Download Basal and Stimulated Sympathetic Responses After Epinephrine No

Basal and Stimulated Sympathetic
Responses After Epinephrine
No Evidence of Augmented Responses
C. Michael Stein, Huai B. He, Alastair J.J. Wood
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Abstract—Delayed facilitation of norepinephrine release through the action of epinephrine (NE) at presynaptic
b-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, 2160.9
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 (0.8560.2 versus 0.8760.2 mg/min; P50.92). 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. (Hypertension. 1998;32:1016-1021.)
Key Words: epinephrine n norepinephrine n sympathetic nervous system n stress
I
t has been suggested that epinephrine plays a role in the
pathogenesis of hypertension.1– 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 b-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 b-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
responses11–14 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
Received August 6, 1998; first decision August 18, 1998; revision accepted August 20, 1998.
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 [email protected]
© 1998 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
1016
Stein et al
and during adrenergic stimulation resulting from mental stress
(Stroop test) and nociception (cold pressor test).
Methods
Subjects
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Nine healthy, normotensive, nonsmoking, white male volunteers
(age, 2160.9 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 Na1 and 70 mmol K1 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,
December 1998
1017
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-inSilastic 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 mCi/mL in normal saline, with
ascorbic acid 1 mg/mL added to the infusion solution. An initial
loading dose of [3H]NE 19 mCi was administered over 2 minutes,
followed by a constant infusion of 0.75 mCi/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 mean6SEM, were analyzed by repeatedmeasures ANOVA, comparing responses obtained before infusion,
1018
Epinephrine and Sympathetic Response
TABLE 1.
Measurements Before Epinephrine or Placebo Infusion
Intervention
Measurement
Statistical Significance
Resting
Stroop Test
Cold Pressor
Drug
Intervention
Drug3Intervention
Before placebo
58.863.1
68.463.2
78.964.5
0.5
,0.001
0.6
Before epinephrine
58.062.3
69.861.9
81.264.6
Before placebo
79.164.1
86.065.8
103.9610.2
0.3
,0.001
0.4
Before epinephrine
79.564.2
87.066.4
107.7613.8
Before placebo
44.165.2
34.464.7
36.866.4
0.3
0.001
1.0
Before epinephrine
52.966.2
41.167.7
43.7611.9
Before placebo
151.2619.1
148.5624.6
242.4645.1
0.7
0.02
0.5
Before epinephrine
166.6630.5
149.9622.0
214.5627.6
Before placebo
17.862.8
19.763.6
52.8617.7
0.9
0.03
0.95
Before epinephrine
17.462.5
18.961.8
56.3614.9
Before placebo
0.7160.09
0.9060.1
0.7
0.003
0.4
Before epinephrine
0.7960.30
Heart rate, bpm
Mean arterial presure, mm Hg
Forearm vascular resistance,
mm Hg z mL21 z 100 mL21 z min
Norepinephrine, pg/mL
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Epinephrine, pg/mL
Norepinephrine spillover, mg/min
1.060.25
2.060.31
1.5560.27
Data are expresssed as mean6SEM. Statistical significance comparing responses regarding Drug (epinephrine or placebo),
Intervention (resting, Stroop test, and cold pressor test), and the Drug3Intervention interaction is shown. Conversion factor: To convert
norepinephrine concentrations from picograms per milliliter to nanomoles per liter, divide by 169.2.
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 drug3intervention
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.
Results
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
drug3intervention 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).
Epinephrine infusion increased plasma epinephrine concentrations 10-fold from 19.363.1 to 217.8618.1 pg/mL
(P,0.001), and this resulted in significant increases in resting
heart rate (57.863.3 compared with 68.462.6 bpm;
P50.004), resting forearm blood flow (1.960.2 compared
with 2.760.4 mL/100 mL per minute; P50.05), and resting
NE spillover (0.6960.07 compared with 1.460.30 mg/min;
P50.02, 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 (127.262.8 mm Hg) than during placebo
(116.961.3 mm Hg) (P50.009) infusion. However, other
than plasma NE concentration (P50.04), the drug3 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 (26.463.4 compared with 30.266.5 pg/mL; P50.58)
(Table 2). The preceding epinephrine infusion had effects that
were of borderline statistical significance on heart rate (drug
effect P50.10, ANOVA). Thus, resting heart rate was significantly higher 1 hour after epinephrine infusion (66.163.0
compared with 60.462.2 bpm; P50.01), 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 (0.8560.2 compared with 0.8760.2 mg/min; P50.92) or
after stimulation by stress (Table 2) (Figure).
Stein et al
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Norepinephrine spillover at rest and after adrenergic stimulation
by Stroop test and cold pressor test before, during, and after
saline or epinephrine infusion.
Discussion
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.11–13 These observations could not be accounted for by circulating levels of
December 1998
1019
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 b-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 possi-
1020
Epinephrine and Sympathetic Response
TABLE 2.
Measurements 1 Hour After Epinephrine or Placebo
Intervention
Measurement
Statistical Significance
Resting
Stroop Test
Cold Pressor
Drug
Intervention
Drug3Intervention
After placebo
60.462.2
69.762.6
80.064.9
0.09
0.003
0.25
After epinephrine
66.163.0
72.961.9
78.764.0
After placebo
79.265.0
81.066.3
104.7614.1
0.56
0.001
0.41
After epinephrine
80.664.8
84.666.9
103.4611.1
After placebo
50.967.0
39.267.5
41.268.3
0.10
0.03
0.91
After epinephrine
68.9611.9
52.6612.0
55.3612.2
After placebo
164.2627.8
166.8626.5
223.7636.6
0.44
0.01
0.19
After epinephrine
168.5624.7
155.7621.8
206.1630.7
After placebo
26.463.4
24.563.5
59.5613.3
0.54
0.04
0.2
After epinephrine
30.266.5
31.965.1
57.768.9
After placebo
0.8560.2
0.9860.2
1.360.2
0.41
0.004
0.26
After epinephrine
0.8760.2
1.360.3
1.560.3
Heart rate, bpm
Mean arterial presure, mm Hg
Forearm vascular resistance,
mm Hg z mL21 z 100 mL21 z min
Norepinephrine, pg/mL
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Epinephrine, pg/mL
Norepinephrine spillover, mg/min
Data are expresssed as mean6SEM. Statistical significance comparing responses regarding Drug (epinephrine or placebo),
Intervention (resting, Stroop test, and cold pressor test), and the Drug3Intervention interaction is shown. Conversion factor: To convert
norepinephrine concentrations from picograms per milliliter to nanomoles per liter, divide by 169.2.
bility 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.
Acknowledgments
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.
References
1. Floras JS. Epinephrine and the genesis of hypertension. Hypertension. 1992;19:1–18.
2. Brown MJ, Dollery CT. Adrenaline and hypertension. Clin Exp
Hypertens Pt A Theory Pract. 1984;6:539 –549.
3. Brown MJ, Macquin I. Is adrenaline the cause of essential hypertension?
Lancet. 1981;2:1079 –1082.
4. Rand MJ, Majewski H. Adrenaline mediates a positive feedback loop in
noradrenergic transmission: its possible role in development of hypertension. Clin Exp Hypertens Pt A Theory Pract. 1984;6:347–370.
5. Majewski H, Rand MJ, Tung LH. Activation of prejunctional betaadrenoceptors in rat atria by adrenaline applied exogenously or released
as a co-transmitter. Br J Pharmacol. 1981;73:669 – 679.
6. Iversen LL. Role of transmitter uptake mechanisms in synaptic neurotransmission. Br J Pharmacol. 1971;41:571–591.
7. Langer SZ. Presynaptic regulation of the release of catecholamines.
Pharmacol Rev. 1980;32:337–362.
8. Stjarne L, Brundin J. Beta2-adrenoceptors facilitating noradrenaline secretion
from human vasoconstrictor nerves. Acta Physiol Scand. 1976;97:88–93.
9. Stein M, Deegan R, He H, Wood AJJ. Beta-adrenergic receptor-mediated
release of norepinephrine in the human forearm. Clin Pharmacol Ther.
1993;54:58 – 64.
10. Chang PC, Grossman E, Kopin IJ, Goldstein DS. On the existence of
functional beta-adrenoceptors on vascular sympathetic nerve endings in
the human forearm. J Hypertens. 1994;12:681– 690.
11. Brown MJ, Brown DC, Murphy MB. Hypokalemia from beta2-receptor
stimulation by circulating epinephrine. N Engl J Med. 1983;309:
1414 –1419.
12. Nezu M, Miura Y, Adachi M, Kimura S, Toriyabe S, Ishizuka, Ohashi H,
Sugawara T, Takahashi M. The effects of epinephrine on norepinephrine
release in essential hypertension. Hypertension. 1985;7:187–195.
13. Blankestijn PJ, Man in’t Veld AJ, Tulen J, van den Meiracker AH.,
Boomsma F, Moleman P, Ritsema van Eck HJ, Derkx FH, Mulder P,
Lamberts SJ. Support for adrenaline-hypertension hypothesis: 18 hour
pressor effect after 6 hours adrenaline infusion. Lancet. 1988;2:1386–1389.
14. Fellows IW, Bennett T, MacDonald IA. The effect of adrenaline upon
cardiovascular and metabolic functions in man. Clin Sci. 1985;69:
215–222.
15. Floras JS, Aylward PE, Mark AL, Abboud FM. Adrenaline facilitates
neurogenic vasoconstriction in borderline hypertensive subjects.
J Hypertens. 1990;8:443– 448.
16. Floras JS, Aylward PE, Victor RG, Mark AL, Abboud FM. Epinephrine
facilitates neurogenic vasoconstriction in humans. J Clin Invest. 1988;81:
1265–1274.
17. Stein CM, Nelson R, He HB, Wood M, Wood AJJ. Norepinephrine
release in the human forearm: effects of epinephrine. Hypertension.
1997;30:1078 –1084.
18. Esler M, Jennings G, Korner P, Willett I, Dudley F, Hasking G, Anderson
W, Lambert G. Assessment of human sympathetic nervous system
activity from measurements of norepinephrine turnover. Hypertension.
1988;11:3–20.
Stein et al
19. Fauvel JP, Bernard N, Laville M, Daoud S, Pozet N, Zech P. Reproducibility of the cardiovascular reactivity to a computerized version of the
Stroop stress test in normotensive and hypertensive subjects. Clin Auton
Res. 1996;6:219 –224.
20. Benjamin N, Calver A, Collier J, Robinson B, Vallance P, Webb D.
Measuring forearm blood flow and interpreting the responses to drugs and
mediators. Hypertension. 1995;25:918 –923.
21. Esler M, Jennings G, Korner P, Blombery P, Sacharias N, Leonard P.
Measurement of total and organ-specific norepinephrine kinetics in
humans. Am J Physiol. 1984;247:E21–E28.
22. He HB, Deegan RJ, Wood M, Wood AJJ. Optimization of high-performance liquid chromatographic assay for catecholamines: determination of
optimal mobile phase composition and elimination of species-dependent
differences in extraction recovery of 3,4-dihydroxybenzylamine. J Chromatogr. 1992;574:213–218.
23. Ferreira SH, Vane JR. Half-lives of peptides and amines in the circulation. Nature. 1967;215:1237–1240.
December 1998
1021
24. Vincent HH, Boomsma F, Man in’t Veld AJ, Schalekamp MA. Stress
levels of adrenaline amplify the blood pressure response to sympathetic
stimulation. J Hypertens. 1986;4:255–260.
25. Lang CC, Stein CM, Brown RM, Deegan R, Nelson R, He HB, Wood M,
Wood AJJ. Attenuation of isoproterenol-mediated vasodilatation in
blacks. N Engl J Med. 1995;333:155–160.
26. Persson B, Andersson OK, Hjemdahl P, Wysocki M, Agerwall S, Wallin
G. Adrenaline infusion in man increases muscle sympathetic nerve
activity and noradrenaline overflow to plasma. J Hypertens. 1989;7:
747–756.
27. Thompson JM, Wallin BG, Lambert G, Jennings GL, Esler MD. Human
muscle sympathetic activity and cardiac catecholamine spillover: no
support for augmented sympathetic noradrenaline release by adrenaline
co-transmission. Clin Sci. 1998;94:383–393.
28. Stein CM, Lang CC, Brown RM, Wood AJJ. Vasodilation in AfricanAmericans: attenuated nitric oxide mediated responses. Clin Pharmacol
Ther. 1997;62:436 – 443.
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Basal and Stimulated Sympathetic Responses After Epinephrine: No Evidence of
Augmented Responses
C. Michael Stein, Huai B. He and Alastair J. J. Wood
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Hypertension. 1998;32:1016-1021
doi: 10.1161/01.HYP.32.6.1016
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