Cigarette Smoking Augments Sympathetic Nerve
Activity in Patients With Coronary Heart Disease
Norihiko SHINOZAKI,1 MD, Toyoshi YUASA,2 MD, and Shigeo TAKATA,3 MD
SUMMARY
It has been shown that cigarette smoking increases blood pressure (BP) and heart rate
(HR), and decreases muscle sympathetic nerve activity (MSNA) in healthy young smokers. The decrease in MSNA might be secondary to baroreflex responses to the pressor
effect. We tested the hypothesis that cigarette smoking increases MSNA in smokers with
impaired baroreflex function.
The effects of cigarette smoking on BP, HR, forearm blood flow (FBF), forearm vascular resistance (FVR), and MSNA were examined in 14 patients with stable effort angina
(59 ± 3 years, group CAD) and 10 healthy smokers (23 ± 1 years, group C). In group
CAD, the arterial baroreflex sensitivity (BRS) was significantly lower than in group C
(4.7 ± 0.8 versus 15.1 ± 2.2 msec/mmHg, P < 0.01). In both groups, cigarette smoking
increased the plasma concentration of nicotine, systolic and diastolic BP, HR, and FVR
significantly (P < 0.01), but decreased FBF significantly (P < 0.01). After smoking,
MSNA was decreased significantly in group C (from 35.2 ± 3.5 to 23.5 ± 3.2 bursts/100
beats, P < 0.01), but increased significantly in group CAD (from 48.8 ± 5.4 to 57.3 ± 5.5
bursts/100 beats, P < 0.01). There was significant correlation between BRS and changes
in MSNA (r = -0.62, P < 0.01).
Cigarette smoking increased MSNA in smokers with impaired baroreflex function.
This demonstrates that cigarette smoking stimulates sympathetic nerve activity by both a
direct peripheral effect and a centrally mediated effect. (Int Heart J 2008; 49: 261-272)
Key words: Cigarette smoking, Nicotine, Coronary artery disease, Angina pectoris, Muscle sympathetic nerve activity, Sympathetic activity, Baroreflex sensitivity
C
IGARETTE smoking is established as a major risk factor for coronary heart
disease.1-5) This effect is caused by sympathetic activation,6-8) accelerated atherosclerosis,9) coronary vasoconstriction,10-14) endothelial dysfunction,15-18) inflammation,19) hypercoagulability,19) and platelet activation20,21) due to cigarette
smoking. There are many reports showing the acute sympathetic effects of cigarette smoking. Cigarette smoking increases heart rate (HR), blood pressure (BP),
and plasma concentration of norepinephrine,6-8,22-24) but decreases muscle sympaFrom the 1 Department of Cardiology, Naganoken Koseiren Shinonoi General Hospital, Nagano, 2 Department of Cardiology, Matto-Ishikawa-chuo Hospital, and 3 Department of Cardiology, Kanazawa Municipal Hospital, Ishikawa, Japan.
Address for correspondence: Norihiko Shinozaki, MD, Department of Cardiology, Naganoken Koseiren Shinonoi General
Hospital, 666-1 Ai, Shinonoi, Nagano, Nagano 388-8004, Japan.
Received for publication May 21, 2007.
Revised and accepted March 24, 2008.
261
262
SHINOZAKI, ET AL
Int Heart J
May 2008
thetic nerve activity (MSNA).25) Cigarette smoking acts mainly via direct stimulation of postganglionic sympathetic nerve endings rather than centrally mediated
activation of efferent sympathetic nerves.
However, a recent clinical study demonstrated that there was a striking
increase in MSNA when the blood pressure increase in response to smoking was
blunted by nitroprusside infusion.26) Cigarette smoking has been shown to
increase skin sympathetic nerve activity,26) which is not attenuated by increased
BP or baroreflex activation. These data show that cigarette smoking increases
sympathetic nerve outflow.
If the decrease in MSNA due to cigarette smoking is caused by baroreflex
stimulation triggered by the smoking-related pressor response, the MSNA in the
patients with impaired baroreflex function is increased by cigarette smoking, and
there is a relationship between the percent changes of the MSNA and baroreflex
sensitivity (BRS). On the basis of these considerations, we examined the effects
of cigarette smoking in patients with stable effort angina who have impaired BRS
as compared with otherwise healthy, habitual smokers. The relationship between
the changes in MSNA and BRS were also tested.
METHODS
Subjects: We studied the effects of cigarette smoking in 14 stable effort angina
subjects (group CAD) and 10 healthy volunteers (group C). All subjects were
habitual cigarette smoking men with normal cardiac function. The mean age of
group CAD was 59 ± 3 years (mean ± SEM; range, 34-72 years), and group C was
23 ± 1 years (mean ± SEM; range, 20-28 years). Myocardial ischemia was verified in the CAD group patients by treadmill stress electrocardiographic testing or
thallium-201 myocardial scintigraphy. Coronary arterial narrowing was also confirmed by coronary angiography. Written informed consent was obtained from
each subject after a detailed explanation of the purpose and procedures of the
study. The protocol was approved by the Ethical Panel of the First Department of
Internal Medicine, Kanazawa University.
Measurements: Subjects were studied in the supine position. HR was monitored
with an electrocardiogram throughout the study. BP was measured directly and
continuously in one arm. Forearm blood flow (FBF) was measured with a straingauge plethysmograph (MedaSonic, Mountain View, California) using a venous
occlusion technique in another arm. The strain gauge was placed approximately
5 cm below the anticubital crease. The pressure in the venous occlusion cuff was
set at 40 mmHg. FBF was taken as the average of 5 flow measurements. Forearm
vascular resistance (FVR) was calculated by dividing the mean BP (diastolic BP
plus one-third of the pulse pressure) by the FBF. A polyethylene catheter was
Vol 49
No 3
SMOKING AUGMENTS SYMPATHETIC NERVE ACTIVITY
263
placed in the anticubital vein to take blood samples for measurement of plasma
concentrations of norepinephrine and nicotine. Plasma concentrations of norepinephrine were measured by high-performance liquid chromatography with an
electrochemical detector.27) Plasma concentrations of nicotine were determined
by capillary column gas chromatography, with detection with electron impact
mass spectrometry and selected ion monitoring according to methods similar to
those described by Jacob, et al.28) Multiunit postganglionic MSNA was recorded
from a muscle nerve fascicle in the perineal nerve at the level of the fibular head
using tungsten microelectrodes (FHC Inc., Bowdoinham, Maine) and microneurographic techniques.29,30) The electrodes were connected to a preamplifier
with a gain of 1000 and an amplifier with a gain of 70. The signal was fed through
a bandpass filter (700-2000 Hz) and a resistance-capacitance integrating circuit
with a time constant of 0.1 second, to produce a mean voltage neurogram. The
signal was fed through a loudspeaker, displayed on an oscilloscope, and recorded
with a paper chart recorder (Nihon Koden, Tokyo). MSNA was identified on the
basis of its relationship to cardiac and respiratory activity, its tendency to increase
during the Valsalva maneuver, and its lack of change during arousal stimuli and
skin stroking. Sympathetic bursts were determined by inspection of the filtered
and mean voltage neurograms. Nerve activity is expressed in both bursts per
minute (BR) and bursts per 100 heart beats (BI).
BRS was assessed as previously described.31) HR and BP were recorded
continuously at a speed of 100 mm/sec. Phenylephrine (100 µg) was given intravenously as two or more bolus injections at intervals of least 5 minutes to raise
systolic arterial pressure. The correlation between systolic arterial pressure and
R-R interval on the electrocardiogram while raising the systolic arterial pressure
was calculated. The slope of the line was defined as BRS when the correlation
coefficient was greater than 0.70.
Protocol and procedures: This study was performed in the afternoon. All subjects were asked to avoid cigarette smoking for at least 6 hours before this study,
and eating was not permitted for at least 3 hours before this study. They were permitted to take medicine as usual. Subjects were studied in the supine position, and
the arterial and venous cannulas were inserted into the brachial artery and anticubital vein.
BP, HR, and MSNA were recorded continuously throughout the procedure.
After 10 minutes of rest, baseline measurements and BRS were obtained. The
subjects were then asked to smoke 2 cigarettes containing 2.2 mg of nicotine. The
subjects were required to finish smoking within 5 minutes. Ten minutes after finishing the cigarettes, the measurements were repeated.
Data analysis: Data from individual subjects are expressed as the mean ± SEM.
The significance of differences in hemodynamic and MSNA variables between
264
Int Heart J
May 2008
SHINOZAKI, ET AL
before and after cigarette smoking was assessed by Wilcoxon single-rank nonparametric analysis. The significance of differences in hemodynamic and MSNA
variables between group CAD and group C was assessed with the Mann-Whitney
U test. Correlations between changes in MSNA and BRS were tested by the Pearson correlation coefficient. Values of P < 0.05 were considered to indicate statistical significance.
RESULTS
Baseline characteristics: The baseline characteristics of the subjects are presented in Table I. There was no significant difference in body weight between the
groups. Age, smoking period, and body mass index in group CAD were significantly larger than in group C. Height in group CAD was significantly smaller
than in group C. Group C had no chronic disease and no medication. In group
CAD, 9 patients had hypertension, 5 patients had diabetes mellitus, and 4, 6, 9,
and 5 patients were treated with nitrates, beta-blockers, Ca-antagonists, and ACE
inhibitors, respectively.
Baroreflex sensitivity: BRS in both groups is shown in Figure 1. The average
BRS in group CAD was 4.71 ± 0.75 msec/mmHg, which was significantly lower
than that in group C (15.11 ± 2.22 msec/mmHg).
Nicotine concentration: The concentrations of nicotine before and after cigarette
smoking in both groups are presented in Figure 2. After cigarette smoking, the
concentrations of nicotine were increased significantly in both groups (group C,
Table I. Clinical Characteristics
Variable
Age (years)
Gender (male/female)
Duration of smoking (years)
Height (cm)
Body weight (kg)
Body mass index (kg/m2)
Hypertension (%)
Diabetes mellitus (%)
Medication
Ca antagonist (%)
ACE inhibitor (%)
Young healthy subjects (n = 10)
Patients with CAD (n = 14)
22.9 ± 0.8
10/0
3.9 ± 0.7
175.6 ± 2.5
64.9 ± 2.2
21.1 ± 0.6
0
0
58.5 ± 2.9*
14/0
35.2 ± 3.3*
165.7 ± 1.0*
64.5 ± 2.3
23.5 ± 0.8†
64.3
35.7
0
0
64.3
35.7
Results are expressed as the mean ± SEM. Statistical difference between young healthy subjects and
patients with coronary artery disease ; *, P < 0.01 ; †, P < 0.05.
ACE indicates angiotensin converting enzyme; and CAD, coronary heart disease.
Vol 49
No 3
SMOKING AUGMENTS SYMPATHETIC NERVE ACTIVITY
Figure 1. Baroreflex sensitivity in young subjects ( ○) and patients with CAD ( ●). Side
circles indicate the mean; Horizontal bars, ± SEM; and CAD, coronary artery disease.
Figure 2. Plasma concentration of nicotine at the baseline and after smoking in healthy
young subjects ( ○) and in patients with CAD (●). Side circles indicate the mean; Horizontal bars, ± SEM; and CAD, coronary artery disease.
265
266
Int Heart J
May 2008
SHINOZAKI, ET AL
from 21.8 ± 1.4 µg/L to 41.2 ± 3.2 µg/L; P < 0.05; group CAD, from 17.0 ± 1.6
µg/L to 25.8 ± 2.2 µg/L; P < 0.05).
Hemodynamic effects of cigarette smoking: The hemodynamic effects of cigarette smoking are shown in Table II. In group C, cigarette smoking caused significant (P < 0.01) increases in HR (by +34.7 ± 4.1%), systolic BP (by +11.7 ±
2.5%), and diastolic BP (by +16.6 ± 1.7%). In group CAD, cigarette smoking
caused significant (P < 0.01) increases in HR (by +8.3 ± 2.1%), systolic BP (by
+9.3 ± 1.7%), and diastolic BP (by +11.3 ± 1.6%). The peripheral hemodynamic
effects of cigarette smoking were a significant (P < 0.01) decrease in FBF (by
-31.4 ± 7.1% in group C, and by -28.2 ± 4.1% in group CAD), and a significant
(P < 0.01) increase in FVR (by +95.1 ± 33.1% in group C, and by +62.1 ± 12.2%
in group CAD).
Table II. Hemodynamic Effects of Cigarette Smoking in Young Subjects and Patients With CAD
Hemodynamic parameter
Heart rate (beats/minute)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Mean blood pressure (mmHg)
Forearm blood flow (mL/100 mL•minute-1)
Forearm vascular resistance (units)
Young subjects
Patients with CAD
Baseline
After smoking
Baseline
After smoking
64.0 ± 1.7
106.3 ± 3.6
64.0 ± 1.8
78.1 ± 2.3
10.14 ± 1.20
8.66 ± 0.96
85.9 ± 2.3*
118.2 ± 2.9*
74.4 ± 1.9*
89.0 ± 2.1*
7.10 ± 1.14*
17.45 ± 4.09*
60.2 ± 1.7
129.5 ± 6.0
65.0 ± 2.8
86.5 ± 3.5
7.90 ± 1.19
13.55 ± 1.75
65.5 ± 2.7*
140.9 ± 5.7*
72.1 ± 2.7*
95.0 ± 3.2*
5.27 ± 0.50*
20.35 ± 2.22*
Results are expressed as the mean ± SEM. Statistical difference between baseline and after smoking ; *, P < 0.01.
CAD indicates coronary artery disease.
Table III. Effects of Cigarette Smoking on Sympathetic Nervous System in Young Subjects and Patients With CAD
Variable
Burst rate (bursts/minute)
Burst incidence (bursts/100 beats)
Plasma norepinephrine concentration (mg/mL)
Plasma epinephrine concentration (ng/mL)
Young subjects
Patients with CAD
Baseline
After smoking
Baseline
After smoking
22.2 ± 1.9
35.2 ± 3.5
0.187 ± 0.027
0.026 ± 0.004
20.0 ± 2.6
23.5 ± 3.2*
0.142 ± 0.020
0.096 ± 0.024
29.7 ± 3.7
48.8 ± 5.4
0.137 ± 0.021
0.023 ± 0.004
37.5 ± 4.3*
57.3 ± 5.5*
0.134 ± 0.020
0.057 ± 0.022
Results are expressed as the mean ± SEM. Statistical difference between baseline and after smoking ; *, P < 0.01. CAD indicates coronary artery disease.
Vol 49
No 3
SMOKING AUGMENTS SYMPATHETIC NERVE ACTIVITY
267
Sympathetic effects of cigarette smoking: The sympathetic effects of cigarette
smoking are shown in Table III. Cigarette smoking caused significant (P < 0.01)
increases in BR (by +7.8 ± 1.2 bursts/minute) and BI (by +8.5 ± 2.0 units) in
group CAD. In group C, cigarette smoking caused a significant (P < 0.01)
decrease in BI (by -11.7 ± 1.0 units), but there was no significant change in BR.
The percentage changes in MSNA between before and after cigarette smoking are shown in Figure 3. In group CAD, the change in BR was +29.5 ± 5.4%,
which was significantly (P < 0.01) higher than that in group C (-10.3 ± 9.3%). In
group CAD, the change in BI was +20.3 ± 5.8%, which was significantly (P <
0.01) higher than that in group C (-32.8 ± 7.0%).
Cigarette smoking caused no significant change in the plasma concentration
of norepinephrine or epinephrine between before and after cigarette smoking in
both groups.
Correlations between changes in MSNA and baroreflex sensitivity: The relationships between changes in MSNA and BRS at baseline are shown in Figure 4 (BR
and BRS) and Figure 5 (BI and BRS). There was significant (P < 0.01) correlation between BRS at baseline and changes in BR (r = -0.53), and between BRS at
baseline and changes in BI (r = -0.62).
A
B
Figure 3. Percent change in burst rate (A) and burst incidence (B) after cigarette smoking. The
results are expressed as the mean ± SEM. Open bars indicate young subjects and filled bars denote
patients with CAD; and CAD, coronary artery disease.
268
SHINOZAKI, ET AL
Figure 4. Relation between the change in burst rate after cigarette smoking and baroreflex sensitivity.
Open circles indicate young subjects and filled circles denote patients with coronary artery disease.
Figure 5. Relation between the change in burst incidence after cigarette smoking and baroreflex sensitivity. Open circles indicate young subjects and filled circles denote patients with coronary artery
disease.
Int Heart J
May 2008
Vol 49
No 3
SMOKING AUGMENTS SYMPATHETIC NERVE ACTIVITY
269
DISCUSSION
Our study is the first report that shows the sympathetic effects of cigarette
smoking in subjects with impaired baroreflex function. Many reports have examined the sympathetic effects of cigarette smoking in young healthy smokers and
animals. In healthy subjects, cigarette smoking has been found to increase HR,
BP, and the plasma concentration of norepinephrine.6-8,22-24) These changes are
attenuated markedly by alpha-adrenergic and beta-adrenergic blockade,7,8,22) indicating that these hemodynamic effects of cigarette smoking are derived from
sympathetic activation. However, the mechanisms of cigarette smoking-mediated
sympathoexcitation are unclear.
We can assume 3 different mechanisms underlying activation of the sympathetic nervous system due to cigarette smoking.32) First, a direct effect on the central nervous system; second, a stimulatory effect on ganglionic sympathetic
transmission that leads to a subsequent increase in postganglionic efferent sympathetic nerve activity; and third, a direct effect on peripheral sympathetic nerve
endings. It has been shown that cigarette smoking stimulates the release of catecholamine directly from postganglionic peripheral sympathetic nerve endings.32-34)
However, the mechanism of the effect of cigarette smoking on the central nervous
system is still controversial.
Animal studies have shown that local injection of nicotine in several brainstem areas caused hypotension and bradycardia, suggesting that cigarette smoking may inhibit central sympathetic nerve activity.35,36) Other studies reported that
local injection of nicotine in other brain-stem areas had a pressor effect, suggesting that cigarette smoking may stimulate central sympathetic nerve activity.37,38)
In healthy smokers, cigarette smoking decreases MSNA,25) which suggests
that cigarette smoking acts mainly via direct stimulation of postganglionic sympathetic nerve endings rather than centrally mediated activation of efferent sympathetic nerves. In contrast to young healthy smokers, cigarette smoking
increased the MSNA significantly in subjects with stable effort angina with
impaired baroreflex function. Our data support the opinion that cigarette smoking
stimulates centrally mediated sympathetic nerve activity. The decrease in MSNA
due to cigarette smoking in young healthy smokers, which gives us the impression that cigarette smoking inhibits central sympathetic nerve activity, is derived
from baroreflex stimulation triggered by the smoking-related pressor response.
Actually, there was significant correlation between changes in MSNA and BRS
at baseline.
The same conclusion was reached in another study. There was a striking
increase in MSNA when the BP increase in response to smoking was blunted by
nitroprusside infusion,26) and cigarette smoking increased skin sympathetic nerve
270
SHINOZAKI, ET AL
Int Heart J
May 2008
activity,26) which is not attenuated by increased BP or baroreflex activation.
Furthermore, cigarette smoking impairs the baroreflex function both acutely
and chronically.39,40) According to our study, the impaired baroreflex function at
baseline stimulates the activation of the sympathetic nervous system due to cigarette smoking even more. This results in a vicious circle in smokers, especially
those with impaired baroreflex function. We must break this vicious circle by
clinical treatment designed to help the person stop cigarette smoking. It has been
shown that cardiac events and mortality are lower in subjects who have given up
smoking than in subjects who continued to smoke.41-44)
However, in contrast to many studies,6,7) our study showed that there was no
change in the plasma concentration of norepinephrine or epinephrine between
before and after cigarette smoking in either group. The reasons for this result are
that it is too short a time to take a sample, and it is too short a time to smoke,
because it has been shown that the plasma concentration of catecholamine begins
to rise 10 minutes after starting to smoke a cigarette.7)
This study has several limitations. First, we did not make our subjects smoke
sham cigarettes. The plasma concentration of nicotine after cigarette smoking
was significantly higher than before smoking. Thus, we are able to discuss the
sympathetic effects of cigarette smoking, but there was no control condition. Second, our patients with stable effort angina were taking some medication. In our
study, 64% of patients took a Ca antagonist and 36% took an ACE inhibitor. It has
been shown that the MSNA was reduced and the baroreflex sensitivity was
enhanced by chronic treatment with an ACE inhibitor in patients with heart failure.45,46) It has also been shown that baroreflex sensitivity was increased significantly by chronic treatment with a Ca antagonist in patients with hypertension47)
and some Ca antagonists inhibited sympathetic nerve activity.48,49) Therefore, in
patients with stable effort angina and with impaired BRS, the same mechanisms
might be observed with an ACE inhibitor or a Ca antagonist. These medications
might alter the effect of cigarette smoking. Third, our control group did not match
group CAD in terms of age and risk factors. It has been demonstrated that baroreflex sensitivity becomes impaired with advancing age,50) and that patients with
hypertension or diabetes mellitus have sympathetic hyperactivity.51) Therefore,
these conditions might influence our results at baseline.
In conclusion, cigarette smoking stimulates activation of the sympathetic
nervous system by a direct peripheral effect and a centrally mediated effect. The
decrease in MSNA in healthy smokers with normal BRS is derived from baroreflex stimulation triggered by the smoking-related pressor response. In patients
with impaired BRS, cigarette smoking increases the MSNA, showing that cigarette smoking increases sympathetic outflow directly. There was significant correlation between BRS and changes in MSNA.
Vol 49
No 3
SMOKING AUGMENTS SYMPATHETIC NERVE ACTIVITY
271
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
The Pooling Project Research Group. Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: Final report of the pooling project. J
Chron Dis 1978; 31: 201-306.
Wilhelmsen L. Coronary heart disease: epidemiology of smoking and intervention studies of smoking. Am
Heart J 1988; 115: 242-9.
Kannel WB, Higgins M. Smoking and hypertension as predictors of cardiovascular risk in population studies. J
Hypertens 1990; 8: S3-8.
Ezzati M, Henley SJ, Thun MJ, Lopez AD. Role of smoking in global and regional cardiovascular mortality.
Circulation 2005; 112: 489-97.
Teo KK, Ounpuu S, Hawken S, et al. Tobacco use and risk of myocardial infarction in 52 countries in the
INTERHEART study: a case-control study. Lancet 2006; 368: 647-58.
Baer L, Radichevich I. Cigarette smoking in hypertensive patients. Blood pressure and endocrine responses.
Am J Med 1985; 78: 564-8.
Cryer PE, Haymond MW, Santiago JV, Shah SD. Norepinephrine and epinephrine release and adrenergic
mediation of smoking-associated hemodynamic and metabolic events. N Engl J Med 1976; 295: 573-7.
Trap-Jensen J, Carlen JE, Svendsen TL, Christensen NJ. Cardiovascular and adrenergic effects of cigarette
smoking during immediate non-selective and selective beta adrenoceptor blockade in humans. Eur J Clin
Invest 1979; 9: 181-3.
Auerbach O, Hammond EC, Garfinkel L. Smoking in relation to atherosclerosis of the coronary arteries. N
Engl J Med 1965; 273: 775-9.
Klein LW, Ambrose J, Pichard A, Holt J, Gorlin R, Teichholz LE. Acute coronary hemodynamic response to
cigarette smoking in patients with coronary artery disease. J Am Coll Cardiol 1984; 3: 879-86.
Winniford MD, Wheelan KR, Kremers MS, et al. Smoking-induced coronary vasoconstriction in patients with
atherosclerotic coronary artery disease: evidence for adrenergically mediated alterations in coronary artery
tone. Circulation 1986; 73: 662-7.
Deanfield JE, Shea MJ, Wilson RA, Horlock P, de Landsheere CM, Selwyn AP. Direct effects of smoking on
the heart: silent ischemic disturbances of coronary flow. Am J Cardiol 1986; 57: 1005-9.
Sugiishi M, Takatsu F. Cigarette smoking is a major risk factor for coronary spasm. Circulation 1993; 87: 76-9.
Moliterno DJ, Willard JE, Lange RA, et al. Coronary-artery vasoconstriction induced by cocaine, cigarette
smoking, or both. N Engl J Med 1994; 330: 454-9.
Zeiher AM, Schächinger V, Minners J. Long-term cigarette smoking impairs endothelium-dependent coronary
arterial vasodilator function. Circulation 1995; 92: 1094-100.
Lekakis J, Papamichael C, Vemmos C, et al. Effect of acute cigarette smoking on endothelium-dependent brachial artery dilatation in healthy individuals. Am J Cardiol 1997; 79: 529-31.
Neunteufl T, Heher S, Kostner K, et al. Contribution of nicotine to acute endothelial dysfunction in long-term
smokers. J Am Coll Cardiol 2002; 39: 251-6.
Yasue H, Hirai N, Mizuno Y, et al. Low-grade inflammation, thrombogenicity, and atherogenic lipid profile in
cigarette smokers. Circ J 2006; 70: 8-13.
Tanriverdi H, Evrengul H, Kuru O, et al. Cigarette smoking induced oxidative stress may impair endothelial
function and coronary blood flow in angiographically normal coronary arteries. Circ J 2006; 70: 593-9.
Benowitz NL. Nicotine and coronary heart disease. Trends Cardiovasc Med 1991; 1: 315-21.
Benowitz NL. Drug therapy. Pharmacologic aspects of cigarette smoking and nicotine addiction. N Engl J Med
1988; 17: 1318-30.
Groppelli A, Omboni S, Parati G. Blood pressure and heart rate response to repeated smoking before and after
beta-blockade and selective alpha 1 inhibition. J Hypertens Suppl 1990; 8: S35-40.
Groppelli A, Giorgi DM, Omboni S, Parati G, Mancia G. Persistent blood pressure increase induced by heavy
smoking. J Hypertens 1992; 10: 495-9.
Trap-Jensen J. Effects of smoking on the heart and peripheral circulation. Am Heart J 1988; 115: 263-7.
Grassi G, Seravalle G, Calhoun DA, et al. Mechanisms responsible for sympathetic activation by cigarette
smoking in humans. Circulation 1994; 90: 248-53.
272
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
SHINOZAKI, ET AL
Int Heart J
May 2008
Narkiewicz K, van de Borne PJ, Hausberg M, et al. Cigarette smoking increases sympathetic outflow in
humans. Circulation 1998; 98: 528-34.
Goldstein DS, Feuerstein G, Izzo JL Jr, Kopin IJ, Keiser HR. Validity and reliability of liquid chromatography
with electrochemical detection for measuring plasma levels of norepinephrine and epinephrine in man. Life Sci
1981; 28: 467-75.
Jacob P 3rd, Yu L, Wilson M, Benowitz NL. Selected ion monitoring method for determination of nicotine,
cotinine and deuterium-labeled analogs: absence of an isotope effect in the clearance of (S)-nicotine-3’, 3’-d2 in
humans. Biol Mass Spectrom 1991; 20: 247-52.
Hagbarth KE, Vallbo AB. Pulse and respiratory grouping of sympathetic impulses in human muscle nerves.
Acta Physiol Scand 1968; 74: 96-108.
Delius W, Hagbarth KE, Hongell A, Wallin BG. General characteristics of sympathetic activity in human muscle nerves. Acta Physiol Scand 1972; 84: 65-81.
La Rovere MT, Specchia G, Mortara A, Schwartz PJ. Baroreflex sensitivity, clinical correlates, and cardiovascular mortality among patients with a first myocardial infarction. A prospective study. Circulation 1988; 78:
816-24.
Haass M, Kübler W. Nicotine and sympathetic neurotransmission. Cardiovasc Drugs Ther 1997; 10: 657-65.
Karlin A. Structure of nicotinic acethylcholine receptors. Curr Opin Neurobiol 1993; 3: 299-309.
Unwin N. Neurotransmitter action: opening of ligand-gated ion channels. Cell 1993; 72 (Suppl): 31-41.
Armitage AK, Hall GH. Further evidence relating to the mode of action of nicotine in the central nervous system. Nature 1967; 214: 977-9.
Robertson D, Tseng CJ, Appalsamy M. Smoking and mechanisms of cardiovascular control. Am Heart J 1988;
115: 258-63.
Brezenoff HE, Jenden DJ. Changes in arterial blood pressure after microinjections of charbalol into the medulla
and IVth ventricle of the rat brain. Neuropharmacology 1970; 9: 340-8.
Tseng CJ, Appalsamy M, Robertson D. Nicotine elicits hypertension in the ventral lateral medulla of the rat.
Pharmacologist 1987; 29: 115-20.
Mancia G, Groppelli A, Di Rienzo M, Castiglioni P, Parati G. Smoking impairs baroreflex sensitivity in
humans. Am J Physiol 1997; 273: H1555-60.
Gerhardt U, Vorneweg P, Riedasch M, Hohage H. Acute and persistent effects of smoking on the baroreceptor
function. J Auton Pharmacol 1999; 19: 105-8.
Gordon T, Kannel WB, McGee D, Dawber TR. Death and coronary attacks in men after giving up cigarette
smoking. A report from the Framingham study. Lancet 1974; 2: 1345-8.
Hallstrom AP, Cobb LA, Ray R. Smoking as a risk factor for recurrence of sudden cardiac arrest. N Engl J Med
1986; 314: 271-5.
Lightwood JM, Glantz SA. Short-term economic and health benefits of smoking cessation: myocardial infarction and stroke. Circulation 1997; 96: 1089-96.
Kinjo K, Sato H, Sakata Y, et al. Impact of smoking status on long-term mortality in patients with acute myocardial infarction. Circ J 2005; 69: 7-12.
Grassi G, Cattaneo BM, Seravalle G, et al. Effects of chronic ACE inhibition on sympathetic nerve traffic and
baroreflex control of circulation in heart failure. Circulation 1997; 96: 1173-9.
Dibner-Dunlap ME, Smith ML, Kinugawa T, Thames MD. Enalaprilat augments arterial and cardiopulmonary
baroreflex control of sympathetic nerve activity in patients with heart failure. J Am Coll Cardiol 1996; 27: 35864.
James MA, Rakicka H, Panerai RB, Potter JF. Baroreflex sensitivity changes with calcium antagonist therapy
in elderly subjects with isolated systolic hypertension. J Hum Hypertens 1999; 13: 87-95.
Murzenok PP, Huang BS, Leenen FH. Sympathoinhibition by central and peripheral infusion of nifedipine in
spontaneously hypertensive rats. Hypertension 2000; 35: 631-6.
Leenen FH, Ruzicka M, Huang BS. Central sympathoinhibitory effects of calcium channel blockers. Curr
Hypertens Rep 2001; 3: 314-21.
Ebert TJ, Morgan BJ, Barney JA, Denahan T, Smith JJ. Effects of aging on baroreflex regulation of sympathetic activity in humans. Am J Physiol 1992; 263: H798-803.
Huggett RJ, Scott EM, Gilbey SG, Stoker JB, Mackintosh AF, Mary DA. Impact of type 2 diabetes mellitus on
sympathetic neural mechanisms in hypertension. Circulation 2003; 108: 3097-101.