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Mechanisms Responsible for Sympathetic
Activation by Cigarette Smoking in Humans
Guido Grassi, MD; Gino Seravalle, MD; David A. Calhoun, MD; Gianni B. Bolla, MD;
Cristina Giannattasio, MD; Monica Marabini, MD; Alberto Del Bo, MD; Giuseppe Mancia, MD

Background The pressor and tachycardic effects of ciga- (integrated activity -31.8±5.1%, P<.01). The reduction was
rette smoking are associated with an increase in plasma inversely related to the increase in mean arterial pressure
catecholamines, suggesting the dependence of these effects on (r= -.67, P<.05), but the slope of the relation was markedly
adrenergic stimulation. Whether the stimulation occurs at a less (-54.1±7.5%, P<.05) than that obtained by intravenous
central or a peripheral level and whether reflex mechanisms infusion of phenylephrine in absence of smoking. The hemo-
are involved is unknown. dynamic and neurohumoral changes were still visible 30 min-
Methods and Results In nine normotensive healthy subjects utes after smoking and occurred again on smoking a second
(age, 33.0+3.5 years, mean±SEM), we measured blood pres- cigarette. Sham smoking was devoid of any hemodynamic and
sure (Finapres device), heart rate (ECG), calf blood flow and neurohumoral effect.
vascular resistance (venous occlusion plethysmography), Conclusions These data support the hypothesis that in
plasma norepinephrine and epinephrine (high-performance humans the sympathetic activation induced by smoking de-
liquid chromatography assay), and postganglionic muscle sym- pends on an increased release and/or a reduced clearance of
pathetic nerve activity (microneurography from the peroneal catecholamines at the neuroeffector junctions. Central sympa-
nerve) while subjects were smoking a filter cigarette (nicotine thetic activity is inhibited by smoking, presumably via a
content, 1.1 mg) or were in control condition. Cigarette baroreceptor stimulation triggered by the smoking-related
smoking (which raised plasma nicotine measured by high- pressor response. The baroreflex is impaired by smoking,
performance liquid chromatography from 1.0±0.9 to 44.2±7.1 however, indicating that partial inability to reflexly counteract
ng/mL) markedly and significantly increased mean arterial the effect of sympathetic activation is also responsible for the
pressure (+13.2±2.3%), heart rate (+30.3±4.7%), calf vascu- pressor response. (Circulation. 1994;90:248-253.)
lar resistance (+ 12.1±4.9%), plasma norepinephrine (+34.8±
7.0%), and plasma epinephrine (+90.5±39.0%). In contrast, Key Words * smoking * blood pressure * nervous
muscle sympathetic nerve activity showed a marked reduction system * baroreflex

C igarette smoking is accompanied by a marked these subjects did not cause an increase in plasma
and prolonged increase in heart rate and blood norepinephrine,1" thus failing to reproduce the smok-
pressure.1-5 These hemodynamic changes are ing-dependent adrenergic activation.
markedly attenuated by a- and /3-adrenergic block- The present study was planned to provide informa-
ade.34'6'7 They are also associated with a marked and tion on this issue. To this aim, we studied habitual
prolonged increase in plasma norepinephrine and epi- smokers in whom smoking was accompanied by a
nephrine,68,9 which has prompted the hypothesis that marked increase in blood pressure, heart rate, and
the mechanisms responsible for the pressor and tachy- plasma norepinephrine. We examined the effect of
cardic responses have an adrenergic nature. smoking on both sympathetic traffic and on barorecep-
After the report of preliminary data from our tor-sympathetic reflex to determine whether, in the
group,10 Niedermaier et al"l have recently reported that presence of a smoking-induced adrenergic activation,
in eight habitual smokers smoking caused a reduction central and reflex sympathetic mechanisms are involved.
rather than an increase in postganglionic muscle sym-
pathetic nerve traffic as assessed by microneurography. Methods
However, these findings are difficult to interpret be- We studied nine normotensive healthy subjects (eight men,
cause these observations are in conflict with those one woman) whose mean age was 33.0±+ 3.5 years
reported by the same authors in a series of 10 habitual (mean+SEM; range, 21 to 48 years). The subjects were all
smokers in whom no smoking-dependent alterations in habitual cigarette smokers (>10 cigarettes daily). They agreed
to participate in the study after being informed of its nature
sympathetic traffic were observed.12 Furthermore, at and purpose. The protocol of the study (see below) was
variance from a large number of studies,6,8'9 smoking in approved by the ethical committee of our institution.
Received February 18, 1994; revision accepted March 29, 1994. Hemodynamic, Microneurographic,
From the Cattedra Medicina Interna, Ospedale S. Gerardo dei and Humoral Measurements
Tintori, Monza (G.G., C.G., G.M.), Centro di Fisiologia Clinica e
Ipertensione and Istituto di Clinica Medica, Universita di Milano Arterial blood pressure was measured by a digital photo-
(G.G., D.A.C., G.B.B., M.M., A.D.B.), and Centro Auxologico plethysmographic device (Finapres, Ohmeda 2300) capable of
Italiano (G.S.), Milano, Italy. providing beat-to-beat systolic and diastolic values similar to
Correspondence to Professor Giuseppe Mancia, Centro Fisio- those obtained intra-arterially under conditions ranging from
logia Clinica e Ipertensione, Via F. Sforza 35, 20122 Milano, Italy. generalized vasodilatation to generalized vasoconstriction."3'14
© 1994 American Heart Association, Inc. Heart rate was monitored by a cardiotachometer triggered by

Downloaded from http://circ.ahajournals.org/ by guest on June 22, 2016

continuous blood pressure and heart rate increase and the MSNA reduc- pressure. This was paralleled by a ments have been described in detail in previous papers. and recorded. heart rate. ments. The samples were drawn pressure. hours after a light breakfast. On the other hand. University of Iowa). which was equally apparent eight subjects. no significant correlation was found between changes in All subjects were asked to abstain from smoking and coffee MSNA and in plasma norepinephrine (r=.83. During this period.to 5-gm uninsulated tip. EC4). The blood set in position. nephrine and epinephrine. displayed on a vascular resistances before and during smoking. (2) After 40 minutes of rest.31). The study proper was conducted in the morning.1 mg nicotine.org/ by guest on June 22. and MSNA were continuously recorded. Smoking the first was withdrawn during the last 30 seconds.17 Results Plasma norepinephrine and epinephrine were measured by As shown in Fig 1. This was done by high-performance liquid chro. fed through a band-pass filter (700 to 2000 period. after which the sequence of a control. and heart rate. The same statistical in traffic with gentle stroking of the skin distal to the recording analysis was used to locate the difference between the smoking site. diastolic blood electrode positioned subcutaneously 1 to 3 cm from the pressure.26) or epi- and alcohol consumption during the 48 hours preceding the nephrine (r=. mean blood pressure. This was the case also for calf hemodynamics flow was measured during the last 2 minutes. individual subjects were averaged for the group as a whole and together with blood pressure.05 was taken as the level of statistical minute multiplied by mean burst amplitude. P<.25 arbitrary units). diastolic blood ples taken from an antecubital vein. etc). when calculated as units and as bursts per minute (see centrations. P<. A value of P<. The tubes were promptly centrifuged and edly increased. and venous blood was withdrawn during the last 30 after completion of smoking and still visible at the end seconds. an increase in systolic blood pressure.05. whereas calf vascular resistance was mark- EGTA glutathione. a g) was measured four times per minute by venous occlusion smoking. 2016 . The nerve signal was graphic data were averaged for each minute of the recording amplified x70 000. The statistical significance of the and respiratory movements (strain-gauge pneumograph). but the subject was required to finish the and MSNA effects qualitatively similar to those of the cigarette within 5 minutes. no change smoking the first and the second cigarette. and MSNA were obtained over a 15. Tektronix). procedure identical to the previous one. Smoking filtered type containing 1. heart rate. heart rate. effects of smoking on blood pressure. tapering to a 1. and venous blood and plasma catecholamines (Fig 4). (23°C to 24°C). calf blood first one. and drinking straw provided with a filter to simulate the respiratory the measurements were made at constant room temperature and behavioral activity of smoking (sham smoking). according to the following protocol: (1) The subject was put in the supine position. The Spearman analysis was used to nerve activity (MSNA) was calculated as burst frequency over assess the correlation between the various changes induced by time (bursts per minute) and/or integrated activity (bursts per smoking. 15-minute control period. The paired t test with Bonferroni's correction was identified by inspection of the mean voltage neurogram and used to locate the difference between the smoking and proved to be directed to muscle districts by currently accepted presmoking values. Quantification of MSNA by these methods has been shown to have a 5% intraobserver variability.15 using a mercury-in-Si. and microneuro- recording electrode served as ground. the protocol described above was performed lateral to the leg used for microneurography (see below). Sympathetic bursts were ANOVA. and Protocol r= -. Integrated Averages were also obtained of the calf blood flows and nerve activity was monitored by a loudspeaker. (4) Blood pressure. respectively).01. expressed in significance. tion induced by the first cigarette were immediate and minute period. heart rate. (Bioengineering Department. Data from storage oscilloscope (model 511 A. These hemodynamic changes were ac- stored at -70°C until assayed. on a changes induced by smoking was assessed by two-way Gould 3800 RS paper recorder. Calf blood flow (mL/min per 100 minutes (recovery).23 and calf vascular resistance (r= -. forearm blood flow. and MSNA measurements were continued for 15 activity. cigarette did not affect ventilation rate and plasma renin heart rate. with the foot circulation excluded by a cuff In a further experimental session on seven subjects. but it caused a consistent increase in plasma Downloaded from http://circ. and Fig 3 shows the blood pressure. "Methods"). weight) capable of producing a pressor response similar to that Multiunit recording of postganglionic sympathetic nerve induced by cigarette smoking. smoking the first cigarette caused high-performance liquid chromatography'9 from blood sam.ahajournals. the positioned at the ankle and inflated at a suprasystolic pressure. and integrated with a custom nerve-traffic analysis system preceding smoking (control) and the 5 minutes of smoking. heart rate. The methods used for these measure.2 gg/min per kilogram body pulse pressure) to blood flow and expressed in arbitrary units. 1 to 2 in one subject is illustrated in Fig 2. as well as between changes induced by criteria (increase in traffic with Valsalva maneuver. and a recovery period was repeated according to a plethysmography (Hokanson. An example of the MSNA reduction study. expressed as means±SEM. Puffing habits were the second cigarette induced blood pressure. These data were further averaged for the 15 minutes Hz). with an instrument (Aerograph 1400) equipped correlated with the increase in mean arterial pressure with a nitrogen phosphorus detector. The changes were only partially reversed minutes. The nerve was impaled posteriorly to the fibular head with a tungsten microelectrode of a diameter of 200 1m in the Data Analysis shaft. and the various measuring devices plus the venous cannula were MSNA values throughout the whole study. no response to arousal. systolic blood pressure. heart rate. The reduction in MSNA was inversely matography. Grassi et al Cigarette Smoking and Sympathetic Activity 249 the R wave of an ECG lead. The a second time except that the cigarette was replaced with a strain gauge was placed 5 to 6 cm below the fibular head. lastic strain gauge applied around the calf of the leg contra. The blood samples were used also to measure plasma renin activity and plasma vasopressin companied by a marked elevation in plasma norepi- by radioimmunoassay. measurements included plasma nicotine con. (3) The subject was asked to smoke a cigarette of a of the recovery and the second control period.67. blood pressure.16-18 Muscle sympathetic and phenylephrine data. and MSNA Calf vascular resistance was calculated as the ratio of mean were compared with those induced by a 5-minute intravenous arterial pressure (diastolic blood pressure plus one third of infusion of phenylephrine (1.24 Phenylephrine was infused traffic was obtained from the peroneal nerve of the leg after a 30-minute recovery from smoking and a subsequent contralateral to the one used for calf blood flow measure. heart rate.20-22 In marked MSNA reduction. Calf blood flow was unchanged into a syringe and collected into ice-chilled tubes containing by smoking. In five subjects. Calf blood flow was measured during the last 2 sustained. left uncontrolled. A reference In each subject.

Fig 5 compares the effects on blood pressure. This was the case also for smoking a second cigarette (Table 1). Downloaded from http://circ. plasma norepinephrine (NE). KGEKG. heart I. * 70.250 Circulation Vol 90. 28- r * f ** Discussion 220' 22 In our subjects. 16- mmHg BP 1005 10 control smoking control smoking 150- FIG 1. 60- As shown in Table 2. and humoral variables. and sustained increase in blood 160. 30 X from one subject in control condition (top) and during cigarette smoking (bottom). Original recording of muscle sympathetic nerve activity (MSNA). . units) and as burst fre- quency (right. phenylephrine caused a reduction in changes in systolic (S) and diastolic (D) blood pressure (BP).4 mil/min/100g CBF Units CVR 5. 901 tistical signfficance between values obtained before and during cigarette smoking. Further.~. heart rate while smoking caused an increase. A O E KG 44 4 -44444 4. phenylephrine infusion in- creased blood pressure and decreased heart rate and smoking smoking S&M MSNA. 70- 'I vasopressin. and MSNA of cigarette smoking and phenyleph- rine infusion. Graphs showing systolic (S) and diastolic (D) blood pressure (BP). 80.05) than that Units MSNA Bs/min MSNA associated with smoking. hemodynamic vari. SO. and electrocardiogram (EKG) 200. sham smoking was devoid of any f A significant effect on ventilation rate. 0 ephrine was significantly greater (P<. 35 ** SMO KING 43 30- 9. 280. 10. ll rate. and muscle sympathetic nerve actvity (MSNA. Values are shown b/min HR as means±SEM. r . Although they caused similar blood FIG 3. 2016 . bursts per minute [Bs/minJ) before (control) and during smoking the first cigarette (smoking). smoking (smoking). 25 200 it 20 I .ahajournals. both when expressed in units and in number of bursts per minute. 60 D BP mmHg l_ so 1~~~~~~~ 40 .1 r - ** --- 5 sec 300' FIG 2. calf blood flow (CBF). blood pressure (BP). **P<. Smoking the first MS NA or the second cigarette strikingly increased the plasma A nicotine levels in contrast with the absence of any increase during sham smoking (Tables 1 and 2). No 1 July 1994 b/min HR CONTROL mmHg up 1005 200- 1r~~ 4* - MSNA > 150. and muscle sympathetic nerve activity (MSNA). As expected. calf vascular resistance (CVR). plasma 100- epinephrine (E). the reduction in MSNA associated with phenyl. marked.org/ by guest on June 22.05. Asterisks (*P<. heart rate (HR).' BP~~~~~ HmmgUm LO pg/mi NE pg/mi E 400. r . heart rate (HR). integrated activity) induced by the first and the second cigarette more. S 80 200 100 ** ----.01) refer to the sta. smoking was accompanied by an immediate. 100. MSNA _ 3. Graphs showing the time course of minute-to-minute pressure increases. expressed as integrated activity (left. . 1 ables. MSNA.

(1) a peripheral pressure. units) and as burst frequency (right. indicating a smoking-associated impairment of the 160j 16. our study provides 280 28. It suggests rather that smoking acts at peripheral sympathetic sites to (1) enhance catechol- amine release from chromaffin tissues and/or (2) reduce the reuptake and the overall clearance of these substances.6±0.9 15. however. and mus- cle sympathetic nerve activity (MSNA). cycles/min 15. ie.9±6. tP<. there are probably two reasons for the sympathoexcita- tory effects of smoking in humans.6+0.05. however. Regardless of the grams) and during (dashed histograms) smoking the second mechanisms.2t Values are means-+SEM.1 Plasma vasopressin. ng/mL per hour 0. Studies in animals have reported that local injection of nicotine in several brain-stem sites is accompanied by 4 hypotension and bradycardia.2+1. *P<. microinjection 3 of nicotine in a number of other brain-stem areas has produced pressor rather than depressor effects.9±0.9 44.1 0.2+0. **P<. We can FIG 4. showed an immediate.28.0+0. This suggests that the adrenergic activation associated with smoking does not have a central origin.ahajournals. and Plasma Nicotine Levels Variable Control 1st Cigarette Smoking Control 2nd Cigarette Smoking Ventilatory rate.8 48.* P-**s3 3. plasma epinephrine (E).2 2.29 Fur- NE thermore. nerve activity changes associated with smoking were on the contrary. marked. norepinephrine and epinephrine.1 0. however.1±+1. baroreflex. bursts per other component of smoking) on the integrating barore- minute [Bs/min]) before (open histograms) and during (dashed flex centers. Downloaded from http://circ. This provides further evidence TABLE 1.5+0. heart speculate also that a nicotine-dependent stimulation of rate (HR). it is due to the baroreceptor stimulation brought about by the smoking-dependent peripheral adrenergic stimulation and blood pressure rise. *P<.5±0. ie. humoral. observations. as a peripheral action of smoking. pglmL 0.4+1.7+0. calf vascular resistance (CVR). The slope of the sympa- lr . and still partly evident 30 minutes after the first smoking sustained reduction specular to the blood pressure episode was completed. nor does it depend on stimulation of ganglionic sympa- thetic transmission.1* q** thetic inhibition was markedly less for the pressor effect 2201 22f of smoking than for the pressor effect of phenylephrine. confirming previous Other aspects of our study deserve to be mentioned.3* Plasma nicotine. n=5). Humoral Variables. however. Grassi et al Cigarette Smoking and Sympathetic Activity 251 mmHO MAP HR change.org/ by guest on June 22. These adrenergic stimulation and (2) a partial loss of the responses were associated with an increase in plasma baroreflex ability to counteract it.1+±3.7+0.4* 1. n=9 (except for plasma nicotine. no increase in First. Bar graphs showing mean arterial pressure (MAP). Effects of Cigarette Smoking on Ventilatory Rate.01 versus control.2627 suggesting that the main product of smoking may inhibit centrally sympa- thetic activity.2 14. this inhibition is mediated by a baroreflex mechanism. This suggests that.1t 8.1 +0. in our subjects the hemodynamic.1 Plasma renin activity. Because smoking is accompanied by a reduc- tion in arterial compliance.2±7. it is clear from our data that cigarette. which. 2016 . expressed as integrated nally. Units MSNA Bs/min MSNA In the above context.32 Fi- plasma norepinephrine (NE). in our patients the degree of sympathetic pg/mi pg/mi E inhibition induced by smoking showed an inverse rela- tion with the magnitude of the pressor and vasoconstric- tor responses. heart rate.30 we can speculate that this 100 ~~~~~~~~10 impairment is due to a reduction in the sensitivity of stretch "sensors" such as the baroreceptors. although this would imply a central as well histograms) smoking the first cigarette and before (open histo.05. and calf vascular resistance. rather than being directly due to smoking (either via nicotine or via other smoking constituents). In other studies. a third possibility is an influence of nicotine (or activity (left.1 15. calf blood flow (CBF). additional new information. Values are shown as means±SEM. ng/mL 1.2 2. arterial chemoreceptors31 impairs the baroreflex.6'8'9 There was.01. and postganglionic muscle sympathetic nerve traffic. The mechanisms involved in the central sympathoin- mUmin/100g CBF Units CVR 51 hibition of smoking are not explained by our data.1 0.

Sympathetic Nerve Activity. MSNA. humoral.0 27. How- pend also on a nonadrenergic mechanism.4±7. Lung. mmHg MAP b/min HR whether smoking affects sympathetic activity in these 100 districts as it does in skeletal muscle (ie. FIG 5.8±1.1 MSNA.115:258-263. and neural effects when baseline plasma vasopressin level was restored of smoking. muscle sympathetic nerve activity.org/ by guest on June 22. 1976.7±1. whether its sympathetic modulation is homogeneous or heteroge- 80- neous) remains to be clarified. B D heart rate and electrocardiogram during cigarette smoking in unre- stricted patients. bpm 62.33.5 275.2 0.6±0. such as ever. Shah SD.9 28. Direct arterial pressure.0 62. (HR). Smoking and cardiovascular function.1 31. mm Hg 84.10:495-499. Units MSNA Bs/min MSNA References 1.6±0. units 28. that the cardiovascular effects of smoking are long. Actions of nicotine and smoking on circulation.1 63.9(suppl 5):S17-S23.7 137.3 Calf blood flow.6±0. significance between values obtained in the two conditions.7±5.2 3. ng/mL per hour 0.0±0. Cryer PA.4±6. units) and as burst frequency (right. microneurography is the only technique that increase in plasma vasopressin levels.4±35.9±0. 1988.5±0.2±4. No change in the various variables was statistically significant. units 216±39 228±35 204±41 234±31 MSNA. Winniford MD.7±0.9±5. Washington.1 Heart rate.7±1. Cellina GU. Groppelli A. Che S.2 84.7±0. this technique does not allow the examination of increased circulating vasopressin.6±0.6±0.4 0.4±1.7 139.4±3. 4.01) refer to the statistical associated hemodynamic and metabolic events.2±1. J Hypertens. was supported by grants HL-03220 and HL-02568 from the National Health.05. Pharmacol Ther.5 85. solid lines) and before (B) and during (D) phenyl. University of Alabama. Downloaded from http://circ. ng/mL 0.8±0.34 Because vasopres.5 Plasma epinephrine.6 Diastolic BP. Mancia G.8 13. smoking was associated with no excludes this as a major factor (see Table 1).5 22. Asterisks (*P<. - Values are means±SEM. change in plasma renin activity but with a marked Finally.8±0. Values are shown as and epinephrine release and adrenergic mediation of smoking- means+SEM.3±9.6±0. pg/mL 0.4+5. No 1 July 1994 TABLE 2.3 0. renal.5±2.2 Plasma vasopressin. 3. 2016 . sympathetic neural activity to extend to splanchnic.8 33. Haymond MW.295:573-577. Graphs showing mean arterial pressure (MAP).252 Circulation Vol 90.4 23. a visiting research scientist from the 40 Hypertension Program.8 Plasma norepinephrine. and other important vascular districts. Effects of smoking on the heart and peripheral B D circulation. 6. Omboni S.3±40.3±1. although persistence of this the cardiovascular system is likely to be under the reduction 30 minutes after smoking the first cigarette permanent hemodynamic. 1982.1 23.7 265. Santiago JV.8 BP indicates blood pressure.5±0. pg/mL 255. Am Heart J. 60 -__ Acknowledgment Dr David A.1 32.7+38. Ventilatory Rate.4±44. n=3). This may suggest allows the effect of smoking on sympathetic nerve that the hemodynamic responses to smoking may de.5±8. pg/mL 28.5±0. and Blood Institute. smoking (-. dashed lines).2 0. Am Heart J.89:18-25.17:129-141.5±3. Calhoun. sin infusion inhibits MSNA.3±3.1±4. 2.9 Ventilatory rate. Trap-Jensen J.1±1. 1992. cycles/min 14.3 0.8 140. 1975.3±3. sistent blood pressure increase induced by heavy smoking. mL/min per 100 g 3.9±1.5±6. Second.3 3. Per- as integrated activity (left.2 0.3 0.3 1.9 13. Littler WA. Parati G.0 278. bursts/min 22. N Engl J Med. and Plasma Nicotine Levels Variable Control 1st Sham Smoking Control 2nd Sham Smoking Systolic BP. DC. bursts per minute [Bs/minJ) before (B) and during (D) cigarette JHypertens. n=5 (except for plasma nico tine. activity to be monitored directly and dynamically.3 28.7 83.9 63.3 Calf vascular resistance. a subject smoking might partly account for the smoking-dependent reduc- 2 to 3 cigarettes per hour or 20 to 40 cigarettes per day) tion in sympathetic firing.3 14. and muscle sympathetic nerve activity (MSNA) expressed 5.0±1.7±0.ahajournals. **P<.4 3.35 an increase in vasopressin lasting and that in a heavy smoker (ie. mm Hg 139. Effects of Sham Smoking on Hemodynamic and Humoral Variables. Thus.1 ±3.2 0.1 ±0. heart rate 1990. Giorgi DMA. Norepinephrine ephrine infusion (o. Honour AJ.1 Plasma renin activity.5±6.1±1.3 Plasma nicotine.

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