Effects of ethanol on cardiovascular and catecholamine responses to mental stress

Journal oj Psychosomoric Printed in Great Britain.

Research.

Vol.

30,

No.

1, pp.

93-102,

1986

0022-3339186 $3.00+ 0.00 0 Pergamon Press Ltd. 1986

EFFECTS OF ETHANOL ON CARDIOVASCULAR AND CATECHOLAMINE RESPONSES TO MENTAL STRESS GRAEME EISENHOFER, DAVID G. LAMBIE and RALPH H. JOHNSON (Received 12 March 1985; accepted in revised form 6 June 1985) Abstract-The purpose of this study was to examine the effects of ethanol on heart rate, blood pressure and plasma noradrenaline and adrenaline responses to mental stress, involving reactions to anxiety and excitement produced using a cognitive task with electric shock and a competitive electronic game respectively. Twenty subjects were studied, each subject acting as his own control by participating twice, with and without prior ethanol consumption. Mental stress was associated with significant increases in all variables except plasma noradrenaline during the cognitive task. Ethanol raised baseline heart rate and plasma adrenaline, but significantly reduced the responses of these variables to the cognitive task but not to the electronic game. Systolic blood pressure responses to both experimental stressors and diastolic blood pressure responses to the electronic game were also significantly reduced after ethanol. These results may reflect a tension-reducing effect of ethanol in situations associated with anxiety, but suggest a more general effect of ethanol on blood pressure reactivity.

INTRODUCTION THE TENSION-REDUCING effect of ethanol has been proposed as an important motivating influence for consumption of ethanol and development of alcoholism ill. Despite a large number of studies attempting to confirm this, the resulting experimental evidence has been conflicting, and whether ethanol actually does reduce tension, or the effects of mental stress, is still open to question [2]. This may be due to the difficulty of relating objective physiological and biochemical measurements to subjective states of anxiety and tension, and is confounded by findings that many biochemical and physiological variables are altered by ethanol consumption in a direction opposite to that normally associated with lowered states of tension and anxiety. For instance, plasma catecholamines and heart rate are raised during mental stress [3] and also following ethanol consumption [4, 51. Experimental support for the tension-reducing effect of ethanol has been more consistent when the effects of ethanol on physiological responses to anxiety provoking situations have been examined. These have included findings of reduced galvanic skin responses [6], heart rate responses [7, 81 and systolic blood pressure responses [9] to mental stress after ethanol. Apart from one study showing that ethanol reduced urinary excretion of noradrenaline in response to glider flying [lo] little evidence has been documented for an effect of ethanol on catecholamine responses to mental stress in man. In the present study we have used a cognitive task with electric shock and an electronic game to elicit anxiety and excitement reactions respectively. Plasma catecholamines, heart rate, blood pressure and subjective variables were measured before and during the experimental stressors, with subjects acting as their own controls by participating on two separate occasions, with and without prior ethanol consumption in random order. Wellington Clinical School of Medicine, Wellington Hospital, Wellington 2, New Zealand. Address for Correspondence: Dr Graeme Eisenhofer, Neuroimmunology Branch, National Institute of Neurological and Communicative Disorders & Stroke, Building 10, Room 5N214, 9000 Rockville Pike, National Institutes of Health, Bethesda, Maryland 20205, U.S.A. 93

94

GRAEME

EISENHOFER el al.

METHODS Subjects Twenty normotensive men aged 21 to 33 yr (mean 24.5 yr) and weighing between 61 and 80 kg (mean 70.3 kg) participated. All subjects had prior experience with consumption of ethanol and at the time of study admitted to drinking a mean (? SD) of 1.10 ? 0.60 ml/kg ethanol on average at social engagements as assessed from drinking history questionnaires. Subjects were fully informed of the nature of the study, which they were told involved examination of physiological reactivity to stress and the effects of ethanol. They were informed that they would be studied on two occasions, once with ethanol consumption and once without ethanol consumption. No attempt was made to administer a placebo during control studies. The study was approved by the Wellington Hospital Ethical Committee. Mental stress Two methods of inducing mental stress in subjects were used, one involving a cognitive task with electric shock and the other a competitive electronic game. The cognitive task involved solving one of two sets of 25 problems requiring visuo-spatial ability, presented consecutively to subjects over a 9 min period using a slide projector. Subjects were given a maximum of 30 set to a minimum of 15 set to solve each problem, with decreasing time as the test progressed. Subjects were signalled to verbally answer problems, at the end of each time period, by a 5 set countdown together with an increase in the frequency of a metronome played to subjects through headphones using a pre-recorded tape. As an incentive to effort, subjects were warned that failure to answer questions correctly would result in an electric shock. In reality all subjects received 3 shocks (30 V, 0.25 msec pulse width at a frequency of 100 Hz), delivered to the lower left leg using a battery powered constant voltage nerve impulse stimulator (Bio-Electronics Manufacturing Co.) The output of this device was adjustable between 0 and 5 mA, and for each individual a setting was chosen just above the sensory threshold. The electronic game involved television soccer (Sportronic Television Ltd) played against an expert opponent who was a collaborator with instructions to ensure that each game was a close contest. All subjects were allowed to become familiar with the game before testing and were told that they would be playing against an experienced opponent, but that the volunteer with the highest total score would win a monetary prize. Three consecutive games were played, each lasting for between 2 and 4 min. Procedure Investigations began between 1200 and 1400 hr, after subjects had abstained from coffee, tea, food and cigarettes for 3 hr and from ethanol for 24 hr. Subjects acted as their own controls by participating in investigations twice, once after consumption of ethanol (I ml/kg, 20% in orange juice) and once after an equivalent volume of orange juice. The order of investigations was randomised, with equal numbers of subjects drinking ethanol or orange juice in first and second studies, which were carried out within 1-8 weeks of each other. Before drinking, a venous cannula was inserted into the nondominant arm and connected to a manometer line to avoid disturbance to subjects during subsequent blood sampling. Subjects were given the ethanol or orange juice to drink over 15 min. A light standard lunch was also provided during this period to prevent the occurrence of hypoglycaemic reactions which could complicate interpretation of results. Subjects then sat quietly listening to music over 30 min. after which five baseline blood pressure and heart rate determinations were made and two heparinised 5 ml blood samples were collected. After baseline sampling, subjects were given tape-recorded instructions concerning the cognitive task. Three blood samples were collected at 3 min intervals and heart rate and blood pressure were determined at 1 min intervals during the cognitive task. A further five blood pressure and heart rate determinations were made at 1 min intervals following completion of the task. There followed a period of quiet rest for 25 min, after which two baseline blood samples were obtained and five blood pressure and heart rate determinations were recorded. During each of the three consecutive electronic soccer games that subjects played, two blood pressure and heart rate determinations were made and one blood sample was taken. Five further blood pressure and heart rate determinations were made at 1 min intervals after completion of games. For 10 of the 20 subjects the cognitive task and electronic games were carried out in reversed order to counterbalance time-order effects. Selfreporfs Self reports were obtained at the end of all baseline and mental stress periods using 10 point scales to express the subjective states of anxiety and excitement. The words ‘very relaxed’ and ‘very anxious and tense’ were used to describe ends of the anxiety scale, while the words ‘very calm’ and ‘very excited’ were used to describe the excitement scale. Bela-adrenoceptor responsiveness Responsiveness to beta-adrenoceptor stimulation was determined using bolus injections sulphate (ISUPREL, Winthrop Laboratories) and construction of dose response curves

of isoprenaline [I I]. Seventeen

Ethanol

and stress responses

95

of the 20 subjects were studied after completion of stress tests, with and without prior ethanol consumption. Beta-adrenoceptor responsiveness was defined as the dose of isoprenaline required to raise heart rate by 25 beats/min, and expressed as ng isoprenaline per kg body weight.

Analytical methods Blood samples were collected on ice and plasma was separated and stored frozen at -70°C before assay for catecholamines using a radioenzymatic assay [12]. The inter-assay coefficients of variation for this assay were 10.3% for noradrenaline and 13.6% for adrenaline while the intra-assay coefficients of variation were 6.4% and 7.6% for noradrenaline and adrenaline respectively. The sensitivity of the assay was 0.09 nmol noradrenaline and 0.06 nmol adrenaline measurable per ml of plasma. To minimise error, samples from each subject for control studies and studies after ethanol, were assayed together. Heart rate was determined using a Mingograf 62 electrocardiogram (Seimens-Elema) and blood pressure was determined using an automatic sphygmomanometer with built-in microphone (Nissei model DS 102). The average variability of four consecutive measurements, made in each of six subjects using the automatic sphygmomanometer, was ? 1.5% and + 3.2% for systolic and diastolic blood pressures respectively. A comparison of the automatic sphygmomanometer with a standard mercury sphygmomanometer indicated an average random variation in measurements between the two instruments of + 3.2% and 2 1.9% for systolic and diastolic blood pressures respectively.

Statistical methods For purposes of data analysis, cardiovascular and biochemical variables were meaned during baseline and stress conditions for each subject. Two way analysis of variance was used to examine the effects of ethanol on cardiovascular, biochemical and subjective variables, with the second factor being prior participation in the study. The significance of changes in variables from baseline to stress conditions was assessed using Wilcoxon’s signed rank-sum test for related variables. Relationships were analysed by linear regression analysis and correlations are shown using Pearson’s correlation coefficient(r). The significance of relationships was checked by nonparametric analysis using Spearman’s correlation coefficient.

RESULTS

Heart rate and bloodpressure responses Mental stress, due to either the cognitive task or competitive electronic games, caused significant @ < 0.01) increases in heart rate and systolic and diastolic blood pressures (Table I). Ethanol consumption was associated with significantly higher baseline heart rates before the cognitive task (F= 12.2, p < 0.005) and electronic games (F= 24.0, p < O.OOl), and resulted in significantly reduced heart rate responses to the cognitive task (F=6.4, p < 0.02) but not to the electronic games. Ethanol consumption was also associated with significantly lower systolic blood pressures during the cognitive task (F= 5.7, p < 0.05) and electronic games (F= 11.5, p < O.OOS),and resulted in reduced systolic blood pressure responses to the cognitive task (F= 8.0, p < 0.01) and electronic games (F= 11.9, p < 0.005). Diastolic blood pressure, apart from showing a reduced response to the electronic games (F= 5.7, p < O.OS), was largely unaffected by ethanol consumption.

Plasma catecholamine responses Mental stress due to the electronic games, but not the cognitive task, resulted in significant increases in plasma noradrenaline of 11% without ethanol consumption @ < 0.01) and 17% with ethanol consumption @ < 0.005). Ethanol consumption resulted in significantly higher plasma noradrenaline concentrations during the cognitive task (F= 5.8, p < 0.05). The cognitive task resulted in significant increases in plasma adrenaline of 52% without prior ethanol consumption (p < O.OOl), and 19% with ethanol consumption @ < 0.05). During the electronic games, plasma adrenaline increased significantly by 78% without ethanol 0, < 0.001) and 48% with

I.--HEART

PRESSCRE

variables

0.05, j-p < 0.01: denotes

All cardiovascular

*p <

TO

task

67 -’ 8 665 14

129 +- 17’ 122 -+ 23’

81* 15 84-+ 12

Stress

Cognitive

RESPOVSES

!5

STRESS

8t6 657

17 t 1tt 9+ 12+

14 rt_ 11’ 10 ? 6’

MENTAL

WTH

WITHOC~

59 i: 9 60~ 13

112 t 10 Ill lt9

68 t 9T 14 i- St_

Baseline

ASD

Stress

742 ?O*

condirions

11 15

140 i- 1st 133 2 221

91 + 16 94i 17

_~~__

games

(‘ONSL%PTIOS

Electronic

PRIOR

significant differences between ethanol and no ethanol groups. were significantly (p < 0.01) higher during stress compared with baseline

59 2 9 602 11

Diastolic blood pressure (mmHg) No ethanol Ethanol

All values are means 2

112 t 11 113 % 14

Systolic blood pressure (mmHg) No ethanol Ethanol

Baseline

BLOOD

SD.

AND

67 f IO+ 74 t 9j-

RATE

Heart rate (beatsjmin) No ethanol Ethanol

Variables

TABLE

14 14

I5 * 6* 102 9*

28 ‘- 14-t 22 * 1st

23~ 20*

h

OF ETHANOL

significant significant

0.23 + O.lOt 0.32 + 0.12t

Plasma adrenaline (nmol/l) No ethanol Ethanol

All values are means ? SD. *p < 0.05, I_I< 0.01; denotes $y < 0.05; Bp < 0.01; denotes

2.22 + 0.96 2.58 -e 1.04

Baseline

No ethanol Ethanol

Plasma noradrenaline (nmol/l)

Variables

0.12 k 0.11* 0.06 k O.ll*

0.07 -c 0.46 0.14 f 0.76

b

groups.

0.23 2 O.lO* 0.29 + 0.14;

2.17 2 0.77 2.36 f 0.96

Baseline

differences between ethanol and no ethanol increase above baseline values.

0.36 f 0.185 0.38 f O.ll$

2.29 + 0.71; 2.73 rt 1.12*

Stress

Cognitive task

0.41 f 0.21§ 0.43 k 0.169

2.40 f 0.57§ 2.77 f l.OO§

Stress

Electronic games

0.18 k 0.16 0.14 + 0.16

0.23 2 0.41 0.41 k 0.43

A

TABLE II.-PLASMA CATECHOLAMINE RESPONSES TO MENTALSTRESSWITH AND WITHOUTPRIORCONSUMPTION OF ETHANOL

GRAEME EISENHOFER et al.

98

ethanol 0) < 0.005). Ethanol consumption was associated with significantly higher baseline plasma adrenaline concentrations before the cognitive task (F= 15.3, p < 0.001) and electronic games (F= 4.4, p < 0.05). Plasma adrenaline responses to the cognitive task, but not to the electronic games, were significantly reduced by ethanol consumption (F=4.2, p < 0.05). Reduced adrenaline responses to the cognitive task after ethanol were not associated with any differences in subjects’ abilities to cope with the cognitive task, as reflected by the number of correct answers. During control studies subjects got a mean (-t SD) of 7.8 * 4.8 correct answers while in studies after ethanol subjects got 7.6 2 3.4 correct answers.

Self reports Ethanol consumption resulted in significantly lower self-reported anxiety before (F= 8.2, p < 0.01) and during (F= 12.3, p < 0.005) the cognitive task and before (F=6.6, p < 0.02) and during (F=4.5, p < 0.05) the electronic games (Table III). During the cognitive task, but not the electronic games, ethanol consumption was also associated with significantly lower self-reported excitement (F= 14.3, p < 0.002) and excitement responses (F= 17.1, p < 0.001). Compared with electronic games, the cognitive task was associated with significantly greater increases in self-reported anxiety relative to increases in excitement, both with @ < 0.001) and without QJ < 0.01) ethanol.

Beta-adrenoceptor

responsiveness

Responsiveness to beta-adrenoceptor stimulation was not altered by ethanol consumption. During control investigations the mean (+ SD) dose of isoprenaline required to raise heart rate by 25 beats/min was 25.4 2 21 .O ng/kg bodyweight while after ethanol it was 29.0 f 17.8 ng/kg.

Relationships between plasma catecholamines and cardiovascular variables with and without ethanol Plasma adrenaline showed positive relationships with heart rate during baseline and stress conditions for both the cognitive task and electronic games, and these relationships were significant during studies without ethanol (Table IV). Heart rate responses were also positively related to adrenaline responses and these relationships were significant during electronic games with and without ethanol. The ethanolinduced reduction of the heart rate response to the cognitive task was significantly related (r=0.59, p < 0.025) to the corresponding reduction of the adrenaline response. Systolic blood pressure responses showed significant positive relationships with heart rate responses to both the cognitive task and electronic games during control studies and to the electronic games during studies after ethanol (Table IV). The ethanol-induced reduction of the systolic blood pressure response to the cognitive task was significantly related (r=0.67, p < 0.001) to the corresponding reduction of the heart rate response. The systolic blood pressure response to the electronic games showed a significant positive relationship (r = 0.55, p < 0.05) to the corresponding increase in noradrenaline during control studies.

4.1 f 1.1 4.2 * 1.1

All values are means ? SD. *p < 0.05, tp < 0.01; denotes significant All subjective measures were significantly

(l-10)

Calm-excited No ethanol Ethanol

Baseline

3.7 + 1.1+ 2.9 f l.Ot

(l-10)

measure

task

2.7 2 1.4+ 1.5 t l.lT

3.3 + 1.3 3.0 + 1.5

B

STRESSWITH AND

4.7 * 1.3 4.1 + 1.5

4.1 + 1.4* 3.2 f 1.2*

Baseline

games

7.6 f 0.8 6.9 + 1.0

6.7 f 0.9; 6.0 2 1.2:

Stress

Electronic

2.9 2 1.4 2.7 + 1.6

2.6 f 1.3 2.8 2 1.1

B

WITHOUT PRIOR CONSUMPTIONOF ETHANOI

differences between ethanol and no ethanol groups. @ < 0.001) higher during stress compared with baseline conditions.

6.8 + l.lT 5.7 + 1.21

7.0 + 1.1-i5.9 + 1.3+

Stress

Cognitive

REPORTED AROUSALDURING MENTAL

Relaxed-anxious No ethanol Ethanol

Subjective

TABLE III.-SELF

100

GRAEME EISENHOFER et al.

TABLE IV.-PEARSONS'CORRELATION COEFFICIENTSFOR RELATIONSHIPS,BETWEEN PLASMA ADRENALINE, HEART RATE AND SYSTOLIC BLOOD PRESSURE WITH AND WITHOUT PRIOR CONSUMPTION OF ETHANOL Cognitive task Baseline Stress A

Variables Adrenaline No ethanol Ethanol

and heart

rate

Heart rate and systolic blood pressure No ethanol Ethanol *p < 0.05,

Electronic games Baseline Stress A

tp < 0.01, $‘p < 0.001;

0.61t 0.33

0.67t 0.33

0.69 0.08

-0.20 0.18

0.48 0.43

0.86$ 0.37

significance

0.42* 0.29

~ 0.02 0.21

0.5510.45

0.47* 0.60t

0.59* 0.73$

0.69-t 0.82$

of relationships.

DISCUSSION

Consumption of ethanol significantly reduced the adrenaline response to the cognitive task, but not to the electronic games, and this was associated with reduced excitement responses to the cognitive task only. The divergence in the effects of ethanol on responses to the cognitive task and electronic games may have resulted from differences in the subjective reactions induced by the two experimental stressors, the cognitive task inducing greater anxiety relative to excitement responses than the electronic games. Ethanol is considered to be effective in reducing anxiety [B, 131, which is consistent with the lower anxiety reported by subjects after ethanol in the present study. This effect may have resulted in the reduced adrenaline response to the cognitive task but not to the electronic games. Alternatively, ethanol reduced the plasma adrenaline response without affecting adrenaline concentrations during the experimental stressors, and it is possible that the reduced response may have been secondary to raised baseline concentrations of adrenaline after ethanol. Ethanol consumption also reduced the heart rate response to the cognitive task, but not to the electronic games, and this is in line with other findings of reduced heart rate responses to anxiety-provoking situations after ethanol [7, 81. Heart rate responses to mental stress are dependent on the responsiveness of cardiac betaadrenoceptors, and increased sympathetic nervous activity which is most accurately reflected during mental stress by the plasma adrenaline response [ 31. This is consistent with the significant relationships found between plasma adrenaline and heart rate in the present study. The lack of effect of ethanol on heart rate responsiveness to beta-adrenoceptor stimulation indicates that the effect of ethanol on heart rate responses to the cognitive task was not secondary to an action of ethanol on adrenoceptor responsiveness. The significant relationship between ethanol-induced reductions in heart rate responses and adrenaline responses suggests that the reduced heart rate response to the cognitive task after ethanol was secondary to attenuated sympathetic nervous activation of the heart. Reduced systolic blood pressure responses to both experimental stressors and diastolic blood pressure responses to the electronic games occurred independently of any action of ethanol on baseline blood pressure. Blood pressure responses to mental stress have been shown to result from an increase in cardiac output and a change in peripheral resistance, the latter dependent on the balance between vasoconstrictor and vasodilator responses [14, 151. The relationship between ethanolinduced depression of the heart rate and systolic blood pressure responses to the

Ethanol

and stress respones

101

cognitive task suggests that an effect of ethanol on cardiac responses may have contributed to the attenuated systolic blood pressure response after ethanol. However, during the electronic games both systolic and diastolic blood pressure responses were reduced by ethanol while the heart rate response was unaffected. A previous study has also shown that ethanol may reduce the systolic blood pressure response to mental stress without affecting the heart rate response, and evidence indicated that this was due to an inhibitory action of ethanol on vasoconstriction [9]. The unaffected noradrenaline response to the electronic games after ethanol in the present study suggests that an action on vasoconstrictor responses is unlikely to be due to reduced noradrenaline release. Ethanol has been shown to reduce alphaadrenoceptor-mediated vasoconstriction, thereby impairing blood pressure responses even though noradrenaline responses may be normal or even raised [16]. This peripheral action may also contribute to the effects of ethanol on blood pressure reactivity to mental stress. Expectation of the effects of ethanol may exert an influence in reducing autonomic and subject reactions to mental stress [17]. In the present study no attempt was made to reduce the effect of expectancy by placebo administration, as this is difficult with doses of ethanol above 0.5 g/kg [8] and would prove impractical in a situation where subjects acted as their own controls. Regardless of whether the present findings reflect a direct pharmacological action of ethanol on autonomic responses or reflect expectancy, they nonetheless demonstrate an effect of ethanol on autonomic and cardiovascular reactivity which would be expected to apply in the normal drinking situation. Acknowledgemenrs-This

was supported subjects.

work was supported by the Medical Research Council by the Maurice and Phyllis Paykel Trust. The authors are grateful

of New Zealand. DGL for the cooperation of

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