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.

Integrative mechanisms of blood pressure regulation in humans and rats: cross-species similarities.

As our understanding of the importance of individualized medicine continues to grow, the clinical relevance of interindividual variability in hemodynamic variables is receiving increasing attention. However, it is not known whether the rat, which is often used for studies of cardiovascular regulation, exhibits similar interindividual variability. In the present study, we evaluated whether the magnitude of interindividual variability in cardiac output (CO) and total peripheral resistance (TPR) was similar in humans and in rats. We assessed interindividual variability of mean arterial pressure (MAP), CO, and TPR during control conditions in normotensive humans (n = 40) and during normotension and deoxycorticosterone acetate-salt hypertension in Sprague-Dawley rats (n = 16). Humans and rats showed marked interindividual variability in CO and TPR but low variability in MAP. During deoxycorticosterone acetate-salt hypertension, CO was maintained, but TPR was elevated compared with the baseline period. We conclude that the magnitudes of interindividual variability of MAP, CO, and TPR are quantitatively similar in humans and rats, providing support for the relevance of this variability in both species and suggesting that studies in rats could be designed to address questions specific to individualized medicine in hypertension.

Unmyelinated tactile afferents signal touch and project to insular cortex.

There is dual tactile innervation of the human hairy skin: in addition to fast-conducting myelinated afferent fibers, there is a system of slow-conducting unmyelinated (C) afferents that respond to light touch. In a unique patient lacking large myelinated afferents, we found that activation of C tactile (CT) afferents produced a faint sensation of pleasant touch. Functional magnetic resonance imaging (fMRI) analysis during CT stimulation showed activation of the insular region, but not of somatosensory areas S1 and S2. These findings identify CT as a system for limbic touch that may underlie emotional, hormonal and affiliative responses to caress-like, skin-to-skin contact between individuals.

Firing properties of single muscle vasoconstrictor neurons in the sympathoexcitation associated with congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) in humans is associated with a marked sympathoexcitation, including an augmented muscle sympathetic nerve activity (MSNA) in intraneural multiunit recordings. In the present study, single-unit recording was used to evaluate whether the firing properties of individual muscle vasoconstrictor neurons can reveal underlying mechanisms for this increase in MSNA. METHODS AND RESULTS: Eight patients with CHF (NYHA class II to IV; left ventricular ejection fraction, 29+/-5%, mean+/-SEM) were studied. In standard multiunit recordings, MSNA burst incidence (bursts/100 heartbeats) ranged from 65% to 100% (88+/-5%). Using selective tungsten microelectrodes, we made recordings from 16 single muscle vasoconstrictor axons. Mean unit firing probability (ie, the percentage of cardiac intervals in which a single axon fired) was 54.5+/-5.2% (range, 21 to 89%), and mean firing frequency was 0.98+/-0.22 Hz (0.14 to 3.86 Hz), both of which were higher than seen previously in healthy subjects (P<0.001). Although single neurons occasionally generated multiple spikes per sympathetic burst, such multiple firing was rare and was not different from that seen in healthy subjects. CONCLUSIONS: An increased firing frequency of individual vasoconstrictor neurons is one mechanism for the increased number of multiunit MSNA bursts at rest in CHF. The neurons discharge in more diastoles than in healthy subjects (ie, firing probability is increased), but the likelihood of discharging >1 impulse per sympathetic burst is not increased. Despite the intense multiunit activity at rest, the firing characteristics of individual vasoconstrictor axons indicate a remaining capacity for transient increases of MSNA in CHF.

Water permeability in resting and stimulated crayfish nerve.

The hydraulic conductivity, L(p), was determined in single axons of the crayfish, Procambarus clarkii, by injecting a hypertonic sample between two drops of silicone oil and photographing the volume increase of the sample. The method has the advantage of minimizing errors due to hydrostatic pressure differences across the membrane. In resting axons an L(p) of 0.236 x 10(-8) cm/ sec per cm H(2)O was found and similar values were obtained with low external calcium concentration and when the nerve was continuously stimulated at 20-30 impulses/sec. Thus the experiments have failed to demonstrate any change of water permeability in cases in which the ionic conductance is known to change. Some possible implications of this are discussed.

Relative ion permeabilities in the crayfish giant axon determined from rapid external ion changes.

The changes in membrane potential of isolated, single crayfish giant axons following rapid shifts in external ion concentrations have been studied. At normal resting potential the immediate change in membrane potential after a variation in external potassium concentration is quite marked compared to the effect of an equivalent chloride change. If the membrane is depolarized by a maintained potassium elevation, the immediate potential change due to a chloride variation becomes comparable to that of an equivalent potassium change. There is no appreciable effect on membrane potential when external sodium is varied, at normal or at a depolarized membrane potential. Starting from the constant field equation, expressions for the permeability ratios P(Cl)/P(K), P(Na)/P(K), and for intracellular potassium and chloride concentrations are derived. At normal resting membrane potential, P(Cl)/P(K) is 0.13 but at a membrane potential of -53 mv (external potassium level increased about five times) it is 0.85. The intracellular concentrations of potassium and chloride are estimated to be 233 and 34 mM, respectively, and it is pointed out that this is not compatible with ions distributed in a Nernst equilibrium across the membrane. It is also stressed that the information given by a plot of membrane potential vs. the logarithm of external potassium concentrations is very limited and rests upon several important assumptions.

Axon-reflex-mediated vasodilatation in the psoriatic plaque?

Blood flow in the psoriatic plaque is increased, but the underlying mechanisms are not known. The aim of the present study was to examine whether neurogenic factors are important for blood flow regulation in the plaque. Local neurogenic mechanisms were inhibited by surface anesthesia and central nervous control by conduction anesthesia of nerves to the psoriatic plaque. The differences in skin perfusion before and after anesthesia were measured with a laser Doppler perfusion imager. The skin perfusion in psoriatic plaques located in hairy skin was unaffected by conduction anesthesia, but surface anesthesia of the plaque evoked a marked blood flow reduction. The perfusion in ultraviolet-B-irradiated skin, used as a control for nonspecific phenomena, was reduced after local application of indomethacin but was unaffected or increased after surface anesthesia. The results are compatible with the idea that a local neurogenic mechanism (axon-reflex) contributes to the high blood flow in the psoriatic plaque.

Increased interstitial histamine concentration in the psoriatic plaque.

The psoriatic plaque contains an increased number of mast cells that are thought to have an important role in the initiation and maintenance of psoriatic lesions through the release of mediators such as histamine, proteoglycans, lipid mediators, and cytokines. It is not known, however, whether the interstitial concentration of histamine (and other mediators) is truly increased in the psoriatic plaque. The aim of the present study was to examine histamine concentration and histamine release from involved and uninvolved skin of psoriatic patients. Intracutaneous microdialysis was performed in lesional and nonlesional skin of 23 psoriatic subjects. The relative recovery of histamine was assessed after calibration in situ to approximately 76% in both lesional and nonlesional skin. The interstitial histamine concentration was 32 +/- 3 nmol per liter in lesional skin and 13 +/- 1 nmol per liter in nonlesional skin (mean +/- SEM) (p < 0.001). Dermal histamine release was estimated according to the Fick principle after measurements of the arterialized venous plasma histamine concentration (3 +/- 1 nmol per liter) and blood flow and was found to be 10-fold increased in lesional compared with nonlesional skin. The results are compatible with the hypothesis that mast cells in lesional skin secrete an increased amount of histamine that may contribute to the immunostimulation and inflammation in the psoriatic plaque.

A quantitative study of muscle nerve sympathetic activity in resting normotensive and hypertensive subjects.

Recordings of multi-unit sympathetic activity were made from muscle branches of the peroneal or median nerves in 33 healthy and 12 hypertensive subjects resting in the recumbent position. Simultaneous recordings of intra-arterial blood pressure were made on 17 normotensive and all hypertensive subjects. The neural activity, quantified by counting the number of sympathetic pulse-synchronous impulse bursts in the mean voltage neurogram (burst incidence) was plotted against the age and the arterial blood pressure level of the subjects. Between different subjects there were marked differences in mean burst incidence, from less than 10 to more than 90 bursts/100 heart beats and there was a tendency for increasing values with increasing age. Taking the age differences into account there was no significant correlation between the amount of activity and the blood pressure level. The effect of spontaneous temporary blood pressure fluctuations was studied by correlation different pressure parameters of individual heart beats to the probability of occurrence of a sympathetic burst and to the mean voltage amplitude of the occurring burst. Irrespective of the mean burst incidence, the occurrence of the bursts and their mean voltage amplitudes were determined mainly by fluctuations of the diastolic blood pressure. The diastolic pressure threshold for sympathetic outflow was found to be reset to higher blood pressure values in the hypertensive subjects and the variability of their thresholds was also greater than for the normotensive controls. At a given diastolic blood pressure, more sympathetic activity occurred if diastolic blood pressure was falling than if it was rising, and this directional dependence was more pronounced in the hypertensive subjects. We suggest that the increased directional dependence accounts for the greater variability of the blood pressure threshold for sympathetic outflow in the hypertensive subjects. The differences can be expalined on the basis of findings in animals with experimental hypertension, and it appears that they are secondary to the hypertension.

The antihypertensive mechanism of clonidine in man. Evidence against a generalized reduction of sympathetic activity.

Recording of multi-unit sympathetic activity were made from muscle branches of the peroneal nerve during i.v. bolus injection of 100 to 275 micrograms clonidine in seven hypertensive patients. Blood pressure was reduced in all patients, but sympathetic activity and heart rate could either increase or decrease. When plasma levels of clonidine were low, sympathetic activity tended to increase, and when plasma levels were high, activity tended to decrease. Irrespective of whether mean level of sympathetic activity increased or decreased with the fall in blood pressure level, transient fluctuations of blood pressure continued to cause dynamic baroreflex modulation of the sympathetic outflow. It is suggested that the drug influences sympathetic outflow by a combination of central and peripheral effects.

Possible genetic influence on the strength of human muscle nerve sympathetic activity at rest.

Large reproducible interindividual differences in the strength of human muscle nerve sympathetic activity have been demonstrated previously without satisfactory explanation. We undertook the present study to investigate whether a genetic influence may be a factor of importance. Microneurographic recordings of sympathetic impulse traffic were made in the peroneal nerve in nine pairs of monozygotic male twins and eight pairs of age-matched male subjects without family relationship. The strength of the sympathetic activity was quantitated as number of sympathetic bursts per 100 heart beats and bursts per minute. Group mean values of muscle sympathetic activity, heart rate, and blood pressure were similar in the two groups. Intrapair differences (mean +/- SEM) of sympathetic activity were 5.4 +/- 1.7 bursts per 100 heart beats (1.7 +/- 0.5 bursts per minute) for the twins and 19.4 +/- 3.2 bursts per 100 heart beats (11.8 +/- 2.5 bursts per minute) for the control subjects (P < .01 for both). The degree of reproducibility between twins is similar to that reported previously between repeated recordings in the same subject. The finding may indicate that the strength of sympathetic outflow to muscle is controlled genetically. If so, we speculate that this may contribute to the heritability of blood pressure in both normotensive and hypertensive subjects.

Dissociation of sympathetic nerve activity in arm and leg muscle during mental stress.

Mental stress, which increases blood pressure and heart rate, increases forearm blood flow but does not change calf blood flow. The purpose of this study was to determine if mental stress increases muscle sympathetic nerve activity in the leg and causes a dissociation of muscle sympathetic nerve activity in the arm and the leg. We recorded heart rate, blood pressure, and efferent sympathetic nerve activity during mental stress (4 minutes of mental arithmetic) in 13 healthy men. Microelectrodes were inserted percutaneously into a fascicle of the peroneal nerve (leg) and radial nerve (arm) to measure sympathetic discharge to muscle. In Study 1, leg muscle sympathetic nerve activity was recorded in seven subjects. Mental stress significantly increased heart rate and blood pressure. Despite the increased blood pressure (which would be expected reflexly to inhibit sympathetic nerve activity), leg muscle sympathetic nerve activity (in total integrated activity, bursts per 100 heart beats or bursts per minute) increased significantly during stress. Further, whereas heart rate and blood pressure returned to normal during recovery, leg muscle sympathetic nerve activity remained elevated during recovery. In Study 2, simultaneous recordings were made of arm and leg muscle sympathetic nerve activity in six subjects. Mental stress increased heart rate and arterial pressure. Leg muscle sympathetic nerve activity again increased significantly during stress and remained elevated during recovery. In contrast, arm muscle sympathetic nerve activity did not change during stress. However, arm muscle sympathetic nerve activity increased significantly during recovery after stress. These studies indicate that a sympathoexcitatory influence of mental stress overrides or inhibits baroreceptor control of leg sympathetic nerve activity and stress causes a dissociation of arm and leg muscle sympathetic nerve activity with increased outflow to the leg but not to the arm. These observations may contribute to differences in blood flow to arm and leg during mental stress.

Acute effects of metoprolol on muscle sympathetic activity in hypertensive humans.

Recordings of multiunit sympathetic activity were made from muscle branches of the peroneal nerve in eight previously untreated subjects with essential hypertension during intravenous administration of the cardioselective beta-adrenoceptor antagonist, metoprolol. Intraarterial blood pressure and central venous pressure were monitored simultaneously. After metoprolol, heart rate fell and central venous pressure increased in all subjects. Blood pressure increased in some subjects and decreased in others whereas the rate of rise of the systolic pulse wave regularly decreased. Sympathetic activity, discharged in pulse synchronous bursts of action potentials, was quantitated by counting the number of bursts and their amplitudes in the mean voltage neurogram. In all subjects, the average diastole was associated with outflow of more sympathetic impulses after metoprolol than before. Total sympathetic activity (expressed as bursts/min multiplied by mean burst strength) also increased after the drug. The mechanism behind the increase of sympathetic activity may be either a direct central nervous effect or a reflex effect elicited from arterial baroreceptors or cardiac receptors.

Sympathetic outflow to muscles during treatment of hypertension with metoprolol.

Microelectrode recordings of multiunit sympathetic vasoconstrictor activity were made in muscle branches of the peroneal nerve in patients with essential hypertension before and during long-term treatment with the cardioselective beta-adrenergic receptor antagonist metoprolol. Nerve activity was quantified by counting the number of sympathetic bursts in the mean voltage neurogram. Metoprolol treatment lowered blood pressure and heart rate in all subjects. During long-term treatment, nerve activity was reduced both when compared to the level of activity after the first dose of the drug (p less than 0.01) and when compared to the control level before treatment (p less than 0.05). It is suggested that the reduction of sympathetic vasoconstrictor outflow to muscles contributed to the blood pressure reduction.

Sympathetic nerve activity and insulin in obese normotensive and hypertensive men.

The relationship between resting levels of muscle sympathetic nerve activity (MSA) and blood pressure is a matter of controversy. Body weight has recently been identified as an independent determinant of muscle sympathetic discharge, which may have influenced previous studies focused on MSA and mechanisms of hypertension. In the present study, we measured resting MSA and plasma insulin levels in 18 obese (body mass index, 32 +/- 4 kg/m2) (mean +/- SD), middle-aged (52 +/- 6 years), hypertensive (155 +/- 11/97 +/- 8 mm Hg) subjects and 16 age- and body mass index-matched normotensive control subjects. In the postabsorptive state, resting MSA was similar in the hypertensive and normotensive groups (43 +/- 4 versus 39 +/- 3 bursts per minute, 69 +/- 5 versus 64 +/- 5 bursts per 100 heart beats, P = NS) (mean +/- SEM) and did not correlate with either systolic or diastolic blood pressure. Weak but significant positive correlations were found between resting MSA and both fasting insulin levels (P < .05) and body mass index (P = .05) in hypertensive but not normotensive subjects. There was a strong positive correlation between fasting insulin and body mass index in both normotensive subjects and the entire study group (P < .005). Fasting insulin and body mass index correlated with diastolic blood pressure (P < .05) in the entire study group. In conclusion, a relationship between fasting insulin, body mass index, and blood pressure was confirmed, whereas only a weak correlation was found between MSA and fasting insulin in hypertensive but not normotensive subjects. The fact that MSA was similar in the two groups argues strongly against augmented MSA being important for the maintenance of hypertension, at least in middle-aged, obese men.

Effect of energy-restricted diet on sympathetic muscle nerve activity in obese women.

Twenty obese women aged 45-65 years with borderline hypertension were allocated randomly to either a group with an energy-restricted diet or to a control group. Body weight, blood pressure, urinary sodium, and urinary excretion of norepinephrine and plasma volume were recorded. Resting muscle sympathetic nerve activity was measured in the peroneal nerve by tungsten microelectrodes and expressed as bursts per minute. These measurements were repeated after 3 days of semistarvation and after a body weight reduction of 7% while each patient's weight was in a steady state. After 3 days of semistarvation, only body weight was reduced, whereas after the long-term energy intake restriction, there were reductions of body weight (79.9 +/- 3.4 versus 74.1 +/- 3.4 kg; p less than 0.001), diastolic blood pressure (93 +/- 3 versus 86 +/- 4 mm Hg; p = 0.01), and muscle sympathetic nerve activity (49 +/- 2 versus 42 +/- 3 bursts/min; p less than 0.05). Other variables were unchanged. There were no changes in body weight, blood pressure, or muscle sympathetic nerve activity in the control group. We conclude that body weight decrease in obesity results in a reduction of blood pressure that is at least partially caused by a reduction of sympathetic vasoconstrictor activity.

Effects of the cold pressor test on muscle sympathetic nerve activity in humans.

The purpose of this study was to determine the effects of the cold pressor test on sympathetic outflow with direct measurements of nerve traffic in conscious humans and to test the strength of correlation between sympathetic nerve discharge and the changes in arterial pressure, heart rate, and plasma norepinephrine. In 25 healthy subjects, arterial pressure, heart rate, and muscle sympathetic nerve activity were measured with microelectrodes inserted percutaneously into a peroneal muscle nerve fascicle in the leg during immersion of the hand in ice water for 2 minutes. Arterial pressure rose steadily during the first and second minutes of the cold pressor test. Muscle sympathetic activity (burst frequency X amplitude) did not increase in the first 30 seconds of the test but increased from 230 +/- 27 to 386 +/- 52 units (mean +/- SE, p less than 0.05) by the end of the first minute of the test and to 574 +/- 73 (p less than 0.01) during the second minute. In contrast, heart rate increased maximally during the first 30 seconds of the cold pressor test and returned to control during the second minute. The increases in heart rate were abolished by beta-adrenergic blockade. The increases in muscle sympathetic activity during the cold pressor test were correlated with the increases in both mean arterial pressure (r = 0.86, p less than 0.01) and peripheral venous norepinephrine (r = 0.72, p less than 0.05); however, large changes in nerve traffic were associated with small changes in plasma norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Measurements of plasma norepinephrine concentrations in human primary hypertension. A word of caution on their applicability for assessing neurogenic contributions.

The relationship between plasma levels of norepinephrine (NE) and sympathetic neural activity is discussed with special reference to human primary hypertension. Since sympathetic discharge is differentiated, neural activity to a given target organ will contribute variably to plasma NE levels in different situations. Hemodynamically, early primary hypertension is often characterized by a mild defense reaction-like pattern with signs of increased sympathetic activity to the heart and vasoconstriction in the renal and splanchnic vascular beds. Although important hemodynamically, these organs seem to be of less importance as contributors to peripheral plasma NE levels. In contrast, muscle sympathetic activity and muscle vascular resistance is unchanged or reduced. Since this organ mass contributes importantly to plasma NE levels, especially in peripheral venous blood, it is not surprising that most patients with primary hypertension have normal NE levels. It is concluded that NE concentrations in forearm or mixed venous blood are unreliable indicators of sympathetic neural contributions to essential hypertension, tending to underestimate this element, and that regional measurements of NE overflow are needed for a reliable analysis.

Increased norepinephrine spillover into the jugular veins in essential hypertension.

In essential hypertension sympathetic nerve firing is commonly increased. A central nervous system origin has been presumed but not tested directly. To estimate cerebral norepinephrine release in essential hypertension, spillover of norepinephrine into the cerebrovascular circulation was measured by isotope dilution, with high internal jugular venous sampling. Norepinephrine was released into the cerebrovascular circulation in both hypertensive patients and healthy volunteers and was present after administration of the ganglion blocker trimethaphan and in patients with sympathetic nervous failure, indicating that brain neurons and not cerebrovascular sympathetic nerves were the probable source. Although differing among hypertensive patients, norepinephrine spillover on average was higher in the hypertensive patients (153 +/- 41 pmol/min) than in healthy subjects (59 +/- 12 pmol/min; p less than 0.05), and was elevated in six of 17 patients, in whom the accompanying whole body norepinephrine spillover rate was higher than in the remaining 11 patients (p less than 0.01). To test for a possible link between brain norepinephrine release and human sympathetic nervous function, the effect of the tricyclic antidepressant desipramine (0.3 mg/kg i.v.) on both brain and whole body norepinephrine spillover was measured in healthy volunteers. Desipramine lowered the cerebrovascular spillover of norepinephrine, its precursor dihydroxyphenylalanine, and its metabolite dihydroxyphenylglycol by 50-80% and produced a mean fall of 35% in whole body norepinephrine spillover. One interpretation of these results is that human sympathetic nerve firing is dependent on norepinephrine release within the brain and that increased cerebral norepinephrine release may possibly be present in some patients with essential hypertension, underlying their higher sympathetic nerve firing rates.