(Hypertension. 1998;32:1016-1021.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Basal and Stimulated Sympathetic Responses After Epinephrine
No Evidence of Augmented Responses
From the Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to Dr C. Michael Stein, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Medical Research Building 1, Room 560, Nashville, TN 37232-6602. E-mail michael.stein{at}mcmail.vanderbilt.edu
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Abstract |
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Abstract—Delayed facilitation of norepinephrine release through the action of epinephrine (NE) at presynaptic ß-adrenoceptors has been postulated to account for the delayed hemodynamic effects of epinephrine and to be a mechanism causally related to the development of hypertension. To determine whether a short-term increase in epinephrine concentrations resulted in subsequent facilitation of sympathetic responses, 9 healthy subjects (age, 21±0.9 years) were studied at rest and during physiological stress on 2 occasions when they received an infusion of either saline or epinephrine (20 ng/kg per minute) in random order. Heart rate, blood pressure, forearm blood flow, epinephrine concentrations, and NE spillover were measured at rest, during mental stress (Stroop test), and during a cold pressor test. Measurements were performed before, during the 1-hour infusion of epinephrine or placebo, and 1 hour after the infusion. A radioisotope dilution method was used to measure NE spillover. Hemodynamic measurements and NE spillover were increased during the infusion of epinephrine, but 1 hour after discontinuation of epinephrine there was no significant augmentation of hemodynamic or sympathetic responses. NE spillover 1 hour after saline or epinephrine infusion was similar (0.85±0.2 versus 0.87±0.2 µg/min; P=0.92). In addition, there was no delayed facilitation of stress-induced hemodynamic or NE responses after epinephrine. These findings do not support the hypothesis that epinephrine results in delayed facilitation of NE release.
Key Words: epinephrine • norepinephrine • sympathetic nervous system • stress
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Introduction |
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It has been suggested that epinephrine plays a role in the pathogenesis of hypertension.1 2 3 4 According to the "epinephrine hypothesis" of hypertension, epinephrine, released from the adrenal medulla during physiological stress, is taken up into sympathetic nerve terminals and later rereleased with norepinephrine (NE) as a cotransmitter. The epinephrine that has been rereleased stimulates further NE release through its action on presynaptic ß-adrenergic receptors and in this way amplifies and prolongs sympathetic responses.1 4 5 Therefore, a brief increase in epinephrine concentrations, such as occurs in response to stress, could, through the mechanisms of uptake, rerelease, and stimulation of NE release, amplify and prolong sympathetic responses and facilitate the development of hypertension.1 3 4
Experimental evidence supports the existence of functional presynaptic ß-adrenergic receptors as well as the process of uptake and rerelease of epinephrine in the nerve terminal5–10: mechanisms that would allow epinephrine to produce a delayed and sustained facilitatory effect on NE release. Support for the physiological relevance of these mechanisms comes from studies that have demonstrated that short-term, systemic infusion of epinephrine resulted in prolonged tachycardic and/or pressor responses11 12 13 14 and that low doses of epinephrine infused directly into the brachial artery augmented vasoconstrictor responses to stimuli that cause release of endogenous NE.15 16 However, while in vitro data support the existence of the individual mechanisms that underlie the epinephrine hypothesis, and while the hemodynamic studies suggest that responses after short-term exposure to epinephrine may be prolonged, there is little evidence to support the proposed underlying mechanism, namely, that a short-term increase in epinephrine concentrations is associated with a prolonged increase in NE release. Recently, using a technique that allowed the intrabrachial artery infusion of epinephrine in doses without detectable systemic effects,17 we did not observe a delayed facilitatory effect of epinephrine on local forearm NE spillover. However, an intriguing and unexplained observation in that study was that systemic NE spillover was higher after the epinephrine infusion. Those data, together with the increased plasma NE concentrations observed by others after systemic epinephrine infusion,1 therefore suggested that epinephrine might enhance NE spillover in vascular beds other than the forearm. The present study set out to examine that hypothesis and determine whether systemic administration of epinephrine, in a dose chosen to reproduce epinephrine concentrations similar to those achieved during physiological stress, was associated with a prolonged increase in systemic NE spillover, both at rest and during adrenergic stimulation resulting from mental stress (Stroop test) and nociception (cold pressor test).
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Methods |
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Subjects
Nine healthy, normotensive, nonsmoking, white male volunteers (age, 21±0.9 years) were studied. All subjects provided written informed consent, and the study protocol was approved by the Vanderbilt Committee for the Protection of Human Subjects. No subject had clinically significant abnormalities on history, physical examination, or routine laboratory tests, including complete blood count, renal and liver function tests, and ECG. Subjects did not take any medications for
2 weeks before the study and were maintained on a diet, provided
by the metabolic kitchen of the Vanderbilt Clinical
Research Center, that was free of caffeine and alcohol and provided
150 mmol Na+ and 70 mmol
K+ per day for 4 days before the study. An
additional 2 subjects only completed 1 study day, and their data have
not been included. One subject was withdrawn because frequent
ventricular ectopic beats were noted during the placebo
study day, and in 1 subject an unrelated illness occurred between the
first and second study days. None of the subjects participated in our
previous study of forearm NE responses to
epinephrine.17 Subjects within a narrow
age range were studied to minimize the potential confounding effects of
age on NE spillover.18
Experimental Protocol
Subjects were studied twice and received an infusion of either
epinephrine or placebo (saline) in a single-blind fashion on
the 2 study days, with the order of administration randomized.
Identical procedures were followed on each study day, and the 2 study
days were separated by 2 to 4 weeks. Subjects were admitted overnight
to the Vanderbilt University Clinical Research Center on the evening of
the fourth day of the controlled diet to minimize the effects of
environmental factors on autonomic responses. All experiments were
performed in the morning in the same temperature-controlled room with
subjects resting supine in bed. Subjects fasted from midnight and
remained fasting throughout the study. An intravenous
cannula was placed in the antecubital fossa of each arm between 5 and 6
AM of the study day. Subjects rested quietly for 60 minutes
after the placement of the intravenous catheters. Then
[3H]NE (norepinephrine
levo-[ring-2,5,6-3H], 56.9 Ci/mmol; New England
Nuclear) was infused intravenously into the left arm for
determination of NE kinetics (as described below).
Forty minutes after the [3H]NE infusion was started, baseline resting heart rate, blood pressure, and forearm blood flow were measured, and blood was drawn for determination of renin and epinephrine concentrations and NE kinetics. Subjects then performed the Stroop test19 as described below. After a 10-minute rest period to allow a return to baseline, a cold pressor test was performed. These 3 data time points are referred to as before epinephrine or placebo resting, Stroop, and cold pressor, respectively. After an additional 10-minute rest period, an intravenous infusion of epinephrine (20 ng/kg per minute) or placebo (saline) was started. To avoid sudden systemic effects that might have been noticed by the subjects, the epinephrine infusion was administered at an initial dose of 67 ng/min and approximately doubled every 2 minutes so that the target dose of 20 ng/kg per minute was reached over 10 minutes. This dose of epinephrine was then continued for the next 50 minutes. Identical procedures were followed on the placebo day, with the infusion rate of saline doubled every 2 minutes, as was done for epinephrine, until the target rate was reached. Resting hemodynamic and catecholamine measurements were obtained 40 minutes after commencement of the epinephrine or saline infusion. Then, while the epinephrine or saline infusion continued, the Stroop test was repeated, and after a 10-minute rest period the cold pressor test was repeated. These 3 data time points are referred to as during epinephrine or placebo resting, Stroop, and cold pressor, respectively. The epinephrine or saline infusion was then discontinued, and 60 minutes were allowed to elapse before we obtained after epinephrine or placebo resting, Stroop, and cold pressor blood samples and hemodynamic measurements.
Measurement of Heart Rate and Blood Pressure
Heart rate was recorded from a continuous ECG monitor and
calculated as the average of the heart rate obtained over 1 minute
during the first minute of the Stroop test and during the second minute
of the cold pressor test. Blood pressure was recorded with a
semiautomated device (Dinamap, Critikon). Stressor blood
pressures were measured 40 seconds after the Stroop test was started
and after 1 minute of the cold pressor test. Resting blood pressure and
heart rate were obtained from the average of 2 readings obtained within
1 minute of each other. Changes in systolic and
diastolic blood pressure were similar, and blood pressure
data are presented as mean arterial pressure.
Measurement of Forearm Blood Flow
Forearm blood flow was measured in the left arm with
mercury-in-Silastic strain gauge
plethysmography,20 as we have previously
described.9 The average of the flow
determinations obtained during the first minute of the Stroop test and
the second minute of the cold pressor test was determined and used for
calculations.
Stroop and Cold Pressor Tests
The Stroop test consists of word stimuli that are
presented on a computer monitor placed in front of the subject
at 2-second intervals. The words (eg, red, yellow) are
presented in varying colors. If the word is presented
in black type, the word is read; however, if the word is in type of
another color, the color must be stated rather than the word read. In
addition, monaural headphones are placed over the subject's ears and
used to carry prerecorded, randomly ordered repetitions of the word
stimuli to create competing task interference. Subjects provide
responses aloud during 2-minute task intervals. Blood was drawn for
catecholamine determinations over the second minute of the
test.
The cold pressor test was performed by immersing the subjects' left foot for 2 minutes to the level of the lateral malleolus in a slurry composed of equal parts water and crushed ice. Subjects were instructed to breathe normally and to avoid straining or performing a Valsalva maneuver. Blood pressure was measured after 1 minute of the cold pressor test. Forearm blood flow measurement, determination of heart rate, and drawing of blood for catecholamines were performed during the second minute of the cold pressor test.
Determination of Norepinephrine Kinetics
[3H]NE (norepinephrine
levo-[ring-2,5,6-3H], 56.9 Ci/mmol; New England
Nuclear) was prepared for human administration by the Vanderbilt
Hospital Radiopharmacy, and appropriate sterility and pyrogen testing
was performed. Immediately before use, [3H]NE
was diluted to a concentration of 1.5 µCi/mL in normal saline, with
ascorbic acid 1 mg/mL added to the infusion solution. An initial
loading dose of [3H]NE 19 µCi was
administered over 2 minutes, followed by a constant infusion of 0.75
µCi/min. Baseline samples were obtained after 30 and 40 minutes, by
which time [3H] NE concentrations achieve
steady state,9 and at the time points described
in the experimental protocol. Samples were drawn into cooled tubes with
EGTA and reduced glutathione (Amersham Corporation), placed on ice, and
centrifuged at 4°C. Endogenous and
[3H]NE concentrations were measured to allow
determination of NE kinetics, as we9 and
others18 21 have previously described.
We measured NE and epinephrine concentrations by high-performance liquid chromatography using electrochemical detection with 3,4-dihydroxybenzylamine as the internal standard, as we have described previously.22 We performed calculations for the determination of NE kinetics using the isotope dilution method,18 21 as we have previously described.9
Data Analysis
Data, expressed as mean±SEM, were analyzed by
repeated-measures ANOVA, comparing responses obtained before infusion,
during infusion, and after infusion on the placebo and
epinephrine study days. The effects of drug
(epinephrine or placebo), intervention (resting, Stroop test,
cold pressor test), and the drugxintervention interaction were
determined. Post hoc analysis, if indicated, was performed with
a 2-tailed Student's t test for paired data if the data
were normally distributed or, for data that were not normally
distributed, with the Wilcoxon matched pairs signed rank test,
as appropriate (SPSS for Windows, Release 6). A 2-tailed P
value of <0.05 was the minimum level accepted for statistical
significance.
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Results |
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Hemodynamic and catecholamine values before the administration of either epinephrine or placebo were similar on the 2 study days, both at rest and after adrenergic stimulation (Table 1
)
(Figure). The application of stressors
(Stroop test and cold pressor test) resulted in significant stimulation
of heart rate, mean arterial blood pressure, forearm
vascular resistance, NE, epinephrine, and NE spillover
(Table 1). The cold pressor test increased heart rate by 
20 bpm,
increased systolic and diastolic blood pressure by
30 mm Hg and 20 mm Hg, respectively, and doubled NE
spillover. The responses to the Stroop test were more modest. The
drugxintervention interaction was not significant for any
variable, indicating a similarity of resting and stimulated
responses before the infusion of epinephrine or placebo on the
2 study days (Table 1).
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Epinephrine infusion increased plasma epinephrine concentrations 10-fold from 19.3±3.1 to 217.8±18.1 pg/mL (P<0.001), and this resulted in significant increases in resting heart rate (57.8±3.3 compared with 68.4±2.6 bpm; P=0.004), resting forearm blood flow (1.9±0.2 compared with 2.7±0.4 mL/100 mL per minute; P=0.05), and resting NE spillover (0.69±0.07 compared with 1.4±0.30 µg/min; P=0.02, Wilcoxon signed rank test). As was observed before infusion of epinephrine or placebo, the interventions used for adrenergic stimulation (Stroop test and cold pressor test) had statistically significant effects on all the parameters measured (data not shown). The absolute values of several measurements obtained during stress (eg, systolic blood pressure during the Stroop test) were significantly greater during epinephrine (127.2±2.8 mm Hg) than during placebo (116.9±1.3 mm Hg) (P=0.009) infusion. However, other than plasma NE concentration (P=0.04), the drugx intervention interaction was not significant for any measurement, indicating that differences in resting values due to the epinephrine infusion accounted for the apparent increased hemodynamic responses to stress during the epinephrine infusion.
One hour after the saline or epinephrine infusion was
discontinued, the plasma concentrations of epinephrine were
similar (26.4±3.4 compared with 30.2±6.5 pg/mL; P=0.58)
(Table 2). The preceding
epinephrine infusion had effects that were of borderline
statistical significance on heart rate (drug effect P=0.10,
ANOVA). Thus, resting heart rate was significantly higher 1 hour after
epinephrine infusion (66.1±3.0 compared with 60.4±2.2 bpm;
P=0.01), but heart rate responses during Stroop or cold
pressor testing were not different (Table 2). There was no evidence of
a delayed stimulatory effect of epinephrine on NE spillover
either at rest (0.85±0.2 compared with 0.87±0.2 µg/min;
P=0.92) or after stimulation by stress (Table 2)
(Figure
).
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Discussion |
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We found no evidence to support the hypothesis that the systemic administration of epinephrine resulted in a delayed, facilitatory effect on NE release, either at rest or after the application of physiological stressors.
Several previous studies have found that a short-term infusion of epinephrine was followed by sustained increase in heart rate and/or increase in blood pressure.11 12 13 These observations could not be accounted for by circulating levels of epinephrine since epinephrine has a half-life of <1 minute23 and plasma concentrations of epinephrine return to baseline within minutes after the discontinuation of a systemic infusion.13 In addition, several studies have shown that a delayed, amplified blood pressure response to sympathetic stimulation occurred hours after the discontinuation of a systemic infusion of epinephrine.13 24 However, few studies have directly examined whether epinephrine does in fact cause a sustained increase in sympathetic activity and NE release, the proposed mechanism for the prolonged physiological responses.
Several earlier studies have found that plasma NE concentrations remained elevated after an epinephrine infusion.1 12 However, plasma NE concentrations are determined not only by the amount released into plasma but also by the amount of NE cleared from plasma. Thus, systemic interventions that alter physiological responses may alter not only NE release but also NE clearance. The radioisotope dilution technique, which takes account of the clearance of NE and thus allows the determination of NE spillover, a measure of neuronal NE release, is sensitive to pharmacological and physiological changes and has been used extensively9 10 18 21 25 as a model to examine changes in neuronal NE release in vivo.
Using NE spillover methodology, Persson and
colleagues26 found that both muscle sympathetic
nerve activity and NE spillover were increased 30 minutes after
systemic infusion of epinephrine (100 ng/kg per minute), while
Esler and colleagues27 found no increase after
infusion of epinephrine (40 ng/kg per minute). The present
study has several advantages. First, the dose of epinephrine
infused, 20 ng/kg per minute, has previously been reported to result in
a delayed increase in hemodynamic and plasma NE
measurements12 and, while resulting in
epinephrine concentrations similar to those achieved during
physiological stress, avoids the confounding effect
that large hemodynamic changes would have on subsequent
measurements. Second, hemodynamic and NE responses were
measured 1 hour rather than 30 minutes after the epinephrine
infusion. We have previously noted that the increase in forearm blood
flow after the administration of intra-arterial
isoproterenol, a ß-adrenergic agonist, is prolonged for up to 30
minutes after discontinuation of the infusion.28
Thus, a longer washout period of 60 minutes allowed time for any
confounding effects resulting from reflex
cardiovascular responses to return to baseline. Third,
the placebo control allowed any potential confounding temporal effects
to be factored out. Our findings, and those of Persson and
colleagues,26 are compatible with a temporary
reflex overshoot in sympathetic response present 30 minutes, but
not 60 minutes, after the discontinuation of the vasodilator. Recently,
such a sympathetic overshoot has been shown to occur after a systemic
epinephrine infusion of 40 ng/kg per minute and to return to
baseline within 20 minutes.27
The significance of minor changes in NE spillover would be uncertain, and it is likely that the effects of epinephrine on NE release would be substantial, if indeed this was a physiologically relevant mechanism. Persson and colleagues26 found that NE spillover was doubled 30 minutes after discontinuation of epinephrine. Our study had 93% power to detect such a doubling of NE spillover after epinephrine, and we can thus confidently exclude the possibility that changes in NE spillover likely to be of physiological significance occur.
The epinephrine hypothesis will be validated or refuted by cumulative evidence provided by studies, such as the present one, that bring increasingly sophisticated techniques to bear on the question. The findings in the present study, our negative findings in the forearm,17 and a recent negative study from Esler and colleagues27 collectively provide strong evidence that delayed facilitation of NE release does not explain the delayed hemodynamic responses that have been observed after administration of epinephrine and thus do not support the epinephrine hypothesis of hypertension.
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Acknowledgments |
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This study was supported by a Grant-in-Aid from the American Heart Association and by US Public Health Service grants HL 56251 and GM 5 M01-RR00095. Dr Stein is the recipient of a Pharmaceutical Manufacturers of America faculty development award in clinical pharmacology.
Received August 6, 1998; first decision August 18, 1998; accepted August 20, 1998.
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