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SUMMARY To assess sympathetic nervous system function in essential hypertension, we measured tbe rates of release to and removal from plasma of the sympathetic neurorransmltter, norepinephrine. In normal subjects, disappearance of tritiated /-norepinephrlne from plasma, after infusion to steady state, was biexponential, with t,V4 = 2.0 ± 0.4 minutes (mean ± standard deviation) and t,Vi = 33 ± 15 minutes. Tbe rapid component of removal seemed to represent neuronal uptake of norepinephrine: the t, W was lengthened by the selective inhibitor of neuronal norepinephrine uptake, desipramine; it was not changed by the extraneuronal uptake blocker, cortlsol; and it was prolonged in patients with peripheral sympathetic nerve dysfunction (idiopathic autonoroic insufficiency). In eight of 37 hypertensive patients, tbe t,V4 was > 2.8 minutes (range, 3.3-6.0 min), longer than in any normal subject; this appears to be presumptive evidence of the existence of defective neuronal norepinephrine uptake. In these patients tbe rate of spillover of norepinephrine to plasma, of transmitter escaping uptake after release, was 0. 8 -* suggests that sympathetic nervous overactivity is involved in the pathogenesis of the blood pressure (BP) elevation. But the plasma concentration of norepinephrine provides a very indirect measure of sympathetic nerve discharge rate. Only a small proportion of the norepinephrine released escapes to plasma; most is subject to local reuptake by the sympathetic nerves.' 1 * Furthermore, the plasma concentration of norepinephrine is determined not only by the rate of spillover to plasma after release, but also by the subsequent rate of removal of norepinephrine from the circulation.' We have developed methods for studying the kinetics of norepinephrine in humans. 9 The rates of spillover of norepinephrine to plasma and clearance of norepinephrine from plasma are determined using radiotracer techniques. With these methods, the rate of norepinephrine spillover to plasma in patients with peripheral autonomic insufficiency has been found to be significantly decreased,' 110 indicating that the norepinephrine spillover rate provides at least qualitative information about net sympathetic nerve activity. In the evaluation of possibly increased norepinephrine spillover in patients with essential hypertension, it seemed important to differentiate between a true increase in norepinephrine release (with increased sympathetic nerve firing rates) and increased spillover from defective local inactivation of transmitter (neuronal reuptake). To this end, a method based on the analysis of tritiated norepinephrine postinfusion decay curves has been developed for assessing neuronal uptake of norepinephrine in humans.We have applied these measures of norepinephrine kinetics to the study of sympathetic nervous system 149 by guest on May 13, 2018 http://hyper.ahajournals.org/ Downloaded from

1. The influence of age on the rate of spillover of noradrenaline into plasma, clearance of noradrenaline from plasma, and plasma noradrenaline concentration at rest was studied in 34 healthy subjects aged 20--69 years. 2. The plasma concentration of noradrenaline was dependent on age, values being higher in older subjects. 3. This age-dependence of plasma noradrenaline concentration was due principally to a reduced clearance of noradrenaline from the circulation in older subjects. 4. The rate of spillover of noradrenaline into plasma was little influenced by age. The higher plasma noradrenaline values found in older subjects do not seem to be due to an increase in sympathetic nervous system tone with aging.

We studied the effect of a single oral dose of the neuronal norepinephrine uptake blocker, desipramine 125 mg, on norepinephrine kinetics. Desipramine reduced the plasma norepinephrine clearance by approximately 20%, from 1.33 +/- 0.22 to 1.08 +/- 0.19 l/m2/min (p less than 0.01). Similarly, plasma norepinephrine clearance was slowed in patients with sympathetic nerves damaged by disease (idiopathic peripheral autonomic insufficiency). Desipramine also reduced the rate of spillover of norepinephrine to plasma, 0.27 +/- 0.07 to 0.15 +/- 0.04 micrograms/m2/min, leaving the plasma norepinephrine concentration unchanged. Disappearance of tritiated norepinephrine from plasma, after infusion to steady state, was biexponential, with half-time of the rapid-removal phase (t1 1/2) = 2.0 +/- 0.4 min and half-time of the second exponential (t2 1/2) = 34 +/- 10 min. The rapid-removal phase was sensitive to disturbances in the neuronal uptake of norepinephrine, the t1 1/2 being prolonged by desipramine and lengthened in the patients with peripheral autonomic insufficiency. In contrast, the selective extraneuronal norepinephrine uptake blocker, cortisol, 500 mg intravenously, had no effect in normal subjects on either plasma norepinephrine clearance or the t1 1/2 value. Neuronal uptake of norepinephrine contributes to the overall removal of norepinephrine from plasma. Extraneuronal uptake of norepinephrine could not be demonstrated at existing plasma norepinephrine concentrations.

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1. Measurement of blood pressure and heart rate over a 24 h period was performed in 10 quadriplegic spinal cord injury patients and 10 immobilized, neurologically intact orthopaedic subjects by using the Spacelabs 90207 automated ambulatory monitoring system. 2. Systolic and diastolic blood pressure fell significantly at night in orthopaedic subjects but not in quadriplegic patients, and night-time blood pressures were similar in both groups. 3. Cumulative summation of differences from a reference value (cusum analysis) confirmed a markedly diminished diurnal blood pressure variation in the quadriplegic patients. 4. These findings could not be accounted for on the basis of blood pressure variations during chronic postural change. 5. Heart rate fell significantly at night in both groups. 6. The findings suggest that the increase in blood pressure during waking hours in neurologically intact subjects is a consequence of a diurnal variation in sympathetic activity (absent in quadriplegic patients with sympathetic decentralization) which is independent of changes in physical activity.

1 The rates of noradrenaline spillover to, and removal from, plasma were measured in ten patients with essential hypertension treated with propranolol, to ascertain if long-term administration of this drug reduces sympathetic nervous system tone. 2 The plasma clearance of noradrenaline fell with propranolol, leading to a small rise in the mean plasma noradrenaline concentration. Sympathetic nervous activity in treated patients cannot be reliably gauged from plasma noradrenaline values because these are distorted by the reduction in noradrenaline clearance. 3 There was no consistent effect on noradrenaline spillover rates, which fell in six patients, but rose in the remaining four. The magnitude of the antihypertensive response was unrelated to these changes in noradrenaline release. During propranolol treatment, noradrenaline spillover rates were in every case within the normal range, much higher than in patients treated with the known sympathetic nervous systems suppressant, clonidine. 4 The principal mode of antihypertensive action of propranolol is something other than central suppression of sympathetic tone or pre-synaptic inhibition of noradrenaline release.