Assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover.
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Adrenal Medulla↗
Biomedical subjects
M Esler
Publications and source records attributed to M Esler.
The place of exercise in the long-term treatment of hypertension.
The antihypertensive effects of exercise have been examined in 2 randomized studies of multiple levels of activity. In 12 normal subjects, 1 month's exercise 3 times weekly lowered blood pressure (BP) and vascular resistance. There was only a slightly greater effect after 7 times/week exercise. In most subjects there was a marked reduction in noradrenaline spillover rate, a measure of sympathetic activity. Exercise also improved glucose utilization and lowered plasma cholesterol. Thirteen previously untreated patients with essential hypertension had an average fall in BP of 11/9 and 16/11 mm Hg after 1 month each of 3/week and 7/week exercise respectively, again associated with fall in vascular resistance and a 20-30% reduction in plasma noradrenaline. BP remained lowered by 3/week exercise for 1 year. In patients who had BP controlled with drug for greater than 1 year, exercise 3 times weekly also prevented the redevelopment of hypertension after long-term drug therapy was ceased. Regular exercise is useful in the initial management of patients with mild hypertension. In more severely hypertensive patients, exercise may also be effective after an initial period of drug therapy.
Blood Pressure↗
Sympathetic tone modulates portal venous pressure in alcoholic cirrhosis.
Sixteen alcoholic cirrhotic patients with portal hypertension were studied before and after 2.5 micrograms/kg intravenous clonidine. In six patients portal venous pressure was assessed simultaneously by wedged hepatic vein and transhepatic portal vein cannulation. Wedged hepatic vein pressure accurately reflected portal venous pressure both before and after clonidine (r = 0.912 and 0.940; p less than 0.01). In all the other ten patients, sympathetic tone, measured by total plasma noradrenaline spillover, was high (755 +/- 123 ng/min; normal 296 +/- 29 ng/min). It fell significantly after clonidine (378 +/- 95 ng/min; p less than 0.01). This fall was associated with a decrease in corrected wedged hepatic vein pressure (18.6 +/- 1.1 to 13.4 +/- 0.5 mm Hg; p less than 0.01) but no change in estimated hepatic blood flow (934 +/- 94 to 976 +/- 102 ml/min), indicating a fall in postsinusoidal hepatic vascular outflow resistance. Clonidine-induced changes in mean arterial pressure and cardiac output were independent of the change in portal venous pressure. The results suggest that in alcoholic cirrhosis there is a labile component of hepatic vascular resistance which is partly under sympathetic nervous control and is thus potentially sensitive to pharmacological control.
Adult↗
Mechanism of elevated plasma noradrenaline in the course of essential hypertension.
Increased sympathetic nervous system tone may be the initiating pathophysiologic event in some patients with essential hypertension. We estimated sympathetic nervous activity from radiotracer-derived measurements of noradrenaline release to plasma in 34 patients with essential hypertension and 23 subjects with normal blood pressure. The plasma concentration of noradrenaline (32% increased) and the rate of release of noradrenaline to plasma (38% increased) were elevated overall in patients with essential hypertension, largely due to higher noradrenaline release in hypertensive patients aged less than 40 years. Noradrenaline release from the kidneys and heart was elevated; renal noradrenaline spillover was 2.4 times normal in patients aged less than 40 years. Increased renal noradrenaline spillover accounted for 42% and increased cardiac noradrenaline spillover for 4% of the excess total noradrenaline spillover in essential hypertension, leaving 54% unexplained. Total noradrenaline spillover to plasma was normal in hypertensive patients aged 60 years and over. The plasma noradrenaline concentration was similar in younger and older hypertensive patients, despite lower noradrenaline release in the latter due to an age-dependent fall in noradrenaline plasma clearance in essential hypertension. Cardiorenal sympathetic nervous system tone appears to be increased in essential hypertension, particularly in younger patients. This contributes substantially to the higher plasma noradrenaline values found.
Adult↗
The effects of changes in physical activity on major cardiovascular risk factors, hemodynamics, sympathetic function, and glucose utilization in man: a controlled study of four levels of activity.
The effects of four levels of activity on heart rate, blood pressure, cardiac index, total peripheral resistance index (TPRI), norepinephrine (NE) spillover rate, insulin sensitivity, and levels of lipids and some hormones were studied in 12 normal subjects. The randomized periods were (1) 4 weeks of below-sedentary activity, (2) 4 weeks of sedentary activity, (3) 4 weeks of 40 min of bicycling three times per week, and (4) 4 weeks of similar bicycling seven times per week. Exercise three times per week reduced resting blood pressure by 10/7 mm Hg (p less than .01) and it was reduced by 12/7 mm Hg after exercise seven times per week (both p less than .01). This was associated with reduction in TPRI, an increase in cardiac index, and cardiac slowing. At the highest level of activity, NE spillover rate, an index of sympathetic activity, fell to 35% of the sedentary value (p less than .001) in eight of 10 subjects. In two other subjects NE spillover rate rose, although blood pressure and TPRI were reduced. Metabolic changes included lowering of total cholesterol, but high-density lipoprotein level was unchanged. Insulin sensitivity rose by 27% after exercise three times per week, but declined to sedentary levels with seven times per week exercise. Maximum oxygen uptake increased linearly with activity. Exercise performed three times per week lowers blood pressure and should reduce cardiovascular risk. The same exercise seven times per week enhances physical performance with little further reduction in cardiovascular risk factors. Exercise is potentially a major nonpharmacologic method of lowering blood pressure.
Adult↗
Total and renal sympathetic nervous system activity in alcoholic cirrhosis.
Basal sympathetic nervous system activity was assessed in 8 unmedicated patients with alcoholic cirrhosis using a previously developed radiotracer method for measuring total and renal noradrenaline release to, and clearance from, plasma. Compared to the control group total noradrenaline clearance was significantly increased in the patients with advanced alcoholic cirrhosis (Pugh grade C) [1.89 +/- 0.13 vs 1.51 +/- 0.11 l/min, P less than 0.05) indicating that endogenous plasma noradrenaline levels underestimate total sympathetic nervous system activity in these patients. Renal noradrenaline clearance was similar to controls independent of the severity of the liver disease. Both total and renal noradrenaline release were significantly increased in the patients with cirrhosis. The ratio of renal to total noradrenaline release was similar in cirrhotic (26 +/- 7%) and control (23 +/- 5%) groups. Increased arterial plasma adrenaline levels, indicative of adrenal medullary stimulation, were also evident in the patients with cirrhosis and correlated significantly with total noradrenaline spillover (r = 0.732, P less than 0.05). These results strongly suggest that in patients with cirrhosis, rather than a preferential increase in renal sympathetic tone, the increase is part of a pattern of generalized sympathoadrenomedullary activation. Although renal renin secretion was significantly increased in the cirrhotic group no correlation with renal noradrenaline release was seen (r = 0.199), raising the possibility that in cirrhosis renal sympathetic tone is not a major determinant of renal renin secretion. Finally, renal noradrenaline release did not correlate with renal blood or plasma flow but an influence of the sympathetic nervous system on renal function was suggested by the correlation observed between total noradrenaline spillover and impaired salt (r = -0.683, P less than 0.05) and water excretion (r = -0.702, P less than 0.05) demonstrated in the cirrhotic patients.
Adrenal Medulla↗
Plasma noradrenaline kinetics in humans.
Recently developed radiotracer methods for measuring the overall rate of release of noradrenaline to plasma, for the body as a whole, can be used to estimate 'total sympathetic nervous system activity' in humans. These techniques find application in clinical studies of sympathetic nervous physiology and pharmacology. The inherent weakness of any biochemical test of global sympathetic tone such as this lies in the fact that sympathetic nervous system responses typically show regional differentiation. Biochemical indices of overall sympathetic activity are insufficiently discriminating to delineate patterns of sympathetic nervous response, representing instead an algebraic sum of all regional increases or decreases in sympathetic tone. Modification of the whole-body radiotracer methodology enables organ-specific sympathetic nervous system activity to be estimated, from measurements of regional release of noradrenaline to plasma. This should facilitate investigation of possible sympathetic pathophysiology in disease states. Illustrative of potential application of the method are preliminary findings of increased renal sympathetic nervous tone in young patients with essential hypertension, and of selective activation of sympathetic nerves to the kidney by diuretics.
Humans↗
How can we measure sympathetic nervous system "tone" in patients?
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Autonomic Nervous System Diseases↗
Two patients with abnormalities of regional sympathetic nervous tone.
The traditional biochemical tests of sympathetic nervous system function used in clinical diagnosis (urine and plasma catecholamine measurements) are indices of "overall" sympathetic nervous activity, and incapable of detecting localised changes in sympathetic tone confined to individual organs. Recently developed radiotracer methods, which enable the pattern of sympathetic nervous dysfunction in disease states to be delineated, were used to detect abnormalities in regional sympathetic nervous system activity in two patients presenting problems in management. In one, the abnormality of sympathetic function was iatrogenic, a post-sympathectomy denervation of the lower regions of the body, associated with incapacitating postural hypotension. In the other, unexplained persistent sinus tachycardia proved to be due to an increase in sympathetic nervous tone restricted to the innervation of the heart. Knowledge of the underlying sympathetic nervous pathophysiology in these patients influenced the choice of drugs subsequently used in their treatment.
Dihydroergotamine↗
Measurement of total and organ-specific norepinephrine kinetics in humans.
A variety of biochemical tests, most notably measurement of the plasma concentration of norepinephrine, have been used to quantify overall sympathetic nervous system activity in humans. Plasma norepinephrine values provide a fallible index of sympathetic activity in that they are dependent in part on the rate of removal of norepinephrine from plasma. Measurement of the rate of release of norepinephrine to plasma is a better guide to overall sympathetic nervous tone because it avoids this confounding influence of norepinephrine plasma clearance. The overall norepinephrine spillover measurement, however, suffers from one major limitation: the sources of the released norepinephrine are not identified. Recently developed radiotracer techniques allow the estimation of regional sympathetic nervous activity from measurements of the organ-specific norepinephrine spillover rate. We find that the lungs are the main source of norepinephrine release to plasma, with mean pulmonary norepinephrine spillover of 159 ng/min constituting 40% of total norepinephrine release. Pulmonary norepinephrine release exceeded the combined norepinephrine spillover from the heart (3%), kidneys (17%), and hepatomesenteric circulation (8%).
Humans↗
Redevelopment of essential hypertension after cessation of long term therapy; preliminary findings.
We have previously found that the vascular hypertrophy that accounts for the maintenance of a substantial fraction of the elevation of the total peripheral resistance index (TPRI) in essential hypertension can be almost completely reversed by one years antihypertensive treatment (1). On ceasing treatment, blood pressure returns rapidly to pretreatment values suggesting that the original cause of the hypertension is still present. In the present study, 7 patients stopped a standard regimen for 10 weeks after at least 2 years of normotension. In the first week, standing and lying blood pressure increased related to rise in supine cardiac index and TPRI. Thereafter standing pressures, supine systolic blood pressure and cardiac index (CI) increased further, but supine diastolic blood pressure and TPRI did not alter. Changes in measurements of resting sympathetic activity, plasma volume or renin-angiotensin did not account for these observations. The return of hypertension after stopping effective therapy has some features previously described in borderline hypertension, particularly increasing systolic blood pressure, CI and postural blood pressure responses. Some of the changes may reflect the relative preponderance of cardiac and vascular amplifiers.
Blood Pressure↗
Total, and organ-specific, noradrenaline plasma kinetics in essential hypertension.
We have developed radiotracer techniques, based on measurement of the rate of spillover of noradrenaline to plasma, to simultaneously estimate total, and organ-specific, sympathetic nervous activity in humans. In 27 unmedicated subjects without renal or liver disease, or cardiac failure, regional noradrenaline spillover rates were as follows: lungs 33% of total noradrenaline release to plasma, kidneys 22%, skeletal muscle 20%, hepatomesenteric 9%, skin 5%, and heart 3%. These findings have relevance to numerous previous studies on the importance of the sympathetic nervous system in the pathogenesis of human essential hypertension. The indices of overall sympathetic nervous tone which have been used, such as measurements of plasma noradrenaline concentration or total NA release to plasma, are seen to be not sufficiently specific, since the organs and regions thought to be central to hypertension pathogenesis (kidney, heart, splanchnic circulation) are responsible for no more than 35% of all noradrenaline released to plasma. Organ-specific noradrenaline spillover measurements are better suited to the elucidation of any sympathetic nervous system pathophysiology in human hypertension. Early results point to an increase in renal sympathetic tone in young patients with essential hypertension.
Humans↗
Contribution of individual organs to total noradrenaline release in humans.
Plasma noradrenaline measurements are a fallible guide to sympathetic nervous tone, being dependent on noradrenaline plasma clearance. We have developed radiotracer techniques, based on measurement of the rate of spillover of noradrenaline to plasma, to simultaneously estimate total, and organ-specific, sympathetic nervous activity in humans. In 27 unmedicated subjects without renal or liver disease, or cardiac failure, regional noradrenaline spillover rates were as follows: lungs 138 +/- 36 ng/min (mean +/- SE) (33% of total noradrenaline spillover), kidneys 77 +/- 10 ng/min (22% of total), skeletal muscle 64 +/- 11 ng/min (20%), hepatomesenteric 29 +/- 9 ng/min (9%), skin 18 +/- 4 ng/min (5%), and heart 11 +/- 4 ng/min (3%). Organ-specific noradrenaline spillover measurements are well suited to the elucidation of sympathetic nervous system pathophysiology in human diseases. Since the sympathetic nervous system outflow to individual organs is not activated or suppressed uniformly in different disease states, biochemical measures of "overall sympathetic nervous activity" are insufficiently specific for this purpose.
Humans↗
The peripheral kinetics of norepinephrine in depressive illness.
Sympathetic nervous system function was studied in patients with primary depressive illness. Tritiated norepinephrine was used to measure the rate of entry to plasma of norepinephrine released from sympathetic nerves ("norepinephrine spillover rate"), and to assess the neuronal uptake of norepinephrine by studying the removal of norepinephrine from plasma. Norepinephrine spillover was elevated in five of 11 patients. This abnormality, which was unrelated to the presence of individual vegetative symptoms, occurred exclusively in patients with endogenous depression. The rapid-removal phase of the disappearance of tritiated norepinephrine from plasma, which seemed to correspond with neuronal uptake of norepinephrine, was accelerated in patients with depressive illness, providing presumptive evidence of increased neuronal uptake. If norepinephrine uptake is also accentuated within the brain, a functional deficiency of the transmitter at adrenergic receptor sites might result.
Adult↗
Noradrenaline turnover during under- and over-eating in normal weight subjects.
Adjustments to sympathetic nervous system activity may regulate constant body weight despite wide variations in energy intake. To test this six normal weight subjects were studied at three different energy intakes (low, weight maintaining and high). Noradrenaline turnover was measured on the tenth day of each diet. Both noradrenaline appearance rate and noradrenaline clearance increased significantly with increasing energy intake and were a more sensitive indices than the plasma noradrenaline concentrations which rose, but not significantly. Fasting triiodothyronine (T3) rose and reverse T3 fell with increasing energy intake, while thyroxine (T4) concentrations did not change. Systolic blood pressure also rose significantly. Underfeeding resulted in reductions in noradrenaline appearance and clearance rates and in the T3 level. These results demonstrate that sympathetic nervous system activity, as determined by noradrenaline turnover in plasma, varies in response to short-term changes in energy intake in normal weight subjects. These changes may partly explain why some individuals maintain body weight constant despite large differences in food intake. The present findings may also be relevant to the variability in susceptibility to become obese.
Adolescent↗
Assessment of sympathetic nervous function in humans from noradrenaline plasma kinetics.
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Humans↗
Impaired pancreatic polypeptide release to insulin hypoglycaemia in chronic autonomic failure with postural hypotension: evidence for parasympathetic dysfunction.
1. Release of pancreatic polypeptide (PP) is largely under vagal control and measurement of change in PP after insulin hypoglycaemia offers a non-invasive method of assessing vagal activity. 2. Changes in blood sugar and PP after intravenous insulin (0.2 unit/kg) were examined in six patients with idiopathic chronic autonomic failure (AF) and 12 control subjects. Six of the controls were studied before and after atropine treatment. 3. The PP levels in controls rose from 32 +/- 9 (mean +/- SEM) to 236 +/- 54 pmol/l after 45 min. Patients had similar baseline values (23 +/- 5 pmol/l) but a markedly reduced and delayed PP response to hypoglycaemia (49 +/- 19 pmol/l at 90 min). This impaired PP response was similar to that seen in controls after atropine. 4. The impaired PP response to insulin hypoglycaemia in patients with AF strongly suggests a dysfunction of vagal activity which is often clinically inapparent.
Aged↗
Biochemical quantification of sympathetic nervous activity in humans using radiotracer methodology: fallibility of plasma noradrenaline measurements.
We have developed radiotracer techniques for studying noradrenaline kinetics, to assess better sympathetic nervous system function in humans. Tritiated l-noradrenaline was infused intravenously (0.35 microCi/m2/min) to plateau plasma concentration. Noradrenaline plasma clearance was calculated from plasma tritiated noradrenaline concentration at steady state, and the rate of spillover of noradrenaline to plasma derived from plasma noradrenaline specific radioactivity. Mean noradrenaline spillover at rest in 34 normal subjects was 0.33 micrograms/m2/min (range 0.17-0.61 micrograms/m2/min). Predictably, noradrenaline spillover was reduced in patients with subnormal sympathetic nervous system activity, 0.16 +/- 0.09 micrograms/m2/min in eight patients with idiopathic peripheral autonomic insufficiency, and 0.11 +/- 0.07 micrograms/m2/min (mean +/- SD) in six patients with essential hypertension treated with clonidine (0.45 mg daily). Noradrenaline line plasma clearance in normal subjects was 1.32 +/- 0.28 L/m2/min. Clearance fell with age, causing the previously described rise in plasma noradrenaline concentration with aging. Unexpected effects of drugs were encountered, for example chronic beta-adrenergic blockade in patients with essential hypertension reduced noradrenaline clearance. Plasma noradrenaline concentration measurements were not in agreement with noradrenaline release rate values, and do not reliably indicate sympathetic nervous system activity, in instances such as these where noradrenaline clearance is abnormal.
Humans↗