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(Circulation. 1996;93:866-869.)
© 1996 American Heart Association, Inc.

Articles

Increased Activation of Sympathetic Nervous System and Endothelin by Mental Stress in Normotensive Offspring of Hypertensive Parents

Georg Noll, MD; René R. Wenzel, MD; Martin Schneider, MD; Valerie Oesch, MD; Christian Binggeli, MD; Sidney Shaw, PhD; Peter Weidmann, MD; Thomas F. Lüscher, MD

From Cardiology, Cardiovascular Research (G.N., R.R.W., V.O., C.B., T.F.L.), and Division of Hypertension (M.S., S.S., P.W.), University Hospital, Bern, Switzerland.

Correspondence to Georg Noll, MD, Cardiology, University Hospital/Inselspital, CH-3010 Bern, Switzerland.

	Abstract

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Background The pathogenesis of essential hypertension is still uncertain, but genetic factors and the sympathetic nervous system are likely to be involved. Sympathetic nerve activity and hormonal circulatory control mechanisms, however, are affected by blood pressure itself. Hence, early functional changes are best investigated in normotensive subjects at risk to develop hypertension, such as normotensive offspring of hypertensive parents.

Methods and Results Muscle sympathetic nerve activity (MSA) was measured in the peroneal nerve of 10 normotensive offspring of parents with essential hypertension and 8 offspring of normotensive parents. Measurements were performed under resting conditions, during a 10-minute period of hypoxia (12.5% O₂/87.5% N₂), and during a 3-minute mental stress test. The tests were separated by a 30-minute resting period. Plasma samples for determination of norepinephrine and endothelin were collected before and after the tests. Baseline values of MSA were comparable in offspring of hypertensive and normotensive parents. During hypoxia, MSA, heart rate, and norepinephrine and endothelin plasma levels increased in offspring of hypertensive and normotensive parents to a comparable degree, whereas no significant changes in blood pressure and plasma norepinephrine levels were observed in either group. During mental stress, MSA and plasma norepinephrine and endothelin increased only in offspring of hypertensive parents (P<.001 to .01). In parallel, blood pressure increased significantly only in offspring of hypertensive parents (P<.001 to .05), but heart rate increased in both groups (P<.001 to .05).

Conclusions The activity of the sympathetic nervous system and plasma norepinephrine and endothelin levels are increased during mental stress only in offspring of hypertensive parents, whereas the response to hypoxia was similar in offspring of hypertensive and normotensive parents, suggesting a genetically determined abnormal regulation of the sympathetic nervous system to certain stressful stimuli in offspring of hypertensive parents. This may play a role in the pathogenesis of essential hypertension.

Key Words: hypertension • nervous system • stress • hypoxia

	Introduction

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The pathogenesis of essential hypertension is still not fully understood. An increased activity of the sympathetic nervous system (SNS) at rest and during hypoxia has been proposed^{1 2 3} ; however, plasma norepinephrine levels showed inconsistent results.^{4 5} Several reasons may account for this discrepancy. First, plasma norepinephrine is a poor indicator of changes in SNS activity. Microneurography is more sensitive in detecting alterations in SNS activity. Furthermore, SNS activity is affected by blood pressure.⁶ Hence, in established hypertension, sympathetic outflow may be inhibited by the increase in blood pressure, thereby obscuring early functional changes. Endothelin is a potent vasoconstrictor that enhances norepinephrine-induced contractions⁷ and activates the SNS in experimental animals.⁸ In humans, the cold pressor test, which is a potent stimulus of muscle sympathetic nerve activity (MSA), increases plasma endothelin levels.⁹ Measurements of baseline plasma endothelin levels in patients with hypertension are inconclusive, and little is known about the activation of this pressor system under stress conditions.¹⁰ Because genetic factors are important in the pathogenesis of hypertension, normotensive offspring of hypertensive parents may be more suitable for assessing early dysfunction of cardiovascular regulation.¹¹ Such dysfunction may occur under baseline conditions or, more likely, during stress.^{12 13} Therefore, we studied peripheral MSA and plasma norepinephrine and endothelin under baseline conditions, during hypoxia, and during mental stress in normotensive offspring of hypertensive parents.

	Methods

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We used microneurography to measure MSA in 18 healthy Caucasian medical students.^{1 14} Ten of them had a genetic background, ie, one of their parents had a history of essential hypertension, and 8 were offspring of two normotensive parents. Informed consent was obtained from all subjects. The study was approved by the ethics committee of the University Hospital (Inselspital), Bern, Switzerland. The investigators performing the experiments were blinded to the history of the subjects. All subjects were studied in a randomized fashion under the same conditions, ie, in the morning (9 AM) after a light breakfast. After micturition to avoid any increase of sympathetic nerve activity through bladder distension,¹⁵ subjects were asked to resume a supine position. The left or right leg was fixed by a vacuum cushion, and ECG, blood pressure cuff, and respiration strain gauge were fixed. A catheter (Venflon, Ohmeda) was inserted into a cubital vein. Multifiber recordings of MSA were obtained from the peroneal nerve posterior to the fibular head with tungsten microelectrodes (200-µm shaft diameter; 1- to 5-µm uninsulated tip; University of Iowa).^{1 14} A reference electrode was inserted subcutaneously 1 to 2 cm from the recording electrode. Electrodes were connected to a preamplifier (gain, 1000) and amplifier (variable gain, 10 to 50). Neural activity was fed through a band-pass filter (bandwidth, 700 to 2000 Hz) and then a resistance-capacitance integrating network (time constant, 0.1 second) to obtain a mean voltage neurogram. The signal was displayed on an oscilloscope and registered on a thermocoupled printer at a paper speed of 5 mm/s (Graphtec Inc). Three criteria for acceptance of MSA recording were required: (1) electrical stimulation (0.1 to 1.0 V, 0.2 ms, 1 Hz) through the electrode in the peroneal nerve elicited involuntary muscle contractions in the peroneal nerve but no paresthesia; (2) tapping or stretching the innervated muscle region elicited afferent mechanoreceptor discharges, whereas stroking the skin did not; and (3) the neurogram revealed spontaneous, intermittent, pulse-synchronous sympathetic bursts that increased during apnea.^{1 16 17 18} Neurograms with cutaneous sympathetic activity or mixed cutaneous sympathetic activity and MSA were not accepted. This was assessed by the response to arousal stimuli that elicited single reflex bursts of cutaneous sympathetic activity but not MSA. If there was any evidence of a dislocation of the electrode position, the experiment was discarded from the study. The number of bursts was counted manually. MSA was expressed as bursts per minute. In addition, the analog signal was digitized by use of an analog-digital board (MIO-16L, National Instruments) and a program written in LabView (National Instruments) with a sampling rate of 500 Hz. Digitized data were used to assess the sum of the amplitude of bursts in the mean voltage neurogram. For that purpose, a program written in MatLab (MathWorks) was used. The results were expressed as cumulative volts per minute. Blood pressure was measured at 3-minute intervals with an oscillometric method (Dynamap, Critikon). After an equilibration period of 30 minutes, baseline values were registered over a period of 3 minutes; then subjects were exposed to hypoxia for 8 minutes. They were breathing a gas mixture of 12.5% O₂/87.5% N₂. Capillary PO₂ was measured in blood obtained from the subject's earlobe before and at the end of exposure to hypoxia with an automated gas analyzer (Radiometer ABL 505, IG Instrumenten Gesellschaft AG). After a resting period of 30 minutes, a mental stress test was performed by unexpectedly asking the subject to perform mental arithmetic consisting of continuous subtractions for 3 minutes. Venous blood samples were drawn from a venous cannula in the brachial vein before and immediately after (mental stress) or 25 minutes after (hypoxia) the end of the tests and stored at -70°C. Plasma norepinephrine was measured by high-performance liquid chromatography and plasma endothelin by radioimmunoassay.¹⁹ Ambulatory blood pressure measurements were performed for 10 to 12 hours at intervals of 30 minutes (CH-Druck Recorder, Disetronic Medical Systems). Data are mean±SEM. Paired and unpaired Student's t tests were used for statistical evaluation of intragroup and intergroup differences, respectively.

	Results

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Subject Characteristics
Age, waist-to-hip ratio, and body mass index were comparable in both groups (offspring of normotensive parents: 27±4 years, 0.80±0.01, and 21.8±0.6 kg/m²; offspring of hypertensive parents: 27±3 years, 0.84±0.01, and 22.4±0.6 kg/m²; P=NS). Ambulatory blood pressure averaged 125±4/81±3 mm Hg in offspring of normotensive parents and 126±3/85±2 mm Hg in offspring of hypertensive parents (P=NS). Heart rate was 75±2 and 72±3 beats per minute, respectively (P=NS).

Mental Stress Test
Under baseline conditions, MSA expressed as number of bursts per minute tended to be lower in offspring of hypertensive compared with offspring of normotensive parents (19.0±2.8 versus 25.9±3.9 bursts per minute; P=NS; Figs 1 and 2). Similar results were obtained expressing MSA as the sum of burst amplitude per minute (offspring of normotensive parents, 54±20 V/min; offspring of hypertensive parents, 24±6 V/min; Fig 2). During mental stress, a significant increase in MSA was observed in offspring of hypertensive parents, whereas in offspring of normotensive parents, MSA remained unchanged (Figs 1 and 2). In parallel, plasma norepinephrine, which was lower in offspring of hypertensives under baseline conditions (Table 1), increased during mental stress only in offspring of hypertensives (Table 1). Similarly, endothelin levels were comparable under resting conditions in offspring of normotensive and hypertensive parents but increased significantly during mental stress only in offspring of hypertensive parents (Table 1). There was a significant increase in systolic and diastolic blood pressures during mental stress in offspring of hypertensive parents only (Table 1), whereas heart rate increased to a comparable degree in both groups (Table 1).

View larger version (18K): [in this window] [in a new window]   Figure 1. Original recordings of muscle sympathetic activity (MSA) in an offspring of normotensive parents (L.B.; left) and an offspring of a hypertensive parent (R.R.; right) at rest and during mental arithmetic (mental stress). BP indicates blood pressure; HR, heart rate; and bpm, beats per minute.

View larger version (17K): [in this window] [in a new window]   Figure 2. Muscle sympathetic activity in the peroneal nerve at rest and during mental stress expressed as bursts per minute (A) and cumulative amplitude of bursts (volts per minute) (B) in offspring of normotensive () and hypertensive () parents. Data are mean±SEM.

View this table: [in this window] [in a new window]   Table 1. Blood Pressure, Heart Rate, Plasma Norepinephrine, and Endothelin-1 During MS in Offspring of Hypertensive and Normotensive Parents

Hypoxia
Resting MSA was slightly but not significantly higher in offspring of normotensive compared with offspring of hypertensive parents before exposure to the hypoxic gas mixture (offspring of normotensives: 18.6±2.4 bursts per minute, 35±17 V/min; offspring of hypertensives: 23.5±3.5 bursts per minute, 20±7 V/min; P=NS; Fig 3). During hypoxia, capillary PO₂ decreased in both groups to the same extent (Table 2), whereas MSA increased significantly in both groups (offspring of normotensives: 29.4±4.1 bursts per minute, 54±21 V/min; offspring of hypertensives: 22.3±2.6 bursts per minute, 31±10 V/min, P<.05). Blood pressure and heart rate did not change during hypoxia (Table 2). There was a slight but statistically insignificant increase in plasma norepinephrine levels during hypoxia (Table 2). Endothelin-1 plasma levels increased significantly in both groups to the same extent after exposure to the hypoxic gas (Table 2).

View larger version (17K): [in this window] [in a new window]   Figure 3. Muscle sympathetic activity in the peroneal nerve before and during hypoxia expressed as bursts per minute (A) and cumulative amplitude of bursts (volts per minute) (B) in offspring of normotensive () and hypertensive () parents. Data are mean±SEM.

View this table: [in this window] [in a new window]   Table 2. Blood Pressure, Heart Rate, Capillary PO2, and Plasma Norepinephrine and Endothelin-1 During Hypoxia in Offspring of Hypertensive and Normotensive Parents

	Discussion

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This study demonstrates for the first time that in normotensive offspring of hypertensive parents compared with offspring of normotensive parents, SNS activity and plasma endothelin increased to a greater extent from respective baseline levels in response to mental stress, whereas the response to hypoxia was similar in the two groups. The groups were comparable with respect to age, blood pressure, waist-to-hip ratio, and body mass index. Hence, common confounding factors that may affect SNS activity and plasma endothelin levels were excluded. The fact that the offspring of hypertensive parents were still normotensive indicates that the observed changes in cardiovascular responsiveness occur at an early stage, are probably of genetic origin, and could play a role in the pathogenesis of hypertension. Indeed, a hyperreactivity of the SNS has long been suspected in the development of hypertension, but most studies have yielded inconsistent results.⁴ In addition to methodological problems, it is likely that the activity of the SNS changes during the natural history of high blood pressure. On the basis of our results and those of the literature, it is likely that in normotensive individuals with a genetic background for hypertension, MSA is increased only in response to factors such as stress, becomes increased even under unstimulated conditions in borderline hypertension,¹ and eventually returns to normal levels in established hypertension.^{2 14} It has been demonstrated previously that offspring of normotensive parents react to psychological stress with a slightly greater pressure response than offspring of normotensive parents.^{12 20 21 22 23 24} Differences in cardiovascular reactivity were more pronounced during active stressors such as mental arithmetic or stressful interview^{12 21 22 23 24} than during passive stressors such as the cold pressor test or watching a stressful film.^{21 24 25 26 27 28 29 30} Our results are in line with these observations and demonstrate that a hyperreactivity of the SNS to mental stress is a likely mediator. Since the response of the SNS and hemodynamics to hypoxia did not differ between normotensive and hypertensive offspring, the abnormal reactivity of the latter group to mental stress must represent a rather specific abnormality.

Endothelin is a locally released vascular regulator that at very low concentrations enhances contractions to norepinephrine and at higher concentrations has potent direct vasoconstrictor properties.⁷ In experimental animals, endothelin stimulates sympathetic outflow.⁸ Hence, alterations in the local release of endothelin could alter the activity and vascular effects of the SNS. In human hypertension, normal and increased plasma levels have been reported under baseline conditions.¹⁰ Endothelin levels during stimulation of the cardiovascular system have not been reported in hypertensive individuals, although hypoxia and exercise increase endothelin plasma levels in normal subjects.¹⁹ In our study, we observed an increase in plasma endothelin-1 levels during exposure to hypoxic gas mixture, in line with a previous observation during hypoxia at high altitude.¹⁹ These changes of plasma endothelin to hypoxia were not influenced by the genetic background for essential hypertension. Since blood pressure did not change in either normotensive or hypertensive offspring but pulmonary pressure does, as demonstrated in a previous study,¹⁹ the hypoxia-induced increase in endothelin appears to be important for the regulation of the pulmonary but not the systemic circulation. In contrast, mental stress caused a parallel increase in endothelin and MSA as well as blood pressure in offspring of hypertensive but not in those of normotensive parents, suggesting that it might contribute to this abnormal circulatory response to mental stress. These early functional changes of central and local cardiovascular regulation may be important in the pathogenesis of essential hypertension.

	Acknowledgments

 
This study was supported by grants from the Swiss National Research Foundation (No. 32-042 560.94 and SCORE No. 32-35591.92) and the German Research Association (DFG No. WE 1772/1-1).

Received October 30, 1995; revision received December 28, 1995; accepted January 2, 1996.

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