CLINICAL RESEARCH: CARDIOVASCULAR EFFECTS OF TOBACCO
Hemodynamic and autonomic effects of smokeless tobacco in healthy young men
Robert Wolk, MD, PhD*,
Abu S.M. Shamsuzzaman, MBBS, PhD*,
Anna Svatikova, BA*,
Christine M. Huyber*,
Corey Huck, BA*,
Krzysztof Narkiewicz, MD, PhD and
Virend K. Somers, MD, PhD, FACC*,*
* Mayo Clinic, Rochester, Minnesota
Medical University of Gdansk, Gdansk, Poland
Manuscript received July 16, 2004;
revised manuscript received November 17, 2004,
accepted November 29, 2004.
* Reprint requests and correspondence: Dr. Virend K. Somers, Mayo Clinic, DO-4-350, 1216 Second Street SW, Rochester, Minnesota 55902
(Email: somers.virend{at}mayo.edu).
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Abstract
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OBJECTIVES: The aim of this study was to investigate the acute hemodynamic and autonomic effects of smokeless tobacco.
BACKGROUND: Smokeless tobacco use is increasing. Its cardiovascular effects are not well understood.
METHODS: Sixteen healthy, male, habitual snuff tobacco users (aged 22 ± 1 year) were studied, using a randomized, double-blind, placebo-controlled, crossover design with two separate experimental sessions: placebo and tobacco. Muscle sympathetic nerve activity (MSNA), electrocardiogram, blood pressure, calf blood flow, nicotine, and catecholamines were measured.
RESULTS: Snuff tobacco increased plasma nicotine from 2.8 ± 0.5 ng/ml to 10.4 ± 1.1 ng/ml. Mean blood pressure increased by 10 ± 1 mm Hg, and heart rate increased by 16 ± 2 beats/min. Peripheral vascular resistance, MSNA, and norepinephrine concentration did not change with tobacco, but epinephrine increased by  50%.
CONCLUSIONS: Oral snuff tobacco increases heart rate, blood pressure, and epinephrine. Despite the increase in blood pressure, there is no decrease in either MSNA or peripheral vascular resistance. Smokeless tobacco is a powerful autonomic and hemodynamic stimulus. Catecholamine release from the adrenal medulla likely contributes to this response.
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Abbreviations and Acronyms
| | BP = blood pressure | | HR = heart rate | | MSNA = muscle sympathetic nerve activity |
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Over 5,000,000 adults and >750,000 adolescents use smokeless tobacco in the U.S. (1). The prevalence is increased in young males, especially athletes (2,3). In contrast to cigarette smoking, the cardiovascular effects of smokeless tobacco are not well understood. Previous studies reported conflicting results regarding cardiovascular risk in persons using smokeless tobacco. Case-control studies suggest no increased risk of myocardial infarction or stroke in regular snuff users (4,5), but a tendency towards increased risk of fatal myocardial infarction (4). A prospective study linked smokeless tobacco to higher risk of cardiovascular death (6), although another study found no association between smokeless tobacco and cardiovascular mortality (7).
Similarly, studies investigating effects of smokeless tobacco on rest blood pressure (BP) (reviewed by Asplund [8]) are inconsistent, noting either an increase (9–12) or no significant change (13) in blood pressure after acute exposure to smokeless tobacco. Many previous studies were not placebo-controlled and/or were not blinded; mechanisms underlying any acute responses to spit tobacco were not investigated.
Effects of chewing tobacco on vascular resistance and sympathetic nerve traffic in humans have never been studied. Using a double-blind, randomized, placebo-controlled, crossover design, we investigated the acute effects of snuff tobacco on heart rate (HR), BP, peripheral vascular resistance, muscle sympathetic nerve activity (MSNA), and catecholamines in healthy male habitual tobacco users.
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Methods
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Study subjects.
We studied 16 healthy, male, habitual spit tobacco users (age 21 ± 1 year; body mass index 27 ± 1 kg/m2). None of the subjects was taking any medication nor had any chronic disease. All subjects were asked to avoid chewing or smoking tobacco for at least 12 h before each study. The study was approved by the Mayo Clinic Institutional Review Board.
Measurements and procedures.
Electrocardiogram was recorded continuously by EKG Bioamplifier (Gould Instrument Systems, Valley View, Ohio). Blood pressure was recorded continuously (Finapres, Ohmeda, Englewood, Colorado) and also measured every minute (Dinamap, Critikon Inc., Tampa, Florida). Calf blood flow was measured by venous occlusion plethysmography (14). Vascular resistance was calculated by dividing mean arterial pressure by flow and is expressed in arbitrary units. Multiunit postganglionic MSNA was recorded from the peroneal nerve with tungsten microelectrodes (15).
Blood samples were drawn at baseline during supine rest, and again after 30 min of tobacco chewing. Plasma nicotine was determined using liquid chromatography tandem mass spectrometry, with interassay variability of 20% at 2 ng/ml, 10% at 5 ng/ml, and 7% at >20 ng/ml. Plasma catecholamines were measured using high-performance liquid chromatography (with interassay and intra-assay variability of 3.4% and 3.1%, respectively).
Study protocol.
Subjects were studied in the supine position. All measurements were obtained using a randomized, double-blind, placebo-controlled, crossover design with two experimental sessions, a placebo session (Smokey Mountain snuff, Smokey Mountain Chew Inc., Darien, Connecticut), and a tobacco session (Copenhagen moist tobacco snuff, U.S. Tobacco, Nashville, Tennessee). Smokey Mountain and Copenhagen snuff are commercially available tobacco products that are similar in taste, texture, and color, except that Smokey Mountain snuff does not contain tobacco and is nicotine-free. Each session was conducted using the same protocol on two separate days, in a random order.
Baseline measurements were obtained after 10 to 15 min of rest. After the end of baseline recordings, the subjects were given orally 1.5 g of snuff tobacco/placebo for 15 min, followed immediately by the second dose of tobacco/placebo (also 1.5 g), which was then kept in the mouth until the end of the study. The second series of measurements was performed 30 min after the beginning of snuff administration, using exactly the same protocol as at baseline.
Hemodynamic and catecholamine data are reported for 16 subjects in whom measurements were obtained during both sessions. Stable MSNA signals of good technical quality were obtained on both sessions in 10 subjects.
Phenylephrine infusion.
Hemodynamic measures and MSNA were also recorded in a separate group of eight healthy subjects (6 males and 2 females; mean age 42 ± 2 years; two subjects were smokers) during phenylephrine infusion in the absence of snuff dipping, in order to mimic the BP responses observed with acute spit tobacco exposure. Phenylephrine was infused in progressively increasing doses to achieve changes in BP similar to those observed after snuff tobacco dipping in the main study cohort of spit tobacco users previously described.
Statistical analysis.
Data were analyzed using two-way analysis of variance for repeated-measures with time (before vs. after snuff dipping) as the within factor and session (placebo vs. tobacco) as the between factor. Paired and unpaired (as appropriate) Student t tests were also used for comparisons between groups with respect to the change ( ) in a given variable. A value of p  0.05 was considered statistically significant. Data are expressed as mean ± SEM.
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Results
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Hemodynamic, MSNA, and biochemical measures before and after placebo and tobacco sessions are shown in Table 1. At baseline, all variables were similar before the placebo and the tobacco sessions. Snuff tobacco dipping increased plasma nicotine (from 2.8 ± 0.5 ng/ml to 10.4 ± 1.1 ng/ml; p < 0.001), whereas levels remained stable during the placebo session (2.6 ± 0.6 ng/ml vs. 2.7 ± 0.6 ng/ml; p = NS). Furthermore, spit tobacco increased BP and HR (Fig. 1).
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Table 1. Hemodynamic Parameters, MSNA, and Biochemical Measurements Before and After Placebo and Tobacco Sessions (n = 16)
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Figure 1 Changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), and peripheral vascular resistance (PVR) during the placebo and tobacco sessions. *p < 0.001. Despite a 10-mm Hg increase in blood pressure, HR increased strikingly during tobacco use, with no change in PVR.
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Despite the increased BP, both peripheral vascular resistance (Fig. 1) and efferent sympathetic drive to peripheral blood vessels (MSNA) (Fig. 2) were unchanged after tobacco administration. In contrast, a similar increase in BP during phenylephrine infusion (at a dose of 1.06 ± 0.14 µg/kg/min) in healthy subjects in the absence of snuff tobacco dipping caused a marked decrease in HR and MSNA (Figs. 3 and 4).
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Figure 2 Changes in muscle sympathetic nerve activity (MSNA), plasma norepinephrine (Norepi), and epinephrine (Epi) during the placebo and tobacco sessions. Despite increased arterial pressure during tobacco use (Fig. 1), there was no difference in MSNA or Norepi, but a clear increase in Epi.
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Figure 3 Systolic blood pressure (SBP), heart rate (HR), and muscle sympathetic nerve activity (MSNA) responses after snuff tobacco (n = 10) as compared to phenylephrine infusion (in the absence of chewing tobacco) (n = 8). Heart rate increased during tobacco, but decreased with phenylephrine. Despite increased blood pressure during tobacco, there was no significant decrease in MSNA, although MSNA was virtually eliminated during phenylephrine. Faster HR and minimal MSNA suppression, despite the similar blood pressures with spit tobacco use compared to phenylephrine, suggest a potent cardiac and vascular excitatory effect of spit tobacco, which overcomes the cardiac and sympathetic inhibitory influences of baroreflex activation in response to the rise in blood pressure.
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Plasma norepinephrine concentration remained unchanged after spit tobacco, but epinephrine levels increased by about 50% (Fig. 2).
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Discussion
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The novel findings of this study are first, that snuff tobacco dipping causes an acute increase in HR and BP; second, that despite the significant BP increase, norepinephrine, peripheral vascular resistance, and efferent sympathetic outflow to muscle resistance vessels are not reduced by acute exposure to spit tobacco; and third, that administration of spit tobacco is associated with a significant increase in plasma epinephrine. These results suggest that the pressor effect of spit tobacco results most likely from an increase in cardiac output. Consistent with this explanation is the observed increase in HR.
Our results suggest the release of epinephrine from the adrenal gland in response to snuff tobacco. Indeed, nicotine evokes catecholamine secretion in adrenal medulla cell cultures (16,17). In dogs whose adrenal glands had been ligated, the pressor response to nicotine was diminished (18). The observed increase in plasma epinephrine speaks to the likelihood of preganglionic sympathetic excitation.
The acute increase in plasma epinephrine with spit tobacco may have implications for both intravascular thrombosis and cardiac arrhythmias. Epinephrine is an important platelet activator and is prothrombogenic; sudden surges in epinephrine may trigger a hypercoagulable state and platelet deposition in damaged arterial wall (19,20). Thus, smokeless tobacco may possibly provide a stimulus for occlusive arterial thrombosis. Epinephrine is also proarrhythmic in animal models and in humans (21); smokeless tobacco may thus conceivably trigger cardiac arrhythmias in susceptible individuals with an arrhythmogenic substrate. Risk for these potential complications may be magnified in the context of significant spit-tobacco-induced increases in BP and HR.
The absence of any significant inhibitory effect of spit tobacco on MSNA (consistent with the lack of any effect on peripheral vascular resistance in the present study) supports the concept of a sympathetic excitatory action of smokeless tobacco. Increasing BP by phenylephrine infusion, to the levels noted after snuff tobacco dipping, activates the baroreflex and elicits profound sympathetic inhibition (Figs. 3 and 4), which would obscure any sympathetic excitatory effects of smokeless tobacco. Therefore, the lack of suppression of MSNA and the increase in HR in the presence of elevated BP, together with the marked increase in epinephrine in response to spit tobacco in our present study, speak further to a potent, spit-tobacco-induced sympathetic excitation.
Several factors may help explain the increase in HR with spit tobacco use despite the BP rise (which would be expected to elicit baroreflex-mediated bradycardia). These include nicotine-induced activation of central sympathetic outflow to the heart, and the tachycardic effects of nicotine-induced epinephrine release. Nicotine also has many indirect actions on the heart, including the release of catecholamines from cardiac sympathetic nerve terminals (17).
Study limitations.
First, we studied the effects of smokeless tobacco only in habitual tobacco users, but we did not investigate the effects of first acute exposure in nonusers. Nevertheless, the practical applications of our results relate primarily to habitual users of smokeless tobacco.
Second, other mechanisms may explain some of the hemodynamic effects of smokeless tobacco, including high sodium content of smokeless tobacco products (which differs between different brands), as well as the presence of pharmacologically active ingredients other than nicotine (e.g., licorice) (22,23), not measured in the present study.
Conclusions.
Oral snuff tobacco leads to acute increases in HR, BP, and plasma epinephrine, in the absence of any reduction of either MSNA or peripheral vascular resistance. Increased epinephrine levels suggest an important role for catecholamine release from the adrenal medulla. These observations suggest that smokeless tobacco is a powerful autonomic and hemodynamic stimulus, with potential implications for cardiac and vascular risk.
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Figure 4 (A) Recordings of electrocardiogram (EKG), blood pressure (BP), muscle sympathetic nerve activity (MSNA), and respiration at baseline and after spit tobacco. Despite increased BP with tobacco use, heart rate (HR) increases, and MSNA is not suppressed. Contrast this with panel B showing the same measurements at baseline and after raising blood pressure using phenylephrine. With phenylephrine, there is a slowing of HR and a complete elimination of MSNA because of baroreflex activation.
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Footnotes
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Financial support: NIH HL-61560, HL-65176, HL-70302, MO1-RR00585, and 3F05-TW-05200.
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