower body negative pressure at 10 mmHg (mean coefficient of variation 28.0%), and responses to cortical arousal (mean coefficient of variation 39.6%). Generally, subjects who showed the largest responses to cold face stimulation also showed the largest responses to the other tests, and vice versa. It is concluded that there is intra-individual variability in the responsiveness and reproducibility of cardiovascular tests and that the cardiovascular responses to cold face stimulation and lower body negative pressure at 50 mmHg are the most reproducible.     

Influence of substantia innominata neuronal activity on neocortex neuronal reactions during conditioned reflex

Impulse activity of substantia innominata (SI) and motor cortex neurons was studied in cats during conditioned placing with food reinforcement. It was shown that SI neurons have been activated first directly by sound stimuli and later by food reward. Stimulation of SI did not change the background activity of neocortex neurons but promoted the modulation of impulse response to conditioned stimuli. The modulating effect of the SI has a mainly excitatory character, that manifested itself either in a change and increase of the impulse responses of cortical neurons which responded initially to sound stimuli, or in the appearance of impulse responses in those neurons which showed no initial reaction to conditioned sound stimuli.     

Clinical significance of the resting heart rate in the assessment of autonomic function by cardiovascular reflex tests

The effect of the resting heart rate on heart rate responses in standard cardiovascular autonomic function tests was studied in a sample of 845 subjects. The responses, which were calculated using instantaneous heart rate changes and R—R interval ratios, were divided into quantiles according to their absolute values. The effect of resting heart rate on each cardiovascular index was studied by linear regression analysis, first in the whole group and then in the group with responses belonging to the lowest quantile. As regards the whole group, eight out of ten indices diminished significantly with increasing resting heart rate. However, no response-attenuating effect of increasing resting heart rate could be found among the responses in the lowest quantile. Since particularly low heart rate responses in cardiovascular reflex testing are of clinical importance when autonomic neuropathy is diagnosed, it can be concluded that the usefulness of standard cardiovascular reflex test based on heart rate changes is not limited by the level of the resting heart rate.     

Simultaneous measurement of parasympathetic reflex vasodilator and arterial blood pressure responses in the cat

We measured the changes in lower lip blood flow and systemic arterial blood pressure evoked by lingual nerve or trigeminal spinal nucleus (Vsp) stimulation to gain an insight into the brainstem integration of sympathetic and parasympathetic responses to nociceptive stimulation. We used artificially ventilated, cervically vago-sympathectomized cats deeply anesthetized with alpha-chloralose and urethane. A lip blood flow increase occurred in an intensity- and frequency-dependent manner following electrical stimulation of Vsp or lingual nerve regardless of whether systemic arterial blood pressure increased or decreased. In contrast, there was no apparent optimal frequency for the changes in systemic arterial blood pressure elicited by electrical stimulation of Vsp or lingual nerve. No relationship was found between the amplitude of the lip blood flow increase and that of the systemic arterial blood pressure change. Microinjection of lidocaine or kainic acid into the Vsp evoked, respectively, reversible and irreversible inhibition of the lip blood flow increase and systemic arterial blood pressure change evoked by lingual nerve stimulation. When microinjected unilaterally directly into the ipsilateral Vsp, the GABA agonist muscimol abolished both lingual nerve-evoked effects (increase in lip blood flow and changes in systemic arterial blood pressure) without changing basal systemic arterial blood pressure, suggesting the presence in the Vsp of GABA receptors serving to modulate both the parasympathetically mediated lip blood flow increase and the sympathetically mediated systemic arterial blood pressure change. Lidocaine microinjection into the salivatory nucleus caused a significant attenuation of the lingual nerve-induced blood flow increase, but had no effect on the lingual nerve-induced systemic arterial blood pressure change. Thus, the neural pathway mediating the lingual nerve-induced lip blood flow increase seems to be simple, requiring a minimum of four neurons: trigeminal afferent-Vsp-parasympathetic pre-ganglionic neurons with cell body located in the inferior salivatory nucleus-otic postganglionic neuron. On the other hand, the pathway underlying the evoked systemic arterial blood pressure changes, presumably mediated via altered sympathetic activity, seems to be more complicated and could be affected by more numerous factors.     

Effects of the cold pressor test on short-term fluctuations of finger arterial blood pressure and heart rate in normal subjects

The effect of the cold pressor test on autonomic cardiovascular control was studied non-invasively by means of spectrum analysis of periodic heart rate and blood pressure fluctuations in ten normal subjects. Fast Fourier Transform algorithm based on a 256-point time series (sampling rate 2 Hz, i.e. 2-min and 8-s) was used to estimate the amplitude spectra of heart rate and blood pressure rhythmicity at the low frequency (70–140 mHz) and respiration related frequency (230–270 mHz) band. Respiration rate was controlled at 250 mHz. Auto- and cross-spectral techniques were used to determine the complex relationship between systolic blood pressure and heart rate fluctuations in the frequency domain. The spectral pattern of systolic and diastolic blood pressure showed a marked increment of the absolute and relative (100 multiplied with absolute value/total area under the curve of the amplitude spectrum from 15–500 mHz) low frequency component: control vs. cold pressor test—systolic blood pressure—absolute values (in [mmHg/Hz^1/2]): 634.4 ± 48.9 vs. 827.4 ± 69.9* relative values (in [%]): 26 ± 2 vs. 32 ± 2*; diastolic blood pressure —absolute values: 433.2 ± 42.3 vs. 537.2 ± 45.8* relative values: 35 ± 3 vs. 40 ± 2*, (average ± SEM, *P < 0.05). The cold pressor test induced no change in average heart rate; the absolute low frequency component in heart rate spectra increased clearly during the test: low frequency component (in [bpm/Hz^1/2]): 586.9 ± 89.9 vs. 712.0 ± 91.4*, while the relative low frequency component did not change: 29 ± 3 vs. 30 ± 3. There was no alteration in the respiration related frequency component in all time series and in the transfer gain and phase functions during cold pressor test. We conclude that the cold pressor test increases low frequency systolic blood pressure fluctuations which reflects an increase in sympathetic vasomotor control. Furthermore the cold pressor test does not induce change in the transfer gain and phase characteristics of modulation of heart rate by systolic blood pressure.     

Subtle involvement of the sympathetic nervous system in amyotrophic lateral sclerosis

The literature on the involvement of the autonomic nervous system (ANS) in amyotrophic lateral sclerosis (ALS) is conflicting. We therefore investigated several aspects of autonomic function, namely muscle sympathetic nerve activity (MSNA), blood pressure, cardiac function (electrocardiogram; ECG), and respiration in 16 patients with sporadic ALS and in 12 age-matched healthy volunteers, both at rest and during sympathoexcitatory stimulation. We measured MSNA by provoking venous pooling during short-lasting lower body negative pressure (LBNP) and during the cold pressor test (CPT). To assess the vagal (baroreflex) control of heart rate (HR), we measured spontaneous baroreflex sensitivity (BRS). To assess the involvement of the ANS beyond the cardiovascular system, we measured the sympathetic skin response (SSR). The stand-up test showed that none of the subjects had orthostatic intolerance. In comparison with the control group, the ALS patients had an increased HR and a decreased BRS at rest, and a reduced MSNA response to LBNP. The CPT response was normal and the total MSNA at rest did not differ significantly from that of controls. The latencies of the palmar and plantar SSR were prolonged, and in 3 ALS patients there was no plantar SSR. The results indicate that the sympathetic nervous system shows subtle abnormalities in ALS, predominantly sympathetic overactivity. They also point to the involvement of the preganglionic sympathetic column as the cause of the higher sympathetic activity and the absence of SSR. The higher sympathetic activity is postulated to be due to changes in modulation of the sympathetic system, whereas the absence of the SSR is probably caused by disruption of the reflex pathway.     

Differential regulation of tyrosine hydroxylase protein and activity in rabbit sympathetic neurones after long-term cold exposure: altered responses in ageing

The aim of this study was to investigate the response of sympathetic neurones to prolonged neural stimulation, using cold exposure as a non-invasive experimental paradigm. We examined the effects of prolonged (8 days and 4 wk) cold exposure on tyrosine hydroxylase (TH) protein and activity and neuropeptide Y (NPY) levels in sympathetic neurones of the superior cervical ganglion (SCG), together with NPY levels in the ear artery from young and aged rabbits. The main findings were as follows. In young rabbits, TH levels and TH activity were differentially regulated in response to prolonged cold exposure. TH levels rose whilst TH activity tended to decline. Decentralization of SCG from young animals before cold exposure abolished the rise in TH levels. TH activity in SCG from young rabbits was reduced by decentralization whilst cold exposure resulted in an increase in TH activity. Thus, TH activity was induced in the SCG in the absence of pre-ganglionic input, demonstrating a non-synaptic regulatory mechanism. In old rabbits, cold-induced changes were either delayed or failed to occur, indicating that the responses of sympathetic neurones to cold stress are impaired in old age.     

Well-maintained reflex responses of sympathetic nerve activity to stimulation of baroreceptor, chemoreceptor and cutaneous mechanoreceptors in neonatal capsaicin-treated rats

Neonatal treatment with capsaicin (CAP) reduced the content of substance P-like immunoreactivity in the area of the nucleus tractus solitarii and the dorsal horn of the spinal cord in rats. The resting values of the mean arterial blood pressure and heart rate of CAP-treated rats were not significantly different from those of control rats. Reflex responses of the renal sympathetic nerve activity to stimulation of baroreceptor, chemoreceptor and cutaneous mechanoreceptor were compared in CAP- and vehicle-treated rats. Under these conditions the reflex responses were quite well maintained in CAP-treated rats.     

Effects of taste stimulation on the efferent activity of the autonomic nerves in the rat

Effects of taste stimulation on the efferent discharges in the pancreatic and hepatic branch of the vagus nerve, and those in the adrenal, pancreatic and hepatic branch of the splanchnic nerve, and the sympathetic nerve innervating interscapular brown adipose tissue, were observed in the anesthetized rat. Sweet taste stimulation with 5% glucose or 10% sucrose caused an increase in activity of pancreatic and hepatic branch of the vagus nerve and brown adipose tissue nerve, and a decrease in discharge rate of the adrenal, pancreatic and hepatic branch of the splanchnic nerve. Salty taste stimulation with 5% NaCl resulted in opposite effects in these nerves. Results suggest preabsorptive reflex control of visceral functions due to taste stimulation.     

Influence of posture on cardiorespiratory reflexes in normal subjects and patients with diabetes mellitus

This study was designed to assess the effect of patient posture, either sitting or supine, on the results and diagnostic yield of tests of cardiorespiratory reflexes on 25 normal subject controls and 128 patients with diabetes mellitus. The heart rate changes during slow breathing at 6 per minute (R6) and during a Valsalva manoeuvre (highest heart rate during manoeuvre divided by lowest heart rate within 30 s after manoeuvre; Valsalva ratio) were measured from the electrocardiographic signal and tachometry. In control subjects, heart rate changes during slow breathing averaged 25.0 when sitting and 21.3 when supine (p < 0.01); Valsalva ratio averaged 1.90 and 1.83 (p > 0.2) respectively. In diabetic patients, mean values for heart rate changes during slow breathing were 6.1 and 5.1, and mean values for Valsalva ratio were 1.23 and 1.28 in sitting and supine postures respectively. According to our normal limits, heart rate changes during slow breathing was below normal in 109 patients tested when sitting and in 113 tested when supine, and Valsalva ratio was abnormal in 103 and 95 respectively. These results indicate that subject posture is an important variable of cardiorespiratory reflex testing, and should be standardized to allow comparisons of individual results.     

Influence of ghrelin on the gastric accommodation reflex and on meal-induced satiety in man

Abstract  Ghrelin increases gastric tone in the fasting state and enhances gastric emptying in gastroparesis. The aims of the study were to evaluate the effect of ghrelin on postprandial gastric tone and on meal-induced satiety in health. Ten healthy volunteers underwent a barostat study on two occasions. After determination of intra-abdominal pressure (minimal distending pressure, MDP), isobaric volume measurement was performed for 90 min at MDP + 2 mmHg. After 20 min, ghrelin (40 μg) or saline was administered i.v. over 30 min in a double-blind-randomized cross-over design, followed 10 min later by a liquid meal (200 mL, 300 kcal). Stepwise isobaric distentions (+2 mmHg per 2 min) were performed 60 min after the meal. Data (mean ± SEM) were compared using paired Student's t -test and anova . Separately, a satiety drinking test (15 mL min⁻¹ until satiety score 5) was performed on 10 subjects twice, after treatment with placebo or ghrelin. Ghrelin infusion significantly inhibited gastric accommodation (mean volume increase adjusted means 108.0 ± 50 vs 23.0 ± 49 mL, P  = 0.03, ancova with the premeal postinfusion volume as covariate) and reduced postprandial gastric volumes (197.2 ± 24.6 vs 353.5 ± 50.0 mL, P  = 0.01). Pressures inducing perception or discomfort during postprandial gastric distentions were not altered. During satiety testing, ghrelin did not alter nutrient volume ingested till maximal satiety (637.5 ± 70.9 vs 637.5 ± 56.2 mL, ns). Ghrelin administered during the meal significantly inhibits gastric accommodation in health, but this is not associated with early satiation.     

Influence of the predicted time of stimuli eliciting movements on responses of tonically active neurons in the monkey striatum

Changes in activity of tonically active neurons of the primate striatum are determined both by the behavioural significance of stimuli and the context in which stimuli are presented. We investigated how the responses of these neurons are modified by the temporal predictability of stimuli eliciting learned behavioural reactions. Single neurons were recorded from the caudate nucleus and putamen of two macaque monkeys performing a visual reaction time task under conditions in which the timing of the trigger stimulus was made more or less predictable. The monkeys' ability to predict the trigger onset was assessed by measuring arm movement reaction times and saccadic ocular reactions. Of 171 neurons responding to the unsignalled presentation of the trigger stimulus, 32% lost their response when an instruction cue preceded the trigger by a highly practised 1.5 s interval, and the response reappeared when this interval was varied randomly from 1 to 2.5 s or prolonged to 3 or 4. 5 s. Although 43% of the neurons remained responsive irrespective of task condition, the responses were stronger with longer intervals than with the accustomed 1.5 s interval. In addition, a number of neurons responding to the instruction lost their response when the trigger appeared more distant from the instruction. These findings demonstrate that neuronal responses to a movement-triggering signal become more numerous and pronounced when the degree of temporal predictability of that signal was decreased. We conclude that tonic striatal neurons are sensitive to temporal aspects of stimulus prediction.     

Real‐time imaging of the medullary circuitry involved in the generation of spontaneous muscle sympathetic nerve activity in awake subjects

To understand the central neural processes involved in blood pressure regulation we recorded muscle sympathetic nerve activity (MSNA) via a tungsten microelectrode in the common peroneal nerve while performing functional magnetic resonance imaging (fMRI) of the brainstem at 3T. Blood oxygen level dependent (BOLD) changes in signal intensity were measured over 4 s every 8 s (200) volumes; MSNA was recorded during the previous 4 s epoch, which takes into account peripheral conduction delays along unmyelinated axons and neurovascular coupling delays. Analysis of temporal coupling between BOLD signal intensity and nerve signal intensity revealed sites in which the two signals covaried, but only in the medulla. Because scans were conducted in a caudorostral direction, we could constrain the analysis to the medulla by only examining the first 1 s of the fMRI and nerve signals. Increases in MSNA were associated with robust bilateral increases in signal intensity in the dorsolateral region of the medulla that corresponds to the human equivalent of the rostal ventrolateral medulla (RVLM). Reciprocal decreases in signal intensity occurred in the regions of the nucleus tractus solitarius (NTS) and caudal ventrolateral medulla (CVLM). Group analysis also revealed increases in signal intensity in the caudal pressor area (CPA), medullary raphé (MR), and dorsal motor nucleus of the vagus (DMX). We have shown for the first time that this combined approach of recording sympathetic neural activity and fMRI provides real‐time imaging of the neural processes responsible for the generation of sympathetic nerve activity in awake human subjects. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.