Skip to main content
  • American Heart Association
  • Science Volunteer
  • Warning Signs
  • Advanced Search
  • Donate

  • Home
  • About this Journal
    • General Statistics
    • Editorial Board
    • Editors
    • Information for Advertisers
    • Author Reprints
    • Commercial Reprints
    • Customer Service and Ordering Information
  • All Issues
  • Subjects
    • All Subjects
    • Arrhythmia and Electrophysiology
    • Basic, Translational, and Clinical Research
    • Critical Care and Resuscitation
    • Epidemiology, Lifestyle, and Prevention
    • Genetics
    • Heart Failure and Cardiac Disease
    • Hypertension
    • Imaging and Diagnostic Testing
    • Intervention, Surgery, Transplantation
    • Quality and Outcomes
    • Stroke
    • Vascular Disease
  • Browse Features
    • AHA Guidelines and Statements
    • Acknowledgment of Reviewers
    • Clinical Implications
    • Clinical-Pathological Conferences
    • Controversies in Hypertension
    • Editors' Picks
    • Guidelines Debate
    • Meeting Abstracts
    • Recent Advances in Hypertension
    • SPRINT Trial: the Conversation Continues
  • Resources
    • Instructions to Reviewers
    • Instructions for Authors
    • →Article Types
    • → Submission Guidelines
      • Research Guidelines
        • Minimum Information About Microarray Data Experiments (MIAME)
      • Abstract
      • Acknowledgments
      • Clinical Implications (Only by invitation)
      • Conflict(s) of Interest/Disclosure(s) Statement
      • Figure Legends
      • Figures
      • Novelty and Significance: 1) What Is New, 2) What Is Relevant?
      • References
      • Sources of Funding
      • Tables
      • Text
      • Title Page
      • Online/Data Supplement
    • →Tips for Easier Manuscript Submission
    • → General Instructions for Revised Manuscripts
      • Change of Authorship Form
    • → Costs to Authors
    • → Open Access, Repositories, & Author Rights Q&A
    • Permissions to Reprint Figures and Tables
    • Journal Policies
    • Scientific Councils
    • AHA Journals RSS Feeds
    • International Users
    • AHA Newsroom
  • AHA Journals
    • AHA Journals Home
    • Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)
    • Circulation
    • → Circ: Arrhythmia and Electrophysiology
    • → Circ: Genomic and Precision Medicine
    • → Circ: Cardiovascular Imaging
    • → Circ: Cardiovascular Interventions
    • → Circ: Cardiovascular Quality & Outcomes
    • → Circ: Heart Failure
    • Circulation Research
    • Hypertension
    • Stroke
    • Journal of the American Heart Association
  • Facebook
  • Twitter

  • My alerts
  • Sign In
  • Join

  • Advanced search

Header Publisher Menu

  • American Heart Association
  • Science Volunteer
  • Warning Signs
  • Advanced Search
  • Donate

Hypertension

  • My alerts
  • Sign In
  • Join

  • Facebook
  • Twitter
  • Home
  • About this Journal
    • General Statistics
    • Editorial Board
    • Editors
    • Information for Advertisers
    • Author Reprints
    • Commercial Reprints
    • Customer Service and Ordering Information
  • All Issues
  • Subjects
    • All Subjects
    • Arrhythmia and Electrophysiology
    • Basic, Translational, and Clinical Research
    • Critical Care and Resuscitation
    • Epidemiology, Lifestyle, and Prevention
    • Genetics
    • Heart Failure and Cardiac Disease
    • Hypertension
    • Imaging and Diagnostic Testing
    • Intervention, Surgery, Transplantation
    • Quality and Outcomes
    • Stroke
    • Vascular Disease
  • Browse Features
    • AHA Guidelines and Statements
    • Acknowledgment of Reviewers
    • Clinical Implications
    • Clinical-Pathological Conferences
    • Controversies in Hypertension
    • Editors' Picks
    • Guidelines Debate
    • Meeting Abstracts
    • Recent Advances in Hypertension
    • SPRINT Trial: the Conversation Continues
  • Resources
    • Instructions to Reviewers
    • Instructions for Authors
    • →Article Types
    • → Submission Guidelines
    • →Tips for Easier Manuscript Submission
    • → General Instructions for Revised Manuscripts
    • → Costs to Authors
    • → Open Access, Repositories, & Author Rights Q&A
    • Permissions to Reprint Figures and Tables
    • Journal Policies
    • Scientific Councils
    • AHA Journals RSS Feeds
    • International Users
    • AHA Newsroom
  • AHA Journals
    • AHA Journals Home
    • Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)
    • Circulation
    • → Circ: Arrhythmia and Electrophysiology
    • → Circ: Genomic and Precision Medicine
    • → Circ: Cardiovascular Imaging
    • → Circ: Cardiovascular Interventions
    • → Circ: Cardiovascular Quality & Outcomes
    • → Circ: Heart Failure
    • Circulation Research
    • Hypertension
    • Stroke
    • Journal of the American Heart Association
Original Articles

Acute Cardiovascular and Sympathetic Effects of Nicotine Replacement Therapy

Boutaïna Najem, Anne Houssière, Atul Pathak, Christophe Janssen, Daniel Lemogoum, Olivier Xhaët, Nicolas Cuylits, Philippe van de Borne
Download PDF
https://doi.org/10.1161/01.HYP.0000219284.47970.34
Hypertension. 2006;47:1162-1167
Originally published May 18, 2006
Boutaïna Najem
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anne Houssière
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Atul Pathak
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christophe Janssen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel Lemogoum
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Olivier Xhaët
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nicolas Cuylits
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Philippe van de Borne
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site

This article has a correction. Please see:

  • Correction - October 01, 2006
  • Article
  • Figures & Tables
  • Info & Metrics
  • eLetters

Jump to

  • Article
    • Abstract
    • Methods
    • Results
    • Discussion
    • Acknowledgments
    • References
  • Figures & Tables
  • Info & Metrics
  • eLetters
Loading

Abstract

Sympathetic overactivity is implicated in the increased cardiovascular risk of cigarette smokers. Excitatory nicotinic receptors are present on peripheral chemoreceptor cells. Chemoreceptors located in the carotid and aortic bodies increase ventilation (Ve), blood pressure (BP), heart rate (HR), and sympathetic nerve activity to muscle circulation (MSNA) in response to hypoxia. We tested the hypothesis that nicotine replacement therapy (NRT) increases MSNA and chemoreceptor sensitivity to hypoxia. Sixteen young healthy smokers were included in the study (8 women). After a randomized and blinded sublingual administration of a 4-mg tablet of nicotine or placebo, we measured minute Ve, HR, mean BP, and MSNA during normoxia and 5 minutes of isocapnic hypoxia. Maximal voluntary end-expiratory apneas were performed at baseline and at the end of the fifth minute of hypoxia. Nicotine increased HR by 7±3 bpm, mean BP by 5±2 mm Hg, and MSNA by 4±1 bursts/min, whereas subjects breathed room air (all P<0.05). During hypoxia, nicotine also raised HR by 8±2 bpm, mean BP by 2±1 mm Hg, and MSNA by 7±2 bursts/min (all P<0.05). Nicotine increased MSNA during the apneas performed in normoxia and hypoxia (P<0.05). Nicotine also raised the product of systolic BP and HR, a marker of cardiac oxygen consumption, during normoxia, hypoxia, and the apneas (P<0.05). Ve, apnea duration, and O2 saturation during hypoxia and the apneas remained unaffected. In conclusion, sympathoexcitatory effects of NRT are not because of an increased chemoreflex sensitivity to hypoxia. NRT increases myocardial oxygen consumption in periods of reduced oxygen availability.

  • sympathetic nervous system
  • chemoreceptors
  • smoking

Tobacco smoking is a well-established cardiovascular risk factor worldwide.1,2 Sympathetic overactivity seems to be a key factor implicated in the excess risk of cardiovascular events with cigarette smoking.3 Cigarette smoking increases efferent sympathetic nerve traffic acutely,4,5 as well as norepinephrine and epinephrine release.6 This catecholamine release increases myocardial work and oxygen consumption through an increase in blood pressure (BP), heart rate (HR), and myocardial contractility.3 In addition, tobacco induces coronary vasoconstriction and increases the risk of tachyarrhythmias.1,7

The adverse effects of cigarette smoking are related to the mixture of chemicals, including nicotine.8,9 The role of nicotine itself on peripheral sympathetic activity, in the absence of the other components contained in tobacco smoke, is not clear. Characterization of the sympathetic effects of nicotine, per se, is important because it is estimated that millions of smokers use nicotine replacement therapy (NRT) each year to aid tobacco cessation.10–12

In this study, we sought to determine whether nicotine increases peripheral chemoreceptor sensitivity. The peripheral chemoreceptors are located near the carotid arteries and the aorta. They are the dominant reflex control mechanism regulating the ventilatory and neural circulatory control response to hypoxia.13,14 These receptors have powerful stimulatory effects on ventilation (Ve) and on sympathetic activity.13–15 Nicotine-induced catecholamine release is probably mediated through nicotinic receptor stimulation in neural tissues.16,17 Nicotine could increase chemoreceptor activity through excitatory nicotinic receptors present on the glomus cells.18–20 This is of potential importance, because smoking is frequently accompanied by hypoxemia as a result of carboxyhemoglobinemia and lung disease. The effects of nicotine on chemoreflex sensitivity in humans are unknown. Some, but not all,21–23 animal studies have been able to show that nicotine increases peripheral chemoreceptor sensitivity to hypoxia.24–26 This is likely because of the fact that the effects of exogenous nicotine on chemoreceptors depend on the predominance of nicotinic and muscarinic receptors on the carotid bodies.27 This ratio differs among species, and animal studies on the effects of nicotine on chemoreceptor control are, therefore, difficult to extrapolate to humans. We decided to test the hypothesis that nicotine increases peripheral sympathetic nerve activity to muscle circulation [muscle sympathetic nerve activity (MSNA)] in humans and that it enhances peripheral chemoreflex sensitivity to hypoxia.

Methods

The study was approved by the Ethical Committee of Erasme Hospital, Brussels. Each subject signed an informed consent before inclusion in the study.

Subjects

Sixteen healthy smokers were included in the study (8 women; 26±7 years of age; body mass index, 21±3 kg/m2). All of the subjects were regular cigarette smokers (18±8 cigarettes per day for 10±7 years). None of the subjects were taking any medication.

Measurements

Breathing was performed via a low-resistance mouthpiece with the use of a nose clip to ensure exclusive mouth breathing. Minute Ve (pneumotachometer, Medical Electronic Equipment) and end-tidal CO2 (Normocap 200 Capnometer, Datex-Ohmeda) were measured every minute in all of the subjects. Respiratory frequency was monitored with a respiratory monitoring band placed around the subject’s thorax (Pletysmograph, Study Data Systems).

Multiunit recordings of postganglionic MSNA were obtained in 11 subjects. In 5 of the subjects, we could not find an adequate MSNA recording site during both experimental sessions (placebo and nicotine). MSNA recording was obtained with an unipolar tungsten electrode inserted selectively into a nerve fascicle of the right or left peroneal nerve, posterior to the fibular head, and a reference electrode was placed subcutaneously 2 to 3 cm from the recording electrode.4,15 Neural activity was fed to a band pass filter (band width, 0.7 to 2.0 Hz) and a resistance-capacitance integrating network (time constant, 0.1 s) to obtain a mean voltage neurogram. Bursts were identified by a single trained observer blinded to the recording session (B.N.). MSNA was calculated as bursts per minute after careful inspection of the mean voltage neurogram. Acceptable recordings met the following 4 criteria: (1) spontaneous bursts of neural discharge synchronous with HR, (2) no response to arousal stimuli or skin stroking, (3) an increase in nerve burst frequency with apnea, and (4) a signal:noise ratio of 3:1. MSNA recordings were acquired and analyzed on a MacLab 8/s data acquisition system (AD Instruments). The amplitude of each burst was determined, and sympathetic activity was calculated as bursts per minute multiplied by mean burst amplitude expressed in arbitrary units. The absolute amplitude of MSNA depends on voltage amplification, which varies from 1 subject to another but is kept constant during every experiment. Modifications in MSNA during hypoxia and apnea were, therefore, calculated as percentages of changes from values recorded during normal Ve.

All of the subjects also underwent continuous recording of HR (Siemens Medical, ECG Monitoring) and oxygen saturation determinations (Nellcor N-100 C pulse oximeter). Systolic, mean, and diastolic oscillometric BP measurements were performed every 2 minutes with a Physiocontrol Colin BP-880 sphygmomanometer (Colin press Mate, Colin Corp). We also recorded finger BP (Portapres, Finapres Medical System) continuously in 7 subjects to determine whether nicotine increased BP during apneas. It was decided not to record finger BP in 9 of the subjects to avoid the modest discomfort of prolonged finger cuff inflation.

Protocol and Interventions

All of the subjects were asked to stop smoking 14 hours before the procedure. Each subject was studied twice in random order: once after sublingual administration of a 4-mg tablet of nicotine (Nicorette microtab, nicotine betadex, Pfizer) and once after administration of a placebo tablet. Smoking abstinence was carefully assessed in each subject before every study. Subjects and investigators were unaware of the composition of the tablets.

To confirm the compliance of subjects to the nonsmoking, we determined plasma cotinine (Immulite/DPC immunoassay system) on blood samples taken at the beginning of the study. As a result, in all of the subjects, cotinine levels before study were <500 ng/mL (267±57 ng/mL), corresponding with those of an abstinent smoker.28

Subjects were studied in the supine position under carefully standardized conditions. Measurements were performed 40 minutes after administration of the tablet and lasted 20 minutes, when the plasma concentration of nicotine remained stable.9,11

The protocol used to test peripheral chemoreflex sensitivity was identical to previous studies.15 Subjects underwent a 5-minute baseline period of room air breathing once stable baseline Ve had been reached, and this was followed by 5 minutes of isocapnic hypoxia (10% O2 in 90% N2, with CO2 titrated to maintain isocapnia). Maximal voluntary end-expiratory apneas were performed at baseline and at the end of the fifth minute of hypoxia to eliminate the inhibitory influence of Ve on sympathetic nerve traffic.

Data Analysis

All of the recordings were analyzed in a blinded fashion. Sympathetic bursts were identified by careful inspection of the mean voltage neurogram during 5 minutes of baseline breathing, during the 5 minutes of hypoxia, and during the apneas. Burst frequency allowed comparison of sympathetic activity recorded during the different experimental sessions (placebo versus nicotine); this is because MSNA amplitude depends on signal amplification, which varies from one experimental session to another but is kept constant within an experimental session. The amplitude of each burst was determined, and sympathetic activity was calculated as bursts per minute multiplied by mean burst amplitude and was expressed as a percentage increase from baseline values within a given experimental session. Burst frequency and amplitude per minute during apneas were obtained by dividing the burst count and amplitude during the apnea by the apnea duration in seconds and then by multiplying this value by 60. This allowed determination of the effects of hypoxia and apneas on sympathetic traffic in the presence of placebo or nicotine. The increase in HR, BP, and Ve was expressed in absolute unit changes from baseline values. In addition, changes in the rate-pressure product (systolic BP multiplied by HR) provided an estimate of the effects of nicotine on myocardial oxygen consumption.29

Statistical Analysis

All of the values were averaged over the entire 5 minutes of baseline and hypoxia. These averaged values were used for the statistical analysis. Results are expressed as mean±SEM. Comparisons were performed using a repeated-measures ANOVA (Statview 5.0, SAS). The ANOVA analysis was followed by post hoc comparisons using Fisher comparisons. Correlations were made with a regression analysis. A P value <0.05 was considered significant.

Results

Effects of Nicotine on Baseline Ve, BP, HR, and MSNA

Systolic, mean, and diastolic BP; HR; the rate-pressure product; and MSNA were higher after nicotine than after placebo (Table 1, Figure 1, and Figure 2). Nicotine also increased HR (79± 6 versus 72±4 bpm; P<0.05), the rate-pressure product (12 315±1139 versus 8779±1052 mm Hg×bpm; P<0.001), and MSNA (56±5 versus 48±4 bursts/min; P<0.05) during the apnea performed in normoxic conditions. Nicotine had no effect on Ve, on the duration of the apneas, or on the minimal oxygen saturation at the end of apneas. There was no difference in tidal volume with nicotine (571±36 mL) in comparison with placebo (561±44 mL; P=0.8). Breathing frequency was 12.0±0.9 breaths/min with nicotine and 12.1±0.7 breaths/min with placebo (P=0.8). End-tidal CO2 was 38.0±0.6 mm Hg under nicotine and 38.0±0.7 mm Hg under placebo (P>0.9). The duration of tobacco addiction (10±2 years) and the number of cigarettes per day (18±2) did not correlate with the ventilatory, hemodynamic, and sympathetic responses to nicotine (r<0.3; P>0.3). Changes in MSNA tended to be less marked in subjects with higher baseline burst frequency (r=−0.65; P=0.04). There were no differences in sympathetic, ventilatory, or hemodynamic responses to nicotine between men and women (P>0.1).

View this table:
  • View inline
  • View popup

TABLE 1. Effects of Nicotine on Baseline BP, HR, MSNA, and Ve

Figure1
  • Download figure
  • Open in new tab
  • Download powerpoint

Figure 1. Individual changes in MSNA burst frequency with nicotine.

Figure2
  • Download figure
  • Open in new tab
  • Download powerpoint

Figure 2. Recordings of ECG, neurogram, and respiration in a subject after taking a placebo tablet and after a nicotine tablet. HR and MSNA were higher after nicotine than after placebo.

Effects of Nicotine on Ve, BP, HR, and MSNA During Isocapnic Hypoxia

Systolic and mean BP, HR, and the rate-pressure product were higher during hypoxia after nicotine than after placebo (Table 2 and Figure 3). Sympathetic activation induced by nicotine during normoxia persisted during hypoxia and during the apnea in hypoxia. HR was higher during the apnea in hypoxia after nicotine than after placebo (99±6 versus 87±6 bpm; P< 0.01), as was the rate-pressure product (14 709±1900 versus 10 839±1173 mm Hg×bpm; P<0.05). Changes in tidal volume after 5 minutes of hypoxia were comparable with nicotine (+191±45 mL) and placebo (+179±39 mL; P=0.8). End-tidal CO2 did not differ at the fifth minute of hypoxia (nicotine, 37.6±0.7 mm Hg; placebo, 37.3±0.6 mm Hg; P=0.4). There was no effect of nicotine on Ve, respiratory frequency, the duration of the apneas, or the minimal oxygen saturation at the end of apneas.

View this table:
  • View inline
  • View popup

TABLE 2. Effects of Nicotine on BP, HR, MSNA, and Ve During 5 Minutes of Isocapnic Hypoxia

Figure3
  • Download figure
  • Open in new tab
  • Download powerpoint

Figure 3. Recordings of ECG, neurogram, and respiration during apnea in hypoxia in a subject after taking a placebo tablet and after a nicotine tablet. The oxygen saturation shown in the figure is the lowest saturation achieved at the end of the apnea (low O2 sat.). HR and MSNA were higher after nicotine then after placebo.

Discussion

This study assessed the acute effects of NRT on MSNA and chemoreflex sensitivity to hypoxia in healthy cigarette smokers. The main new findings of our study are that: (1) nicotine, per se, increases peripheral sympathetic nerve traffic; (2) this peripheral sympathetic overactivity persists during marked chemoreflex activation and apnea; and (3) these effects are not mediated by increased chemoreceptor sensitivity.

Nicotine Effects During Normoxia

Sympathetic overactivity is one of the mechanisms implicated in the higher cardiovascular risk in cigarette smokers.1,4,6,7,9 The adverse effects of sympathetic overactivity are, mainly, an increase in myocardial work, a decrease in ventricular fibrillation threshold, an acceleration of atrioventricular node conduction, and an induction of coronary vasoconstriction.30–32 All of these elements contribute to the increased incidence of acute cardiovascular events in cigarette smokers. A considerable decrease in the risk of cardiovascular events occurs immediately after the discontinuation of cigarette smoking.33 Alterations in BP, HR, and autonomic nervous function are thought to be at least in part responsible for this rapid decrease.34

We observed that nicotine induces acute increases in BP, HR, myocardial oxygen consumption, and sympathetic activity while subjects were breathing room air. In a previous study,4 smoking the first cigarette was also associated with a marked increase in both mean BP and HR but induced a baroreflex-mediated decrease in MSNA. However, smoking increases mean BP (±10 mm Hg)4 more than nicotine (±5 mm Hg in our study). When the BP increase in response to smoking was blunted by nitroprusside infusion, there was an increase in MSNA. Thus, both cigarette smoking and nicotine increase sympathetic activity when mean BP rises only by 5 mm Hg.

The exact mechanisms implicated in the increased sympathetic outflow induced by nicotine are unclear. Nicotine binds to nicotinic receptors located in autonomic ganglia, the adrenal medulla, the neuromuscular junction, and the brain.9,16,17 Sympathetic stimulation could be because of a direct effect of nicotine on the brain and autonomic ganglia. It could also result from catecholamine release from the adrenal glands or from direct release or enhanced release from vascular nerve endings.16,17,35 The peripheral chemoreceptors regulate resting sympathetic nerve traffic.13–15 Nicotine did not, however, affect chemoreflex sensitivity, as evidenced by similar minute Ve, apnea duration, and oxygen saturation after nicotine and placebo in normoxia. Thus, chemoreflex excitation is unlikely to play an important role in the sympathoexcitatory and cardiovascular effects of nicotine.

Nicotine Effects During Hypoxia

Our study provides the first direct evidence that NRT increases efferent sympathetic nerve traffic in healthy cigarette smokers, and it also reveals that this effect persists during marked chemoreflex activation and apnea. In many circumstances, increased baseline sympathetic activity reduces MSNA reactivity to acute stress, because the saturated system has no further reserve to increase sympathetic nerve firing.36,37 This contrasts with our observation that the nicotine-induced sympathoexcitation and hypertensive and tachycardic effects persisted even during the intense sympathetic nerve traffic activation elicited by hypoxia and apneas. This highlights the importance of the sympathetic facilitating effects of nicotine in habitual smokers.

Our study reveals that increases in myocardial oxygen consumption with nicotine persist during acute reductions in oxygen availability. This observation has potentially important implications, because cigarette smokers are often hypoxemic as a result of increased carbon monoxide concentrations and lung disease. Smoking is associated with a decrease in nocturnal oxygen saturation.38 Whether smoking increases the incidence of sleep apnea is debated.39 However, both conditions are so prevalent that it is likely that many smokers experience repeated episodes of hypoxemia in the presence of elevated nicotine concentrations. This could precipitate cardiac events and sudden death at night.40

The sympathetic effects of nicotine are also of primary concern with respect to the clinical risks of NRT. The cardiovascular risk of NRT has not been fully elucidated. There have been anecdotal reports of acute myocardial infarction and stroke in patients taking NRT. However, there is no evidence that NRT increases cardiovascular risk as compared with placebo in smokers with cardiovascular disease.8–11 NRT encourages smoking cessation. Moreover, it does not increase carbon monoxide concentrations and does not induce a hypercoagulable state, which contribute to the adverse cardiovascular effects of tobacco.8,9 Nevertheless, whereas NRT is less risky than cigarette smoking, the risk associated with NRT, as compared with other substitution therapies, should not be underestimated in patients with limited coronary reserve and at risk of sudden hypoxic events.

Nicotine and Chemoreflex Sensitivity to Hypoxia

Nicotine did not affect Ve during hypoxia, the duration of the apneas, or the reductions in oxygen saturation. This suggests that nicotine does not increase peripheral chemoreflex sensitivity. We did not expect these results, because glomus chemoreceptor cells contain excitatory nicotinic receptors.18–20 However, 2 elements have to be taken into consideration. First, nicotine increased BP in our subjects. This increase in BP, by itself, could decrease peripheral chemoreceptor sensitivity through a baroreflex-mediated mechanism.41 Further studies are, therefore, needed to determine whether suppression of the BP effects of nicotine may not unmask some increased nicotine-associated chemosensitivity to hypoxia. Second, chronic exposure to nicotine decreases the sensitivity of, or even completely inactivates, nicotinic receptors.42 Observations of acute chemoreflex sensitization with nicotine in animal studies may, therefore, not apply to adult chronic cigarette smokers.21,23–25

Perspectives

A study on the dose–response effects of nicotine on sympathetic activity and chemoreflex sensitivity, as well as a study evaluating the effects of nicotine in nonsmokers, are needed to determine whether the effects of nicotine on chemoreflex sensitivity are masked by a relative or complete inactivation of nicotinic receptors in habitual smokers. In conclusion, this study reveals that NRT exerts acute deleterious cardiovascular effects and sympathetic activation. These effects persist during marked chemoreflex activation and apnea.

Acknowledgments

This study was supported by the Erasme Foundation (B.N.), the Belgian National Fund of Research (P.v.d.B., A.H.), the Foundation for Cardiac Surgery, Belgium (P.v.d.B.), the Emile Saucez-René Van Poucke Foundation (P.v.d.B.), the David and Alice Van Buuren Foundation (P.v.d.B., B.N.), and the French Federation of Cardiology (A.P.). We thank Dr Gilbert Vassart for his advice and constructive comments on this article.

  • Received January 8, 2006.
  • Revision received January 26, 2006.
  • Accepted March 17, 2006.

References

  1. ↵
    Hallstrom AP, Cobb LA, Ray R. Smoking as a risk factor for recurrence of sudden cardiac arrest. N Engl J Med. 1986; 314: 271–275.
    OpenUrlPubMed
  2. ↵
    Willett WC, Green A, Stampfer MJ, Speizer FE, Colditz GA, Rosner B, Monson RR, Stason W, Hennekens CH. Relative and absolute excess risks of coronary heart disease among women who smoke cigarettes. N Engl J Med. 1987; 317: 1303–1309.
    OpenUrlCrossRefPubMed
  3. ↵
    Ambrose JA, Barua RS. The pathophysiology of cigarette smoking and cardiovascular disease: an update. J Am Coll Cardiol. 2004; 43: 1731–1737.
    OpenUrlCrossRefPubMed
  4. ↵
    Narkiewicz K, van de Borne PJ, Hausberg M, Cooley RL, Winniford MD, Davison DE, Somers VK. Cigarette smoking increases sympathetic outflow in humans. Circulation. 1998; 98: 528–534.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Niedermaier ON, Smith ML, Beightol LA, Zukowska-Grojec Z, Goldstein DS, Eckberg DL. Influence of cigarette smoking on human autonomic function. Circulation. 1993; 88: 562–571.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    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: 573–577.
    OpenUrlPubMed
  7. ↵
    Winniford MD, Wheelan KR, Kremers MS, Ugolini V, Van den Berg E Jr, Niggemann EH, Jansen DE, Hillis LD. Smoking-induced coronary vasoconstriction in patients with atherosclerotic coronary artery disease: evidence for adrenergically mediated alterations in coronary artery tone. Circulation. 1986; 73: 662–667.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    Benowitz NL. The role of nicotine in smoking-related cardiovascular disease. Prev Med. 1997; 26: 412–417.
    OpenUrlCrossRefPubMed
  9. ↵
    Benowitz NL. Drug therapy. Pharmacologic aspects of cigarette smoking and nicotine addition. N Engl J Med. 1988; 319: 1318–1330.
    OpenUrlCrossRefPubMed
  10. ↵
    Benowitz NL, Gourlay SG. Cardiovascular toxicity of nicotine: implications for nicotine replacement therapy. J Am Coll Cardiol. 1997; 29: 1422–1431.
    OpenUrlCrossRefPubMed
  11. ↵
    Henningfield JE. Nicotine medications for smoking cessation. N Engl J Med. 1995; 333: 1196–1203.
    OpenUrlCrossRefPubMed
  12. ↵
    Gray N, Boyle P. The future of the nicotine-addiction market. Lancet. 2003; 362: 845–846.
    OpenUrlCrossRefPubMed
  13. ↵
    Gonzalez C, Almaraz L, Obeso A, Rigual R. Carotid body chemoreceptors: from natural stimuli to sensory discharges. Physiol Rev. 1994; 74: 829–898.
    OpenUrlFREE Full Text
  14. ↵
    Lugliani R, Whipp BJ, Seard C, Wasserman K. Effect of bilateral carotid-body resection on ventilatory control at rest and during exercise in man. N Engl J Med. 1971; 285: 1105–1111.
    OpenUrlCrossRefPubMed
  15. ↵
    Ciarka A, Najem B, Cuylits N, Leeman M, Xhaet O, Narkiewicz K, Antoine M, Degaute JP, van de Borne P. Effects of peripheral chemoreceptors deactivation on sympathetic activity in heart transplant recipients. Hypertension. 2005; 45: 894–900.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Balfour DJ. The effects of nicotine on brain neurotransmitter systems. Pharmacol Ther. 1982; 16: 269–282.
    OpenUrlCrossRefPubMed
  17. ↵
    Nedergaard OA, Schrold J. The mechanism of action of nicotine on vascular adrenergic neuroeffector transmission. Eur J Pharmacol. 1977; 42: 315–329.
    OpenUrlCrossRefPubMed
  18. ↵
    Dinger B, Gonzalez C, Yoshizaki K, Fidone S. Localization and function of cat carotid body nicotinic receptors. Brain Res. 1985; 339: 295–304.
    OpenUrlCrossRefPubMed
  19. ↵
    Hayashida Y, Eyzaguirre C. Voltage noise of carotid body type I cells. Brain Res. 1979; 167: 189–194.
    OpenUrlPubMed
  20. ↵
    Obeso A, Gomez-Nino MA, Almaraz L, Dinger B, Fidone S, Gonzalez C. Evidence for two types of nicotinic receptors in the cat carotid body chemoreceptor cells. Brain Res. 1997; 754: 298–302.
    OpenUrlCrossRefPubMed
  21. ↵
    Holgert H, Hokfelt T, Hertzberg T, Holgert H. Functional and developmental studies of the peripheral arterial chemoreceptors in rat: effects of nicotine and possible relation to sudden infant death syndrome. Proc Natl Acad Sci U S A. 1995; 92: 7575–7579.
    OpenUrlAbstract/FREE Full Text
  22. ↵
    Lee LY, Morton RF, Frazier DT. Influence of nicotine in cigarette smoke on acute ventilatory responses in awake dogs. J Appl Physiol. 1985; 59: 229–236.
    OpenUrlAbstract/FREE Full Text
  23. ↵
    Sasaki M, Yamaya M, Hida W, Nakamura M, Sasaki T, Sasaki H, Takishima T. Effect of hypercapnia on ventilatory response to intravenous nicotine administration in anesthetized dogs. Respir Physiol. 1989; 78: 177–186.
    OpenUrlPubMed
  24. ↵
    Fernandez R, Larrain C, Zapata P. Acute ventilatory and circulatory reactions evoked by nicotine: are they excitatory or depressant? Respir Physiol Neurobiol. 2002; 133: 173–182.
    OpenUrlCrossRefPubMed
  25. ↵
    Kopczynska B, Szereda-Przestaszewska M. Response of respiratory muscles to intravenous nicotine challenge in anaesthetized cats. Respir Physiol. 1999; 116: 145–157.
    OpenUrlPubMed
  26. ↵
    Szereda-Przestaszewska M, Kopczynska B, Kaczynska K, Chrapusta SJ. Diverging respiratory effects of serotonin and nicotine in vagotomised cats prior to and after section of carotid sinus nerves. J Physiol Pharmacol. 2001; 52: 71–79.
    OpenUrlPubMed
  27. ↵
    Hirano T, Dinger B, Yoshizaki K, Gonzalez C, Fidone S. Nicotinic versus muscarinic binding sites in cat and rabbit carotid bodies. Biol Signals. 1992; 1: 143–149.
    OpenUrlPubMed
  28. ↵
    Sepkovic DW, Haley NJ. Biochemical applications of cotinine quantitation in smoking related research. Am J Public Health. 1985; 75: 663–665.
    OpenUrlPubMed
  29. ↵
    Gobel FL, Norstrom LA, Nelson RR, Jorgensen CR, Wang Y. The rate-pressure product as an index of myocardial oxygen consumption during exercise in patients with angina pectoris. Circulation. 1978; 57: 549–556.
    OpenUrlAbstract/FREE Full Text
  30. ↵
    Esler M. Sympathetic nervous system: contribution to human hypertension and related cardiovascular diseases. J Cardiovasc Pharmacol. 1995; 26 (suppl 2): S24–S28.
    OpenUrlPubMed
  31. ↵
    Podrid PJ, Fuchs T, Candinas R. Role of the sympathetic nervous system in the genesis of ventricular arrhythmia. Circulation. 1990; 82: I103–I113.
    OpenUrlPubMed
  32. ↵
    Seals DR, Dinenno FA. Collateral damage: cardiovascular consequences of chronic sympathetic activation with human aging. Am J Physiol Heart Circ Physiol. 2004; 287: H1895–H1905.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    LaCroix AZ, Lang J, Scherr P, Wallace RB, Cornoni-Huntley J, Berkman L, Curb JD, Evans D, Hennekens CH. Smoking and mortality among older men and women in three communities. N Engl J Med. 1991; 324: 1619–1625.
    OpenUrlCrossRefPubMed
  34. ↵
    Minami J, Ishimitsu T, Matsuoka H. Effects of smoking cessation on blood pressure and heart rate variability in habitual smokers. Hypertension. 1999; 33: 586–590.
    OpenUrlAbstract/FREE Full Text
  35. ↵
    Kruger C, Haunstetter A, Gerber S, Serf C, Kaufmann A, Kubler W, Haass M. Nicotine-induced exocytotic norepinephrine release in guinea-pig heart, human atrium and bovine adrenal chromaffin cells: modulation by single components of ischaemia. J Mol Cell Cardiol. 1995; 27: 1491–1506.
    OpenUrlCrossRefPubMed
  36. ↵
    Francis GS, Goldsmith SR, Ziesche S, Nakajima H, Cohn JN. Relative attenuation of sympathetic drive during exercise in patients with congestive heart failure. J Am Coll Cardiol. 1985; 5: 832–839.
    OpenUrlPubMed
  37. ↵
    Ng AV, Callister R, Johnson DG, Seals DR. Sympathetic neural reactivity to stress does not increase with age in healthy humans. Am J Physiol. 1994; 267: H344–H353.
    OpenUrlPubMed
  38. ↵
    Casasola GG, Alvarez-Sala JL, Marques JA, Sanchez-Alarcos JM, Tashkin DP, Espinos D. Cigarette smoking behavior and respiratory alterations during sleep in a healthy population. Sleep Breath. 2002; 6: 19–24.
    OpenUrlCrossRefPubMed
  39. ↵
    Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med. 2002; 165: 1217–1239.
    OpenUrlCrossRefPubMed
  40. ↵
    Shepard JW Jr, Garrison MW, Grither DA, Dolan GF. Relationship of ventricular ectopy to oxyhemoglobin desaturation in patients with obstructive sleep apnea. Chest. 1985; 88: 335–340.
    OpenUrlCrossRefPubMed
  41. ↵
    Heistad DD, Abboud FM, Mark AL, Schmid PG. Interaction of baroreceptor and chemoreceptor reflexes. Modulation of the chemoreceptor reflex by changes in baroreceptor activity. J Clin Invest. 1974; 53: 1226–1236.
    OpenUrlCrossRefPubMed
  42. ↵
    Hulihan-Giblin BA, Lumpkin MD, Kellar KJ. Effects of chronic administration of nicotine on prolactin release in the rat: inactivation of prolactin response by repeated injections of nicotine. J Pharmacol Exp Ther. 1990; 252: 21–25.
    OpenUrlAbstract/FREE Full Text
View Abstract
Back to top
Previous ArticleNext Article

This Issue

Hypertension
June 2006, Volume 47, Issue 6
  • Table of Contents
Previous ArticleNext Article

Jump to

  • Article
    • Abstract
    • Methods
    • Results
    • Discussion
    • Acknowledgments
    • References
  • Figures & Tables
  • Info & Metrics
  • eLetters

Article Tools

  • Print
  • Citation Tools
    Acute Cardiovascular and Sympathetic Effects of Nicotine Replacement Therapy
    Boutaïna Najem, Anne Houssière, Atul Pathak, Christophe Janssen, Daniel Lemogoum, Olivier Xhaët, Nicolas Cuylits and Philippe van de Borne
    Hypertension. 2006;47:1162-1167, originally published May 18, 2006
    https://doi.org/10.1161/01.HYP.0000219284.47970.34

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
  •  Download Powerpoint
  • Article Alerts
    Log in to Email Alerts with your email address.
  • Save to my folders

Share this Article

  • Email

    Thank you for your interest in spreading the word on Hypertension.

    NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

    Enter multiple addresses on separate lines or separate them with commas.
    Acute Cardiovascular and Sympathetic Effects of Nicotine Replacement Therapy
    (Your Name) has sent you a message from Hypertension
    (Your Name) thought you would like to see the Hypertension web site.
  • Share on Social Media
    Acute Cardiovascular and Sympathetic Effects of Nicotine Replacement Therapy
    Boutaïna Najem, Anne Houssière, Atul Pathak, Christophe Janssen, Daniel Lemogoum, Olivier Xhaët, Nicolas Cuylits and Philippe van de Borne
    Hypertension. 2006;47:1162-1167, originally published May 18, 2006
    https://doi.org/10.1161/01.HYP.0000219284.47970.34
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Related Articles

Cited By...

Subjects

  • Basic, Translational, and Clinical Research
    • Autonomic Nervous System

Hypertension

  • About Hypertension
  • Instructions for Authors
  • AHA CME
  • Guidelines and Statements
  • Permissions
  • Journal Policies
  • Email Alerts
  • Open Access Information
  • AHA Journals RSS
  • AHA Newsroom

Editorial Office Address:
7272 Greenville Ave.
Dallas, TX 75231
email: hypertension@heart.org

Information for:
  • Advertisers
  • Subscribers
  • Subscriber Help
  • Institutions / Librarians
  • Institutional Subscriptions FAQ
  • International Users
American Heart Association Learn and Live
National Center
7272 Greenville Ave.
Dallas, TX 75231

Customer Service

  • 1-800-AHA-USA-1
  • 1-800-242-8721
  • Local Info
  • Contact Us

About Us

Our mission is to build healthier lives, free of cardiovascular diseases and stroke. That single purpose drives all we do. The need for our work is beyond question. Find Out More about the American Heart Association

  • Careers
  • SHOP
  • Latest Heart and Stroke News
  • AHA/ASA Media Newsroom

Our Sites

  • American Heart Association
  • American Stroke Association
  • For Professionals
  • More Sites

Take Action

  • Advocate
  • Donate
  • Planned Giving
  • Volunteer

Online Communities

  • AFib Support
  • Garden Community
  • Patient Support Network
  • Professional Online Network

Follow Us:

  • Follow Circulation on Twitter
  • Visit Circulation on Facebook
  • Follow Circulation on Google Plus
  • Follow Circulation on Instagram
  • Follow Circulation on Pinterest
  • Follow Circulation on YouTube
  • Rss Feeds
  • Privacy Policy
  • Copyright
  • Ethics Policy
  • Conflict of Interest Policy
  • Linking Policy
  • Diversity
  • Careers

©2018 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. The American Heart Association is a qualified 501(c)(3) tax-exempt organization.
*Red Dress™ DHHS, Go Red™ AHA; National Wear Red Day ® is a registered trademark.

  • PUTTING PATIENTS FIRST National Health Council Standards of Excellence Certification Program
  • BBB Accredited Charity
  • Comodo Secured