Multiple subpial transection in kainic acid-induced focal cortical seizure

Hypoxia is a potent activator of the sympathetic nervous system by stimulating arterial chemoreceptors. However, out of 15 laboratory studies on the effects of acute and prolonged hypoxia on catecholamines, 14 failed to show any changes in plasma or urinary noradrenaline and only four studies showed significant increases in plasma or urinary adrenaline. By contrast, six out of eight studies on MSNA showed increased sympathetic nerve activity to the leg. An increased clearance of plasma catecholamines during hypoxia may be a possible explanation. Furthermore, many of the studies had limitations in a number of subjects and catecholamine assays used. Emotional aspects of the study protocols, which could contribute to the increase in adrenaline, was only assessed by sham runs in one chamber study. However, 13 out of 14 reviewed field studies on subjects staying for more than 1 week at high altitude, reported increased plasma or urinary excretion of noradrenaline which may be compatible with increased sympathetic activity. Adrenaline changed to a lesser degree. Out of seven studies on more short-term (4 h to 3 days) exposure to high altitude, only one demonstrated significantly increased plasma noradrenaline. In this study, however, several subjects had been exposed to high altitude less than 1 week before the experiment. In a new study on 12 climbers reported in this paper, a temporary reduction in plasma catecholamines was found 2 days after arrival at 4200 m. There was a steady increase towards normal levels after 1 week. Plasma vasopressin (AVP) increased suggesting a compensatory mechanism. Both plasma noradrenaline and adrenaline were positively correlated with oxygen saturation in these subjects. Thus, in previously unacclimatized subjects, short-term exposure to high altitude does not increase plasma catecholamines, rather plasma levels decreased. In addition to increased clearance, there is some evidence of reduced synthesis of catecholamines during short-term hypoxia. The oxygen sensitivity of tyrosine hydroxylase (TH) activity, may be one possible mechanism.     

Replica cytology in cancer of the larynx: an evaluation of a replica method in the diagnosis of laryngeal malignancy

Dopamine, noradrenaline and adrenaline were measured in plasma and in urine, using double-isotope derivative techniques, in 46 normal subjects and in 17 tetraplegic patients with physiologically complete cervical spinal cord transections above the sympathetic outflow. Dopamine was present in plasma in normal subjects in a concentration of 0.33 mug/l +/- 0.06 (SEM). Twenty-four hour urinary excretion of dopamine averaged 248 mug +/- 22. There was a significant correlation between the 24 h urinary excretion of dopamine and of noradrenaline. In the normal subjects plasma dopamine and the urinary excretion of dopamine did not change during three days of fasting while urinary excretion of adrenaline increased twofold. In the normal subjects exercise significantly increased plasma dopamine from 0.25 mug/l to 0.43 mug/l, but significantly decreased the urinary excretion of dopamine. Exercise significantly increased the excretion of noradrenaline. In the tetraplegic patients the plasma dopamine concentration and the urinary excretion of dopamine were lower but not significantly different from the corresponding values in the normal subjects. Plasma noradrenaline and the urinary excretion of noradrenaline and adrenaline were significantly lower in the tetraplegic patients. It is concluded that dopamine is present in human plasma in concentrations similar to that of noradrenaline. Free dopamine in plasma and urine of normal subjects is not dependent on foot intake. Urinary dopamine may be derived from circulating dopamine. Urinary dopamine does not necessarily appear to reflect changes in plasma dopamine. The relationship between plasma dopamine and changes in adrenergic nervous activity deserves further investigation.     

Drugs and toxins associated with myopathies

BACKGROUND: The sympathetic nervous system has long been believed to be involved in the pathogenesis of panic disorder, but studies to date, most using peripheral venous catecholamine measurements, have yielded conflicting and equivocal results. We tested sympathetic nervous function in patients with panic disorder by using more sensitive methods. METHODS: Sympathetic nervous and adrenal medullary function was measured by using direct nerve recording (clinical microneurography) and whole-body and cardiac catecholamine kinetics in 13 patients with panic disorder as defined by the DSM-IV, and 14 healthy control subjects. Measurements were made at rest, during laboratory stress (forced mental arithmetic), and, for 4 patients, during panic attacks occurring spontaneously in the laboratory setting. RESULTS: Muscle sympathetic activity, arterial plasma concentration of norepinephrine, and the total and cardiac norepinephrine spillover rates to plasma were similar in patients and control subjects at rest, as was whole-body epinephrine secretion. Epinephrine spillover from the heart was elevated in patients with panic disorder (P=.01). Responses to laboratory mental stress were almost identical in patient and control groups. During panic attacks, there were marked increases in epinephrine secretion and large increases in the sympathetic activity in muscle in 2 patients but smaller changes in the total norepinephrine spillover to plasma. CONCLUSIONS: Whole-body and regional sympathetic nervous activity are not elevated at rest in patients with panic disorder. Epinephrine is released from the heart at rest in patients with panic disorder, possibly due to loading of cardiac neuronal stores by uptake from plasma during surges of epinephrine secretion in panic attacks. Contrary to popular belief, the sympathetic nervous system is not globally activated during panic attacks.     

Lymphocyte cAMP and ageing: significance of subset composition, plasma noradrenaline, regular physical training and long-term smoking

1. We studied 37 healthy men at rest in the supine. position to examine the effect of ageing, smoking and physical training of beta 2-adrenoceptor function, plasma catecholamines and the proportions of various lymphocyte subsets. 2. In 14 young subjects the proportion of natural killer cells was correlated with cAMP production in lymphocytes and inversely correlated with plasma noradrenaline level. 3. In 16 elderly non-smokers plasma noradrenaline was negatively correlated with the natural killer cell subset CD3-CD16+. Lymphocyte cAMP responses did not differ between young and elderly non-smokers, whereas plasma noradrenaline increased slightly but significantly with age. Physical training did not influence either plasma noradrenaline or adrenaline at rest or cAMP in lymphocytes. 4. In seven elderly long-term smokers cAMP production and the viability of lymphocytes were reduced. Plasma noradrenaline attained its highest values in long-term smokers. 5. It is concluded that cAMP production and plasma noradrenaline are related to lymphocyte subset composition. The greater the proportion of natural killer cells and related subsets, the higher is cAMP production and the lower is plasma noradrenaline. Thus, the inverse correlation between lymphocyte cAMP and plasma noradrenaline is indirect and most likely mediated by variability in lymphocyte subset composition. In elderly subjects, reduced cAMP production was observed in long-term smokers, and this abnormality was probably due to a reduced viability of lymphocytes and especially of natural killer cells. The negative correlation between the proportion of natural killer cells and plasma noradrenaline at rest contracts with a well-known mobilizing effect of adrenaline on natural killer cells.     

Heart rate and blood pressure variability in obese normotensive subjects

OBJECTIVE: To assess autonomic modulation of cardiovascular activity in massively obese subjects. DESIGN: Cross-sectional clinical study. SUBJECTS: 43 age-matched normotensive subjects: 15 moderately obese (body mass index (BMI) < 40); 14 massively obese (BMI > 40) and 14 nonobese controls (BMI < 26). MEASUREMENTS: Using power spectral analysis, heart rate and arterial pressure variability were determined at rest and after sympathetic stress (tilt). Two spectral components were analysed: a low-frequency (LF) component at around 0.1 Hz, predominantly reflecting sympathetic modulation and a high-frequency (HF) component at around 0.26 Hz, reflecting parasympathetic modulation. RESULTS: Spectral data for heart rate showed that the massively obese subjects had lower LF [mean +/- s.e.m.] normalized units (NUs) at rest (35.1 +/- 0.9) and after tilt (56.1 +/- 2.1), than the moderately obese subjects (LF NUs at rest 53.9 +/- 4.2, P < 0.001; LF NUs tilt: 66.8 +/- 5.6, P < 0.001) and nonobese control subjects (LF NUs at rest, 56.6 +/- 3.0, P < 0.001); (LF NUs tilt: 81.7 +/- 1.7, P < 0.001). Data for systolic arterial pressure variability measured at rest exhibited the inverse pattern, the massively obese group having higher mean LF values (LF mm Hg2 rest: 15.0 +/- 1.4; LF mm Hg2 tilt: 15.7 +/- 1.5) than the moderately obese group (LF mm Hg2 rest 3.2 +/- 0.7, P < 0.001; LF mm Hg2 tilt: 7.2 +/- 2.0, P < 0.001) and than the nonobese control subjects (LF mm Hg2 rest 3.5 +/- 0.5, LF mm Hg2 tilt 8.5 +/- 0.8, P < 0.001). Regression detected a significant association between BMI and LF of systolic pressure (beta = 0.364; P = 0.0007), In LF of heart rate (beta = -5.555; P = 0.00001) and very low frequency (VLF) of diastolic pressure (beta = -3.305; P = 0.0020). CONCLUSION: Obesity seems to increase sympathetic modulation of arterial pressure, but diminishes modulation of heart rate. Because our obese subjects had high plasma noradrenaline levels, their low LF power of heart rate could reflect diminished adrenoceptor responsiveness.     

Muscle sympathetic nerve activity is reduced in IDDM before overt autonomic neuropathy

Studies of heart-rate variability have demonstrated that abnormal cardiac parasympathetic activity in individuals with IDDM precedes the development of other signs or symptoms of diabetic autonomic neuropathy. To determine whether IDDM patients have impaired sympathetic activity compared with normal control subjects before the onset of overt neuropathy, we directly recorded MSNA. We also examined the effects of changes in plasma glucose and insulin on sympathetic function in each group. MSNA was recorded by using microneurographic techniques in 10 IDDM patients without clinically evident diabetic complications and 10 control subjects. MSNA was compared during a 15-min fasting baseline period and during insulin infusion (120 mU.m-2.min-1) with 30 min of euglycemia. A cold pressor test was performed at the end of euglycemia. Power spectral analysis of 24-h RR variability was used to assess cardiac autonomic function. IDDM patients had lower MSNA than control subjects at baseline (8 +/- 1 vs. 18 +/- 3 burst/min, P < 0.02). MSNA increased in both groups with insulin infusion (P < 0.01) but remained lower in IDDM patients (20 +/- 3 vs. 28 +/- 3 burst/min, P < 0.01). In the IDDM group, we found no relationships between MSNA and plasma glucose, insulin, or HbA1c concentrations. BP levels did not differ at rest or during insulin. Heart-rate variability and the MSNA response to cold pressor testing in IDDM patients did not differ from those in healthy control subjects. IDDM patients had reduced MSNA at rest and in response to insulin. The lower MSNA is not attributable to differences in plasma glucose or insulin, but, rather, is most likely an early manifestation of diabetic autonomic neuropathy that precedes impaired cardiac parasympathetic control.     

Body weight reduction, sympathetic nerve traffic, and arterial baroreflex in obese normotensive humans

BACKGROUND: Previous studies have shown that sympathetic cardiovascular outflow is increased in obese normotensive subjects and that this increase is associated with a baroreflex impairment. The purpose of this study was to determine whether these abnormalities are irreversible or can be favorably affected by body weight reduction. METHODS AND RESULTS: In 20 obese normotensive subjects (age, 31.3+/-1.7 years; body mass index, 37.6+/-0.9 kg/m2, mean+/-SEM), we measured beat-to-beat arterial blood pressure (Finapres technique), heart rate (ECG), postganglionic muscle sympathetic nerve activity (microneurography at a peroneal nerve), and venous plasma norepinephrine (high-performance liquid chromatography) at rest and during baroreceptor stimulation and deactivation induced by increases and reductions of blood pressure via stepwise intravenous infusions of phenylephrine and nitroprusside. Measurements were repeated in 10 subjects after a 16-week hypocaloric diet with normal sodium content (4600 to 5000 J and 210 mmol NaCl/d) and in the remaining 10 subjects after a 16-week observation period without any reduction in the caloric intake. The hypocaloric diet significantly reduced body mass index, slightly reduced blood pressure, and caused a significant and marked decrease in both muscle sympathetic nerve activity (from 50.0+/-5.1 to 32.9+/-4.6 bursts per 100 heart beats, P<.01) and plasma norepinephrine (from 356.2+/-43 to 258.4+/-29 pg/mL, P<.05). This was associated with a significant improvement in the sensitivity of the baroreceptor heart rate (+71.5 +/- 11%, P<.01) and muscle sympathetic nerve activity (+124.5 +/- 22%, P<.001) reflex. Total body glucose uptake also increased significantly (+60.8 +/- 12.0%, P<.05), indicating an increase in insulin sensitivity. All variables remained unchanged in subjects not undergoing caloric restriction. CONCLUSIONS: In obese normotensive subjects, a reduction in body weight induced by a hypocaloric diet with normal sodium content exerts a marked reduction in sympathetic activity owing to central sympathoinhibition. This can be due to the consequences of an increased insulin sensitivity but also to a restoration of the baroreflex control of the cardiovascular system with weight loss.     

Effects of buspirone on plasma neurotransmitters in healthy subjects

Buspirone is an anxiolytic drug which exerts several central effects. It antagonizes presynaptic inhibitory DA2 autoreceptors at dopaminergic neurons and acts as an agonist for 5-HT1A inhibitor autoreceptors at serotonergic cells. Thus, buspirone respectively enhances and depresses the firing rates of both type of neurons. At doses which correlate with dopaminergic stimulation, but not 5-HT inhibition, buspirone also increases the firing rates of the central noradrenergic cells. We measured levels of circulating neurotransmitters before and up to 240 minutes after the oral administration of 20 mg of buspirone in 32 healthy volunteers. Buspirone significantly increased levels of noradrenaline, dopamine, and free serotonin but did not affect levels of adrenaline, tryptophane, or platelet serotonin. Small but significant drops in systolic blood pressure and heart rate were observed after buspirone ingestion. Atropine administration before buspirone ingestion annulled the free serotonin increase as well as systolic blood pressure-heart rate decrease. We found significant positive correlations between noradrenaline and dopamine levels. The strength and significance of these correlations were increased by using the noradrenaline/adrenaline ratio instead of noradrenaline absolute values. This finding indicates that increases in both noradrenaline and dopamine arise from sympathetic nerves rather than the adrenal glands. We also found significant negative correlations between free serotonin increases and systolic blood pressure-heart rate decreases. Our results indicate that buspirone stimulates central sympathetic activity. These acute effects of buspirone are reflected in an increased peripheral neural sympathetic activity, but not adrenal sympathetic activity in healthy individuals. In addition, buspirone increases free serotonin plasma concentrations and decreases systolic blood pressure plus heart rate levels through mechanisms associated with parasympathetic activation.     

Pressure-independent inhibition of sympathetic activity by noradrenaline: role of baroreceptor C fibres

The effect of i.v. infusion of noradrenaline on activity in the renal sympathetic nerve was studied in rabbits anesthetized with chloralose and urethane. Noradrenaline (3--8 microgram/kg-min) initially increased mean arterial pressure 20--40 mmHg and consequently reduced renal nerve activity. However, studies over a wide range of pressures--obtained by changing the blood volume, revealed that noradrenaline after a few minutes had induced a pressure-independent reduction of sympathetic discharge. The effect disappeared with baroreceptor denervation. An unchanged relationship between arterial pressure and integrated activity in the whole left aortic nerve (which is largely a measure of activity in A fibres) suggested that the sympathetic depression was due to excitation of aortic nerve C fibres. This conclusion was supported by studies of sympathetic responses to selective stimulation of aortic nerve A and C fibres at equal pressures before and during infusion of noradrenaline. Compared to the reflex activity from A fibres, C fibre stimulation was invariably less effective in suppressing renal nerve activity during the infusion. Our studies indicate that noradrenaline may effect a negative feedback control of sympathetic discharge through activation of baroreceptor C fibres.     

Human obesity is associated with a chronic elevation in brain 5-hydroxytryptamine turnover

The afferent signals that evoke changes in energy intake with regard to body weight regulation are presumed to arise partly from body stores, with the most likely candidate being adipose tissue depots. However, clinical investigation of the neuronal circuitry involved in the central nervous system's processing of such satiety signals remains largely unexplored. Using percutaneously placed catheters in either the right or left internal jugular veins, we were able to quantify the release of central nervous system monoamine and indoleamine neurotransmitters in 64 weight-stable male subjects with varying degrees of adiposity. Veno-arterial plasma concentration differences and internal jugular blood or plasma flow were used, according to the Fick Principle, to quantify the amount of neurotransmitter stemming from the brain. By combining this technique with a noradrenaline and adrenaline isotope dilution method for examining neuronal transmitter release, we were able to examine the association between central nervous system neurotransmitters and efferent sympathetic nervous outflow and adrenomedullary function in human obesity. We found that brain 5-hydroxytryptamine (serotonin) turnover is chronically elevated in proportion to adiposity and is increased postprandially to a similar degree in lean and obese individuals. There was no difference in the degree of sympathetic nervous activity or rate of adrenaline secretion in the subjects examined. It therefore seems that in human obesity, in the face of a chronic elevation in peripheral satiety signals, brain serotonergic processes are switched on accordingly, but the subsequent physiological response involving a reduction in food intake, increased thermogenesis and sympathetic activity is in some way impeded.     

Changes in plasma dopamine-beta-hydroxylase activity during the perioperative period of cardiac surgery: an index of sympathetic nerve activity

To evaluate the usefulness of plasma dopamine-beta-hydroxylase (DBH) activity as an index of sympathetic nerve activity during cardiac operations, we examined the serial changes in plasma DBH activity, in relation to the plasma noradrenaline (NA) level and hemodynamic parameters, in patients who underwent cardiac surgery. The plasma DBH activity decreased significantly after cardiopulmonary bypass, and remained low during dopamine (DA) infusion until 72 h after the operation. However, recovery of the hemodynamic parameters, being the mean arterial pressure, heart rate and cardiac index, was seen as early as 1-3 h postoperatively. It was therefore assumed that the plasma DBH activity takes a long time to recover after an operation. The time-course changes in the plasma NA level were quite different from the changes in DBH activity, with an apparent negative correlation being observed between them. Thus, there is a possibility that exogenously administered DA, as well as increased plasma NA, might inhibit DBH activity during cardiac surgery. Moreover, since catecholamines are often administered upon completion of cardiac surgery, measurement of the plasma catecholamine level would be inappropriate for evaluating real sympathetic nerve activity. From the results of this study, it is surmised that measurement of the plasma DBH activity could be useful for estimating the intrinsic sympathetic nerve activity of patients who have undergone cardiac surgery.     

T4 DNA ligase reduces chromosome damage and enhances cell survival in CHO cells treated with bleomycin

OBJECTIVE: Recent clinical studies suggest that the reflex increase in sympathetic nervous activity accompanying a reduction in blood pressure may contribute to the untoward effects of dihydropyridine calcium antagonists. The aim of this study was to examine whether plasma noradrenaline levels and renin activity are increased with the reduction of blood pressure during the initial phase of administration of the long-acting dihydropyridine calcium antagonist amlodipine. METHODS: The effects of amlodipine on ambulatory blood pressure and on diurnal variations in plasma noradrenaline and renin activity were examined 1, 4, and 7 days after the start of amlodipine administration in eight inpatients with essential hypertension. RESULTS: The 24-h mean systolic and diastolic blood pressure on day 7 was significantly lower than it was 1 day before the start of treatment. There was no change in the mean heart rate. The mean trough to peak ratios of systolic and diastolic blood pressure of seven patients were 61% and 71%, respectively. Diurnal patterns of plasma noradrenaline levels and renin activity 1, 4, and 7 days after the start of amlodipine administration were unchanged. CONCLUSION: The antihypertensive effects of amlodipine were of slow onset and long duration and were not accompanied by an increase in sympathetic activity or activation of the renin-angiotensin system.     

The haemodynamic and antithrombotic effects of intermittent pneumatic calf compression of femoral vein blood flow. A comparison between different pump types

Postural changes in plasma renin activity were studied in three groups of age and duration-matched male diabetics (potent, impotent and with postural hypotension) and in non-diabetic control subjects. Those diabetic subjects with postural hypotension due to automatic neuropathy had no increase in plasma renin activity to the erect posture whereas both the potent and impotent groups had similar plasma renin activity responses to the control subjects. There was a significant inverse correlation between the rise in plasma renin activity on standing and the postural drop in blood pressure (r = 0.476, P less than 0.01) but no correlation with other tests of autonomic reflex function such as the Valsalva manoeuvre and blood pressure response to sustained handgrip. The results suggested that the lesion responsible for the postural hypotension is in the efferent sympathetic pathway. However, neuropathy per se did not wholly explain the decreased postural plasma renin activity response. Diabetic nephropathy, with involvement of cells of juxtaglomerular apparatus, may also be implicated.     

Adrenomedullary secretion of epinephrine is increased in mild essential hypertension

To assess whether patients with mild essential hypertension have excessive activities of the sympathoneuronal and adrenomedullary systems, we examined total body and forearm spillovers and norepinephrine and epinephrine clearances in 47 subjects with mild essential hypertension (25 men, 22 women, aged 38.1 +/- 6.7 years) and 43 normotensive subjects (19 men, 24 women, aged 36.5 +/- 5.9 years). The isotope dilution method with infusions of tritiated norepinephrine and epinephrine was used at rest and during sympathetic stimulation by lower body negative pressure at -15 and -40 mm Hg. Hypertensive subjects had a higher arterial plasma epinephrine concentration (0.20 +/- 0.01 nmol.L-1: mean +/- SE) than normotensive subjects (0.15 +/- 0.01) (P < .01). The increased arterial plasma epinephrine levels appeared to be due to a higher total body epinephrine spillover rate in the hypertensive subjects (0.23 +/- 0.02 nmol.min-1.m-2) than the normotensive subjects (0.18 +/- 0.01) (P < .05) and not to a decreased plasma clearance of epinephrine. The arterial plasma norepinephrine level, total body and forearm norepinephrine spillover rates, and plasma norepinephrine clearance were not altered in the hypertensive subjects. The responses of the catecholamine kinetic variables to lower body negative pressure were not consistently different between normotensive and hypertensive individuals. These data indicate that individuals with mild essential hypertension (1) have elevated arterial plasma epinephrine concentrations that are due to an increased total body epinephrine spillover rate, indicating an increased adrenomedullary secretion of epinephrine; (2) have no increased generalized sympathoneuronal activity and no increased forearm norepinephrine spillover; and (3) have similar responses of both the sympathoneuronal and adrenomedullary systems to sympathetic stimulation by lower body negative pressure.     

Physical training and baroreceptor control of sympathetic nerve activity in humans

In nine sedentary subjects (16.5 +/- 0.4 years, mean +/- SEM) we measured blood pressure (Finapres device), heart rate (electrocardiogram), and postganglionic muscle sympathetic nerve activity (microneurography from the peroneal nerve) at rest and during intravenous infusion of phenylephrine and nitroprusside. These measurements were performed before and after 10 weeks of endurance training (2 h/d, 5 d/wk) that increased maximum oxygen consumption from 34.8 +/- 2.1 to 40.4 +/- 1.8 mL/kg per minute (P < .02). Basal mean blood pressure and muscle sympathetic nerve activity were lower after than before endurance training (86.5 +/- 2.6 versus 97.5 +/- 1.8 mm Hg, P < .05, and 14.0 +/- 1.8 versus 21.2 +/- 2.3 bursts per minute, P < .02), and the changes in these variables were closely related (r = .95, P < .01). Similar mean blood pressure increases induced by phenylephrine caused greater reductions in heart rate and muscle sympathetic nerve activity after than before endurance training (-8.6 +/- 0.8 versus -6.1 +/- 1.1 beats per minute, P = NS, and -78.0 +/- 4.6% versus -53.6 +/- 4.8%, P < .05). Likewise, similar mean blood pressure reductions induced by nitroprusside caused greater increases in heart rate and muscle sympathetic nerve activity after than before endurance training (18.6 +/- 3.0 versus 12.4 +/- 2.4 beats per minute, P < .05, and 128.1 +/- 26% versus 63.2 +/- 11%, P < .02). No alteration in hemodynamics, oxygen consumption, muscle sympathetic nerve activity, and baroreceptor reflex sensitivity occurred in four other age-matched sedentary subjects studied before and after a 10-week observation period without endurance training.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic effects of thiothixene and chlorpromazine in schizophrenic patients at rest and during exercise

The hemodynamic effects and plasma levels of noradrenaline were studied in schizophrenic patients at rest and during exercise after long-term treatment with chlorpromazine (150-600 mg daily) and thiothixene (60-80 mg daily). The results are compared with those from previous studies in untreated patients and patients receiving very large doses of chlorpromazine. The effects of thiothixene on the different hemodynamic variables were very moderate, and the observed differences between this group and the control group may be due to the different patient materials. In the two groups of patients receiving chlorpromazine, the heart rate at rest and durng exercise tended to be higher than in the control group. There was also a tendency towards a lower stroke volume after this drug and thiothixene during exercise. The noradrenaline levels in plasma were highest after the high dose of chlorpromazine both at rest and during exercise, while they were lower after the moderate chlorpromazine dose. After thiothixene, the values were between those of the group on the low chlorpromazine dose and those of the control group.     

Effects of simulated microgravity on closed-loop cardiovascular regulation and orthostatic intolerance: analysis by means of system identification

Microgravity-induced orthostatic intolerance (OI) continues to be a primary concern for the human space program. To test the hypothesis that exposure to simulated microgravity significantly alters autonomic nervous control and, thus, contributes to increased incidence of OI, we employed the cardiovascular system identification (CSI) technique to evaluate quantitatively parasympathetic and sympathetic regulation of heart rate (HR). The CSI method analyzes second-to-second fluctuations in noninvasively measured HR, arterial blood pressure, and instantaneous lung volume. The coupling mechanisms between these signals are characterized by using a closed-loop model. Parameters reflecting parasympathetic and sympathetic responsiveness with regard to HR regulation can be extracted from the identified coupling mechanisms. We analyzed data collected from 29 human subjects before and after 16 days of head-down-tilt bed rest (simulated microgravity). Statistical analyses showed that parasympathetic and sympathetic responsiveness was impaired by bed rest. A lower sympathetic responsiveness and a higher parasympathetic responsiveness measured before bed rest identified individuals at greater risk of OI before and after bed rest. We propose an algorithm to predict OI after bed rest from measures obtained before bed rest.     

Relation between the site of origin of ventricular premature complexes and the presence and severity of coronary artery disease

Dopamine-beta-hydroxylase (DBH) and norepinephrine (NE) have been determined in over 350 plasma samples from 174 subjects while resting supine (basal sample), standing, or exercising. Although increments in both NE and DBH were found with postural change, the further increase in plasma levels of NE during exertion was not attended by any change in levels of DBH. There was no significant correlation between basal levels of DBH and NE nor was there any correlation in their increments after standing or exercising. DBH activity in plasma of subjects with moderate essential hypertension was not different from that of normotensive subjects. It is concluded that plasma DBH is a poor index of acute sympathetic neuronal activity.     

Scintigraphic assessment of regionalized defects in myocardial sympathetic innervation and blood flow regulation in diabetic patients with autonomic neuropathy

OBJECTIVES: This study sought to evaluate whether regional sympathetic myocardial denervation in diabetes is associated with abnormal myocardial blood flow under rest and adenosine-stimulated conditions. BACKGROUND: Diabetic autonomic neuropathy (DAN) has been invoked as a cause of unexplained sudden cardiac death, potentially by altering electrical stability or impairing myocardial blood flow, or both. The effects of denervation on cardiac blood flow in diabetes are unknown. METHODS: We studied 14 diabetic subjects (7 without DAN, 7 with advanced DAN) and 13 nondiabetic control subjects without known coronary artery disease. Positron emission tomography using carbon-11 hydroxyephedrine was used to characterize left ventricular cardiac sympathetic innervation and nitrogen-13 ammonia to measure myocardial blood flow at rest and after intravenous administration of adenosine (140 microg/kg body weight per min). RESULTS: Persistent sympathetic left ventricular proximal wall innervation was observed, even in advanced neuropathy. Rest myocardial blood flow was higher in the neuropathic subjects (109 +/- 29 ml/100 g per min) than in either the nondiabetic (69 +/- 8 ml/100 g per min, p < 0.01) or the nonneuropathic diabetic subjects (79 +/- 23 ml/100 g per min, p < 0.05). During adenosine infusion, global left ventricular myocardial blood flow was significantly less in the neuropathic subjects (204 +/- 73 ml/100 g per min) than in the nonneuropathic diabetic group (324 +/- 135 ml/100 g per min, p < 0.05). Coronary flow reserve was also decreased in the neuropathic subjects, who achieved only 46% (p < 0.01) and 44% (p < 0.01) of the values measured in nondiabetic and nonneuropathic diabetic subjects, respectively. Assessment of the myocardial innervation/blood flow relation during adenosine infusion showed that myocardial blood flow in neuropathic subjects was virtually identical to that in nonneuropathic diabetic subjects in the distal denervated myocardium but was 43% (p < 0.05) lower than that in the nonneuropathic diabetic subjects in the proximal innervated segments. CONCLUSIONS: DAN is associated with altered myocardial blood flow, with regions of persistent sympathetic innervation exhibiting the greatest deficits of vasodilator reserve. Future studies are required to evaluate the etiology of these abnormalities and to evaluate the contribution of the persistent islands of innervation to sudden cardiac death complicating diabetes.     

Secondary structure of the DNA-binding domain of the c-Myb oncoprotein in solution. A multidimensional double and triple heteronuclear NMR study

Euglycemic hyperinsulinemia evokes both sympathetic activation and vasodilation in skeletal muscle, but the mechanism remains unknown. To determine whether insulin per se or insulin-induced stimulation of carbohydrate metabolism is the main excitatory stimulus, we performed, in six healthy lean subjects, simultaneous microneurographic recordings of muscle sympathetic nerve activity, plethysmographic measurements of calf blood flow, and calorimetric determinations of carbohydrate oxidation rate. Measurements were made during 2 h of: (a) insulin/glucose infusion (hyperinsulinemic [6 pmol/kg per min] euglycemic clamp), (b) exogenous glucose infusion at a rate matched to that attained during protocol a, and (c) exogenous fructose infusion at the same rate as for glucose infusion in protocol b. For a comparable rise in carbohydrate oxidation, insulin/glucose infusion that resulted in twofold greater increases in plasma insulin concentrations than did glucose infusion alone, evoked twofold greater increases in both muscle sympathetic nerve activity and calf blood flow. Fructose infusion, which increased carbohydrate oxidation comparably, but had only a minor effect on insulinemia, did not stimulate either muscle sympathetic nerve activity or calf blood flow. These observations suggest that in humans hyperinsulinemia per se, rather than insulin-induced stimulation of carbohydrate metabolism, is the main mechanism that triggers both sympathetic activation and vasodilation in skeletal muscle.