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Nicotine Effect on Cardiovascular System and Ion Channels

Hanna, Salma Toma MD, PhD

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Journal of Cardiovascular Pharmacology: March 2006 - Volume 47 - Issue 3 - p 348-358
doi: 10.1097/01.fjc.0000205984.13395.9e
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Smoking adversely affects the cardiovascular system in human subjects. Smoking is associated with an increased risk of atherosclerotic vascular disease, hypertension, myocardial infarction, unstable angina, sudden cardiac death, and stroke.1 The adverse effects of smoking on vascular function have been examined in human subjects. These studies have shown that acute and chronic cigarette smoking impairs nitric oxide synthase mediated relaxation of large blood vessels.2 In addition, it appears that cessation of smoking is associated with improvement of endothelial function in human subjects. Mechanisms that contribute to impaired endothelium-dependent relaxation of large blood vessels during cigarette smoking have been investigated. Studies by Motoyama3 and Heitzer4 found that impaired endothelium-dependent vasodilatation observed in chronic smokers could be restored by acute treatment with vitamin C, an antioxidant. Thus it appears that oxygen radical formation plays an important role in impaired reactivity of large conduit vessels in chronic smokers.

Studies using animal models have shown that smoking and the components of cigarette smoke impair endothelium-dependent responses of blood vessels.5,6 Mechanisms that contribute to impaired endothelium-dependent reactivity of blood vessels after exposure to cigarette smoke also have been examined. It has been found that cigarette smoke extract-induced endothelium-dependent dilatation of cheek pouch arterioles could be restored by treatment with indomethacin, suggesting an impairment role for oxygen free radicals and/or vasoconstrictor prostanoids.7 This was confirmed by Suzuki et al5 (1996) who found that smokeless tobacco impaired endothelium-dependent dilatation of cheek pouch arterioles and that impairment could be reversed by treatment with indomethacin. Cigarette smoking is one of the risk factors for hypertension and stroke. However, a consensus of the causal relationship between cardiovascular disorders and consumption of smokeless tobacco has not yet been reached yet. What has been known is the acute hypertensive effect observed in smokeless tobacco users.8 During smokeless tobacco use (5 to 30 minutes), systolic and diastolic blood pressure persistently increased. This increase remained up to 90 minutes after smokeless tobacco use. The potential long-term risk of using smokeless tobacco is obvious because smokeless tobacco induced transient hypertension may predispose smokeless tobacco users to myocardial infarction, hypertension, and stroke.9 The most significant substance that raises blood pressure in smokeless tobacco is nicotine, a tertiary amine composed of a pyridine ring (Fig. 1). Yet the vascular effects of nicotine and the underlying mechanisms are still to be clarified. Nicotine, in smokeless tobacco, is absorbed rapidly through the oral mucosa in smokeless tobacco users. Absorbed nicotine may release catecholamine from sympathetic nerve endings.10,11 The subsequent activation of α-adrenoceptors in vascular smooth muscle cells contracts vascular tissues and elevates blood pressure.12 Nicotine may also act directly on vascular smooth muscle cells to induce vascular relaxation or contraction.13,14 The direct effect of nicotine on vascular smooth muscle cells as well as the nicotine-induced adrenergic stimulation would substantially contribute to altered cardiovascular function with smokeless tobacco consumption.

Structure of nicotine. Nicotine is a tertiary amine composed of a pyridine and a pyrrolidine ring.


Smoking is the primary risk factor in coronary and peripheral vascular disease. However, the precise component of cigarette smoke that contributes to the pathogenesis of vascular disease remains unclear. In vivo, acute infusion of nicotine at low concentrations causes impairment of the endothelium-dependent dilatation of peripheral resistance arterioles contained within the microcirculation of the hamster cheek pouch.15 High concentrations of nicotine, which increased plasma level of nicotine to 14 ng/ml, which is similar to that observed in smokers, produced a profound selective impairment in endothelium-dependent but not endothelium-independent vasodilatation. The effect of nicotine on endothelium-dependent vasodilatation is reversed by topical application of superoxide dismutase. Therefore, it has been suggested that nicotine impairs endothelium-dependent arteriolar dilatation via an increase in the synthesis/release of oxygen-derived free radicals.16 Cigarette smoke and products of cigarette smoke produce diffuse vascular injury in many organ systems and impair nitric oxide synthase-dependent dilatation of large peripheral arteries17 and resistance arterioles.7 Investigators have shown that nicotine has toxic effects on endothelium, and thus nicotine may play a key role in impaired nitric oxide synthase dependent vasoreactivity observed in users of tobacco. Nicotine produces morphologic abnormalities of the endothelium causing direct alteration of the vascular reactivity. It produces its toxic effect via the production of oxygen free radicals.18 Heitzer et al4 reported that treatment of smokers with vitamin C, an antioxidant, improved impaired endothelium-dependent reactivity of large peripheral arteries.

The acute model of nicotine treatment has important implications for the chronic effect of smoking on vascular reactivity. In animal models implanted with pumps containing nicotine, it has been shown that plasma levels were strongly related to the dose of nicotine administered (0.18–4.7 mg/kg/d). There was a strong positive correlation between plasma levels of nicotine and its major metabolite cotinine in nicotine treated rats. It is probable that nicotine concentration in habitual smokers is elevated throughout the course of the day. In support of this, Isaac and Rand19 have shown that the plasma level of nicotine is 25±6 ng/ml at 6.5 hours after ad libitum smoking. Furthermore, several previous studies have shown that plasma levels of nicotine are elevated in chronic smokers.3,9,20 Thus, although many of the above studies examined the acute effects of nicotine infusion on arteriolar reactivity, it is believed that longer-term studies have important implications for the chronic effects of cigarette smoking and the use of smokeless tobacco products on vascular reactivity because this might more accurately reflect that found in chronic smokers. And indeed, it has been shown that in hamsters chronically treated with nicotine (2 μg/kg/d) for 2 to 3 weeks the resistance arterioles of the cheek pouch produces a selective impairment of endothelium-dependent arteriolar dilatation via a mechanism related to the synthesis/release of oxygen derived free radicals.21 The magnitude of vasodilatation in resistance arterioles after acetylcholine was significantly less in hamsters treated with nicotine than in control hamsters. Superfusion with superoxide dismutase potentiates responses of the arterioles to acetylcholine. Thus it appears that superoxide dismutase, although it does not affect the baseline diameter of resistant arterioles, it can prevent the impairment of endothelium-dependent arteriolar reactivity in hamsters treated with nicotine. Although, these previous studies provide insights into the mechanisms by which acute and chronic treatment of nicotine could alter the endothelium-dependent reactivity of resistance vessels there are other studies that showed nicotine might not have altered acetylcholine-induced changes in perfusion pressure of isolated mesenteric circulation. Li and colleagues22 examined the pressure drop across the isolated perfused mesenteric arteries in rats in response to acetylcholine. These investigators found that chronic (2 weeks) treatment with nicotine did not alter acetylcholine-induced changes in perfusion pressure of isolated rat mesenteric circulation. Thus they did not directly examine vascular reactivity of the resistance arterioles in an in vivo setting. In addition, because they did not examine the role of nitric oxide in acetylcholine-induced changes in perfusion pressure of the mesenteric circulation, the precise role of nitric oxide in this response is not clear. Furthermore, they did not examine the possibility that the experimental procedures damaged the endothelium and thus affected the degree of vasodilatation observed in response to acetylcholine.

Previous physiological and histopathological studies showed that smokeless tobacco (snuff) affects vasomotor tone and the barrier function of microvessels in the oral mucosa. It has been shown that aqueous extracts of smokeless tobacco (moist snuff) can significantly attenuate vasodilatation in an endothelium-dependent manner.5 In the rat, two types of innervations of peripheral blood vessels have been identified: adrenergic nerves causing vasoconstriction and sensory nerves that produce a vasodilator response.23 Rat tail artery is studied in many cases as a model of a peripheral artery, yet it is not considered a resistance artery. Nicotine causes a transient contraction of rat tail artery strips. Nicotine also induces transient contractions of rat tail artery strips in an extracellular Ca2+-dependent and endothelium-independent fashion.13 This study also showed that the nicotine-induced contraction may not be due to the stimulation of postjunctional α2-adrenoceptors or due to the effect of ATP putatively released from nerve endings. The activation of α1–adrenoceptors may account for the nicotine-induced contraction. Furthermore, the nicotine-induced vasoconstriction was not affected by tetrodotoxin excluding the possible presynaptic depolarization induced by nicotine. However, in another study on rat tail artery rings no vasoconstriction was found in the presence of nicotine.24 There is controversy about smoking as an independent predictor of abnormal vasomotor function in the coronary circulation; although recent studies reported impaired flow-mediated vasodilation of brachial artery in clinically healthy smokers, stimulated endothelium-dependent relaxation of peripheral resistance vessels was found to be unaffected. Importantly, the underlying mechanisms involved in the pathophysiology of endothelial dysfunction in hypercholesterolemia or long-term smoking are not clearly identified. Several mechanisms such as reduced synthesis and release of EDRF or enhanced inactivation of EDRF after its release from endothelial cells by radicals or oxidized low density lipoprotein (LDL) have been postulated. Previous studies have noted increased plasma levels of autoantibodies against oxidized LDL and increased circulating products of lipid peroxidation in long-term smokers, raising the possibility that long-term smoking potentiates endothelial dysfunction in hypercholesterolemia by increasing circulating and tissue levels of oxidized LDL. Heitzer et al4,25 have shown that both smoking and hypercholesterolemia were significant factors for plasma levels of autoantibodies against oxidized LDL. Patients with both risk factors showed a marked increase of autoantibodies against oxidized LDL. There was a significant relation between autoantibody titers and maximal forearm blood flow response to acetylcholine. This study extends previous observations by demonstrating that long-term smoking is associated with markedly reduced acetylcholine response in forearm resistance vessels. This impairment seems to be restricted to endothelium-mediated dilation. Whether smoking causes endothelial dysfunction in resistance arterioles appears to be dependent on the degree of cigarette consumption. Rangemark and Wennmalm26 demonstrated that in young smokers an enhanced vascular response to acetylcholine, sodium nitroprusside, and reactive hyperemia, suggesting a smoking-induced nonspecific enhancement of sensitivity of forearm resistance vessels to all tested vasodilator stimuli. Furthermore, Jacobs et al27 showed no significant differences in forearm blood flow in response to methacholine in young smokers compared with healthy control subjects. In these particular studies, however, the patient population was younger and the degree of cigarette consumption was considerably less than in the Heitzer study. A dose dependence of smoking-related endothelial dysfunction is also supported by other studies showing a significant inverse correlation between pack-years smoked and flow-mediated dilation of the brachial artery. The work of Celermajer et al17 established that the vasodilator response to acetylcholine in human is in part related to the release of NO. Therefore, the demonstration of an impaired acetylcholine response in smokers is consistent with the notion that smoking is associated with impaired stimulated release or availability of NO from peripheral resistance vessels.


The aorta acts as both a conduit and elastic buffering chamber that modulates left ventricular function and coronary blood flow. It has been shown that oxygen free radical species contained in the water-soluble component of cigarette smoke extract contract arteries such as aorta. Smokers appear to be susceptible to the activity of oxygen free radicals and have decreased concentrations in plasma vitamin E2, vitamin C, and β-carotene, possibly in response to a sustained oxidant stress. Others showed that endothelium-dependent relaxation is impaired in smokers. It has been demonstrated that cigarette smoke extract decrease levels of Nox, stable metabolites of NO. This is in agreement with other clinical studies, which showed that NO activity in the coronary arteries is decreased in chronic cigarette smokers.28 Cigarette smoke extract is known to contain a considerable amount of oxygen free radicals such as superoxide anions, hydroxyl radicals, or hydrogen peroxides. Ota et al6 demonstrated that superoxide dismutase (SOD), N-acetylcysteine (NAC), glutathione (GSH), and dimethyl sulfoxide (DMSO), scavengers of oxygen free radicals, attenuated the cigarette smoke extract-induced impairment of endothelium-dependent relaxation of rabbit aorta. Clinical studies in patients showed that passive and active smoking is associated with an acute deterioration in the elastic properties of the aorta.29 Furthermore, other investigations demonstrated increased aortic stiffness in female but not in male smokers.30 This indicates that the aorta of women might be more vulnerable to smoking with regard to stiffening and degeneration than the aorta of men.

Treatment of young rats with vitamin D3 plus nicotine has been proposed as a model of cardiovascular calcium overload (Fig. 2). Analysis of the tissue showed pronounced calcium overload in compliance vessels (aorta and carotid artery), with small but significant changes in small muscular arteries (mesenteric and tail arteries).31 This was accompanied by a 1.6-fold elevation of pulse pressure. In essential hypertension in humans or genetic hypertension in rats, calcium accumulation occurs preferentially in the terminal portion of the arterial system (ie, in small muscular arteries and arterioles), and may be one of the factors leading to increases in total peripheral resistance and diastolic arterial pressure. In the vitamin D3 plus nicotine (VDN) model, calcium accumulation in small muscular arteries (tail and mesenteric) is far less important than that in the aorta. This pattern of calcium overloading, which is similar to that observed in atherosclerosis, may explain the increase in diastolic blood pressure. An increase in pulse pressure is a complication of vascular aging and occurs primarily in subjects over the age of 60 years. The vitamin D3 plus nicotine represent the only available model that shows an isolated increase in pulse pressure in a non-hypertensive animal that is in reasonably good health. Many scientists have stressed the importance of the development of drugs, which produce a selective decrease in pulse pressure in the treatment of cardiovascular diseases, and this model may be a useful tool in the search for such a substance.32

Schematic diagram of vitamin D3 plus nicotine (VDN) model.

In humans, aging produces many structural changes in blood vessels, one of the most pronounced being arterial calcium overload. Simultaneously arteries become increasingly more rigid.32

Calcium accumulates preferentially on the internal elastic membrane. This may explain the decrease in endothelial vasodilator function in the VDN model. Calcification of the internal elastic membrane leads to the formation of a less permeable barrier between the endothelial and the smooth muscle cells. A similar hypothesis may be applicable to vascular aging in humans. Furthermore, endothelial factors modify carotid compliance; thus calcification of the internal elastic membrane may be involved in the decrease in compliance in the VDN model. In VDN rats there is significant correlation between aortic calcium content and two independent indexes of large vessel wall rigidity (ie, carotid arterial compliance and aortic pulse wave velocity). This suggests that vascular calcium overload renders the large elastic compliance vessels more rigid. This can happen in three possible ways. First, is that deposition of calcium on the internal elastic membrane modifies endothelial function. The second possibility is that deposition of calcium on medial elastic fibers modifies their functional properties leading to a change in the viscoelastic properties of the extracellular matrix. A third possibility is that calcification of the medial elastic fibers, together with cyclic stress, leads to fragmentation of elastic fibers. This could have two consequences. First, arterial dilatation may occur and the ensuing reduction in wall stress would lead, according to the Laplace law, to medial hypertrophy. The second consequence of fracture of elastic fibers may be the accumulation of collagen and ground substances following a connective tissue repair process that occurs in the VDN model; however, an increase in the collagen to elastin ratio would also lead to an increase in arterial wall stiffness.


Hemodynamic studies in canine and simian models clearly demonstrated that penile erection is the result of increased arterial flow, decreased venous flow, and sinusoidal relaxation. Anatomic and pharmacological studies showed that the smooth muscles of the arterial and sinusoidal spaces play a key role in erection and detumescence. In the flaccid state, the cavernous muscles and the helicine arteries are contracted and allow minimal arterial flow and free venous drainage. Sexual stimulation results in relaxation of cavernous and arterial smooth muscles with increased compliance of sinusoidal spaces; the drop in resistance to the internal pudendal artery allows maximal flow into the sinusoidal spaces. Distension of these spaces against the relatively inelastic tunica albuginea results in compression of the venules and emissary veins, effectively reducing venous flow during erection. Previous studies33 have demonstrated that the erection response in dogs is affected by cigarette smoking. Smoking has a greater effect on the venous mechanism, which is primarily controlled by cavernous smooth muscle, than on the arterial smooth muscles. However, human studies have shown that cigarette smoking causes erectile dysfunction largely by impairing arterial flow to the penis. Levine and Gerber34 have demonstrated that, in humans, duplex ultrasound revealed adequate (>30 cm/s) flow velocity in the deep penile arteries. Duplex ultrasound allows the measurement of the size and the dilatation of the cavernosal arteries as well as the blood velocity in the cavernosal and dorsal penile arteries. Cavernosometry and cavernosography revealed extensive venous leakage in the deep dorsal and cavernosal venous system. After the patients smoked 2 cigarettes, there was a decrease in the caliber of the entire pudendal artery and nonvisualization of the deep penile artery. These observations suggested that cigarette smoking might cause acute vasospasm of the penile arteries.

In a study done on 132 consecutive patients with erectile impotence three vascular risk factors, smoking, diabetes mellitus, and hypertension, were investigated for their impact on vasculogenic impotence.35 The incidence of penile vascular impairment was found to be higher in patients with one vascular risk factor than in those with none. The proportion of abnormal penile vascular findings increases significantly as the number of risk factors increase. In human studies, to examine the relation between smoking and erectile physiology, evaluation should include interviews, physical examinations, and polysomnography assessment of sleep-related erections. It has been found that penile rigidity during nocturnal erection inversely correlates with the number of cigarettes smoked per day. Hirshkowitz et al20 demonstrated that the group of men who smoked the most (more than 40 cigarettes per day) had the fewest minutes of nocturnal tumescence, and detumesced the fastest. These data were discussed with respect to the findings of Juenemann et al,33 which demonstrated smoking-related reduction in arterial flow and venous restriction. These findings suggest that smoking may further compromise penile physiology in men experiencing difficulty in maintaining erections long enough for satisfactory intercourse.


Nicotine produced cholinergic excitatory and adrenergic and non-adrenergic inhibitory responses in guinea-pig isolated trachea, which were blocked by hexamethonium or tetrodotoxin, demonstrating that nicotine acetylcholine receptors (nAchRs) in nervous tissue were being activated.36 However, the contractile response of the bronchial preparation to nicotine was inhibited by hexamethonium and D-tubocurarine, but not influenced by atropine, physostigmine, tetrodotoxin and BTM-1042, an inhibitor of acetylcholine release from parasympathetic nerve.37 These results suggest that nicotine does not bring about contraction by stimulation of parasympathetic ganglion cells. Furthermore, Takayanagi38 showed that in tracheal preparations where nicotine stimulated the nicotine receptors in the parasympathetic ganglion cells, the nicotine-induced contraction was considerably enhanced by the treatment of the guinea pig with egg-albumin. However, the contractile response of the bronchial preparation to nicotine was affected by the same treatment, suggesting that a site of action of nicotine in the bronchial preparation was not on the cholinergic nerve cells. The fact that the contractile response of bronchial preparations to nicotine was not influenced by tetrodotoxin suggests that a possible site of action in the bronchial preparations is on the smooth muscle cells and not on the nerve cells. However, another possibility exists that nicotine caused release of transmitters from the nerve ending by a process not involving a tetrodotoxin-sensitive Na+ channel.

A preponderance of evidence from prospective studies with autopsy follow-up, from autopsy studies with retrospective smoking data, and from experimental studies indicates that cigarette smoking and especially nicotine aggravates and accelerates the development of atherosclerosis. Although the specific mechanisms by which smoking affects arteriosclerosis have not been clearly determined, the interaction of toxic substances with vascular wall cells, especially in smooth muscle cells and endothelial cell, seems to be a key mechanism. The difficulty of most experimental studies consists of the lack of a valid quantification method for the reactions of these cells to toxic substances. Csonka et al39 found a rise in intracytoplasmic filaments in endothelial cells under the influence of nicotine and an increase in smooth muscle cell mitotic rate, whereas the mitotic rate of fibroblasts was not increased. In contrast, Strohschneider et al40 found that in in vivo experiments there was an increase in the bromodeoxyuridine (BrDu) labeling index of endothelial cells under the effect of chronic nicotine consumption. Chronic nicotine delivery for either 7 or 14 days did not increase the plaque size significantly compared with controls. Cholesterol diet for 14 days, however, led to a clear increase in plaque size compared with controls.

Most data demonstrate that cigarette smoking has a significant positive relationship to atherosclerosis.1,2,6,8,40–42 Numerous investigators have studied the effect of nicotine administration on experimentally induced changes in the aorta and coronary arteries of animals. When administered alone, nicotine induces certain degenerative or necrotic changes in the arterial wall, but these are characteristically medical changes rather than the intimal changes that characterize atherosclerosis. When nicotine is delivered in combination with a cholesterol diet, it seems to aggravate arterial damage, according to a preponderance of studies, and typical atherosclerotic plaques develop.40 Strohschneider and colleagues40 showed no increase in the BrdU labeling index of smooth muscle cells under the effect of nicotine in preformed plaques. In contrast under a cholesterol diet a significant increase in BrdU positive smooth muscle cells could be seen. This is in contrast to the results of cell culture experiments showing an increased smooth muscle cell proliferation rate. However, these results showed the indirect effect of altered total cholesterol and triglyceride concentrations and the altered high-density lipoprotein/low density lipoprotein (HDL/LDL) ratio that could be observed under nicotine delivery.

Development of intimal hyperplasia after vessel wall injury is initiated by the activation and proliferation of smooth muscle cells in the tunica media. Subsequently, the smooth muscle cells migrate to the subendothelial space, where they proliferate and synthesize the extracellular matrix.41,42,43 In vivo studies clarified the role of basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) in the formation of intimal lesions; bFGF is essential for smooth muscle cell proliferation, whereas PDGF promotes smooth muscle cell migration to subendothelial space.42,43 Cell migration is preceded by the breakdown of the extracellular space by matrix metalloproteinases (MMPs). The major groups of MMPs are collagenases, stromelysins, and gelatinases. The collagenases digest collagen types I, II, and III, whereas the stromelysins degrade collagen type IV, basal laminins, and basement membranes. The gelatinases degrade denatured collagens and collagen style IV.43

Decreased patency rates44,45 for aortic and infrainguinal grafts, as well as an increased restenosis rates after carotid endarterectomy among cigarette smokers, have been well documented but were often attributed to the progression of atherosclerosis and the alteration of blood coagulation rather than the development of intimal hyperplasia. Law et al43 showed that inhalation of cigarette smoke enhanced the development of intimal hyperplasia in an experimental arterial injury in rats. Nicotine levels in plasma peak within 10 minutes of the initiation of smoking and range from 6 to 19×10−8 mol/L in active smokers. The elimination of half-life of nicotine is 2 hours.46 Cotinine is formed in the liver by oxidation of nicotine and has a biologic half-life of approximately 20 hours. Cotinine plasma concentrations in passive smokers can be as high as 3.6 to 11×10−8 mol/L.47–49


Cigarette smoking is known to be associated with atherosclerosis and to be an important risk factor for stoke. Although chronic cigarette smoking has been reported to reduce cerebral blood flow (CBF), acute inhalation of cigarette smoke or administration of nicotine has been reported to increase,50 to maintain, or to decrease51 CBF levels in smokers. These apparent discrepancies between the effects of chronic and acute smoking and among acute studies could arise from many factors, including the dose of cigarette smoke or nicotine, the individual's smoking history, and different timing of the measurements. Mainstream cigarette smoke has been said to contain more than 4000 or more constituents (eg, nicotine, tar, phenol, acetic acid, CO, CO2, and NO2). The influence of cigarette smoking on cerebral vasculature seems likely to be a net effect of not only nicotine but also other constituents of mainstream cigarette smoke. In isolated coronary arteries, cigarette smoke extract produces a biphasic action on vascular tone (contraction followed by relaxation). In addition to the potential biophysiological differences between coronary and cerebral arteries, in vivo cigarette smoking is quite different from the in vitro situation. In vitro studies bypass the airways and eliminate the filtering action of the lungs.

Results from pharmacological studies in isolated vascular preparations have indicated that cerebral arteries from several species receive vasodilator and constrictor nerves.52 Using in vitro tissue bath technique, transmural nerve stimulation (TNS) or field electrical stimulation of the intramural nerves has been shown to elicit vasoconstriction, dilatation, or bi-model response in isolated cerebral arteries, depending on the region of the arteries and species of the experimental animals examined. The neurogenic vasodilator response on TNS, however, is predominant in cerebral arterial segments from most species examined. Few cerebral arteries such as the basilar arteries from rabbits and sheep constricted predominantly upon TNS. The constriction results from excitation of the adrenergic sympathetic nerves, and the dilatation from that of the non-adrenergic nerves. Because TNS depolarizes all intramural nerves, the TNS-elicited responses, therefore are the net results of constriction and relaxation. In rabbit basilar arteries, TNS-elicited sympathetic vasoconstriction was reversed to a vasodilatation in the presence of guanethidine (GUA), an adrenergic neuronal blocker, suggesting that sympathetic nerves are regulating the rabbit basilar arterial tone. In basilar, middle, cerebral arteries, and the circle of Willis from several other species including the pig and cat, TNS elicited exclusive relaxation. However, GUA did not significantly affect this TNS-elicited vasodilation.53 Although these arteries receive dense catecholamine fibers with high content of endogenous norepinephrine that is readily released upon TNS, these vascular beds sympathetic nerves may play a minimum role in regulating vascular tone. The mechanism of action of nicotine in inducing cerebral vasodilatation is different from that of TNS in that its effects are receptor mediated.12 It has been demonstrated that nicotine acts on nicotinic receptors on the adrenergic nerves to release norepinephrine, and on the nitric oxidergic nerves to release NO. Zhang et al,54 demonstrated that both nicotine and TNS induced relaxation in the porcine basilar arteries without endothelial cells. Both relaxations were neurogenic in nature and were mediated primarily by NO because the relaxation produced by nicotine and TNS were abolished by N-nitro-L-arginine. Nicotine appears to act on nicotinic receptors on the presynaptic adrenergic nerve terminals to release norepinephrine or a related substance, which then stimulates release of nitric oxide from the neighboring nitric oxidergic nerves. However, the TNS-elicited nitric oxide mediated relaxation, is resulted from direct depolarization of nitric oxidergic nerves. This is consistent with findings reported by others that nicotine-induced relaxation in cerebral blood vessels is mediated by NO. The nicotine-induced nitric oxide mediated relaxation is dependent on intact adrenergic innervation.54

Acute inhalation of mainstream cigarette smoke has been reported to produce a significant biphasic changes in the diameter of cerebral arterioles. Smoke inhalation caused pial arterioles to constrict followed by a dose-related vasodilatation. Nicotine infusion caused a vasodilatation of pial vessels without an initial vasoconstriction. The vasoconstriction induced by smoke inhalation was blocked by seratrodast (thromboxane A2 receptor blocker), suggesting that the substance responsible for vasoconstriction is TxA2. Mecamylamine (nicotinic receptor antagonist), propranolol (β-adrenoceptor antagonist), L-NAME (NO synthase blocker), and glibenclamide (ATP-sensitive channel blocker) all reduced or prevented the dilatation of cerebral vessels induced by acute cigarette smoking in the rat model. Inhalation of nicotine, contained in the mainstream smoke from a low or high nicotine containing cigarette causes the vascular tone to decrease and involve, at least in part, sympathetic activation, stimulation of NO production, and the opening of ATP-sensitive K+ channels.55


Nicotine is the main constituent of tobacco smoke responsible for the elevated risk of the cardiovascular disease and sudden coronary death associated with smoking, presumably by provoking cardiac arrhythmias. The cellular mechanisms may be related to the ability of nicotine to prolong action potentials and depolarize membrane potential. However, the underlying ionic mechanisms remained unknown. Wang and colleagues56 demonstrated that nicotine blocked multiple types of K+ currents (including A-type currents, delayed rectifier current and inward rectifier current) with preferential inhibition of transient outward currents Ito/Kv4.3. Those results indicate that nicotine is a non-specific blocker of K+ channels with certain selectivity toward A-type currents. The effects of nicotine were independent of cholinoceptor stimulation or catecholamine release because the effects were not reversed or prevented by mecamylamine (100 μM, nicotinic cholinoceptor antagonist), atropine (1 μM, muscarinic cholinoceptor antagonist), or propranolol (2 μM, non-selective β-adrenoceptor antagonist). Thus the inhibitory effects are likely to be the consequence of direct interactions between nicotine molecules and the channel protein. Reports on the effect of nicotine on ion channels are not conclusive. Wang et al56 provided insight into potential mechanisms underlying nicotine-induced block of A-type currents. Approximately 40% of the total inhibition could be ascribed to tonic block, with the remainder (60%) due to use-dependent block, for both Kv4.3 and Ito. Nicotine inhibits cardiac A-type K+ channels, with blockade probably due to block of closed and open channels. This may contribute to the ability of nicotine to affect cardiac electrophysiology and induce arrhythmias. The cardiac effects of nicotine have been ascribed to enhanced release of catecholamines. However, accumulating evidence has shown that nicotine can also exert its effects without involvement of nAchRs and catecholamine release. Studies under conditions devoid of nAchR stimulation demonstrated the ability of nicotine to alter action potential (AP) characteristics in guinea pigs,57 rabbits,58 and dogs59 in different tissues such as sinus nodes, atrium, ventricle, and Purkinje fibers. The most noticeable changes were decreases in resting potential and prolongation of later AP phases. It is therefore quite conceivable that nicotine might be able to interact directly with ion channels. However, nicotine effect through stimulation of nicotine receptors has been reported by Hamon et al.60 Nicotine inhibited slowly inactivating K+ currents in rat cultured striatal neurons. The effects were attributed to stimulation of nicotine receptors, because the nicotinic antagonist dihydro-β-erythroidine reversed and nicotinic agonists reproduced the block.

Direct effects on K+ channels were not revealed until recently by our laboratory14 in experiments that used vascular smooth muscle cells. Tang et al14 demonstrated that in rat tail artery SMCs nicotine differentially affect the whole-cell K+ channel currents.14 At low concentrations (1–100 μM), nicotine increased K+ channel currents via the stimulation of nAchRs. At high concentrations (0.3 mM–3 mM), nicotine inhibited K+ currents due to its direct effect on K+ channel proteins because the inhibitory effect of nicotine cannot be abolished by a nicotinic receptor antagonist. These observations on isolated vascular SMCs were reconciled by a vascular contractility study. Nicotine induced three types of vasoactive responses of isolated rat tail artery tissues (ie, contraction, relaxation, and rebound contraction upon the removal of nicotine).13 Nicotine caused a transient contraction of rat tail artery strips in an extracellular Ca2+-dependent and endothelium-independent fashion. Incubating tail artery tissues with the nicotine receptor antagonist dihydro-β-erythroidine hydrobromide at 10 μM did not affect the nicotine-induced vasoconstriction, vasorelaxation, or the nicotine withdrawal induced rebound contraction. When the concentration of dihydro-β-erythroidine hydrobromide was increased to 300 μM, the nicotine-induced vasodilatation, but not the vasoconstriction or the nicotine withdrawal induced rebound contraction, was significantly reduced. Nicotine can also exert its cellular effects without the involvement of nAchRs or catecholamine release. Several studies performed under conditions devoid of nAchR stimulation demonstrated the ability of nicotine to alter action potential characteristics in various species including guinea pig57 and rabbit,58 as well as in different types of tissues such as sinus node, atrium, ventricle, and Purkinje fiber. In a very recent study from our laboratory61 we were the first one reporting the effects of nicotine on Kir6.1 channel protein expressed in human embryonic kidney cells (HEK-293). KATP channels are composed of a pore forming inwardly rectifying K+ channel (Kir6.x) tetramer and a regulatory sulphonylurea receptor (SUR) tetramer that confers sulphonylurea sensitivity. Different combinations of Kir6.x and SUR yield the tissue-specific KATP channel subtypes with different electrophysiological and pharmacological features. Kir6.1 subunit has been recognized as the main pore-forming subunit of KATP channel complex in vascular smooth muscle cells (SMCs).61 Nicotine at low concentrations (30 μM–100 μM) immediately increased, but at millimolar concentrations gradually inhibited, Kir6.1 currents. The presence of Kir6.1 antibody (Kir6.1 Ab) abolished both the inhibitory and stimulatory effects of nicotine at different concentrations on Kir6.1 currents. Because the Kir6.1 Ab was against a 79 aa fragment of Kir6.1 at its C terminus,62 the interaction of nicotine with Kir6.1 channels in the presence of Kir6.1 Ab suggest that this 79 aa C-terminal epitope may be the interacting sites of Kir6.1 channel protein with nicotine. Nicotine at 100 μM increased the production of superoxide anion (O2•−) by 20.3+/−5.7%, whereas at 1 mM it significantly decreased the production of O2•− by 37.7+/−4.3%.61 Co-application of hypoxanthine (HX) and xanthine oxidase (XO) to the transfected HEK-293 cells resulted in a significant and reproducible increase in Kir6.1 currents. The stimulatory effect of HX/XO on Kir6.1 current was abolished by tempol, a scavenger of O2•−. Tempol also abolished the stimulatory effect of 30 μM nicotine on Kir6.1 currents. In conclusion, nicotine stimulates Kir6.1 channel at least in part through the production of O2•−.61

In hamster's cheek pouch resistance arterioles the nicotine-induced endothelium-dependent vasodilatation was reversed by topical application of superoxide dismutase (SOD), O2•− scavenger.16 Modulation of K+ channel activity by oxidative stress is important for cellular functions. O2•− has been reported to increase KATP channel activity in guinea-pig cardiac myocytes but to decrease KATP channel opening in cerebral vasculature.63,64 Both hydrogen peroxide (H2O2) and peroxynitrite (ONOO) enhance KATP channel activity in the myocardium65 and in the coronary,66 renal, mesenteric,67 and cerebral vascular beds.68,69 Our study suggested that O2•− may directly stimulate the Kir6.1 channel. In our patch-clamp study,61 HX alone did not alter Kir6.1 currents and co-application of HX and XO produced a significant increase in Kir6.1 currents in all cells tested. This stimulatory effect was abolished by tempol, a scavenger of O2•−. A causative relationship between O2•− and Kir6.1 channel function is therefore strongly indicated.

At micromolar concentrations, nicotine enhanced superoxide production.61 That may explain the stimulatory effect of nicotine on Kir6.1 channels because superoxide anion directly stimulated the Kir6.1 channel and tempol abolished the stimulatory effect of nicotine on Kir6.1 channels. On the other hand, nicotine at millimolar concentrations inhibited basal superoxide production. A lower basal level of superoxide anion can be linked to a reduced stimulation on Kir6.1 channels. Thus, this would underline the inhibitory effect of nicotine on Kir6.1 channels. The results of our study61 have several important implications. Firstly, oxidative stress related to nicotine consumption may underlie some cellular changes induced by smoking and/or smokeless tobacco usage. Secondly, superoxide anions may alter cellular functions by interacting with Kir6.1 channels. Further studies using these lines of information will help to better understand the modulation mechanisms of KATP channels.61

It has been suggested that Kv4.3 and Kv4.2 are the major molecular constituents of native cardiac Ito. The ability of nicotine to block Kv4.3 and Kv4.2 might contribute to the previously observed lengthening of cardiac action potential duration in many preparations.57,58 Nicotine preferentially prolongs initial repolarization and the subsequent plateau phases, consistent with the participation of Ito in early phases of repolarization. A-type K+ channels are not limited to cardiac cells. Both cloned and native A-type currents have been identified in a variety of tissues, including brain and vascular smooth muscle. The A-type K+ current in vascular smooth muscle is believed to act as a “break” to counteract depolarizing influences that may induce spontaneous action potential activity or oscillatory vasoconstriction. Nicotine is known to have vasoconstriction properties that contribute to an elevation of blood pressure and stroke risks.13,14,61 Nicotine is one of the most potent blockers of A-type channels.56 4-aminopyridine (4-AP) is in widespread use as a pharmacological tool for its ability to inhibit A-type K+ current selectively.14 However, as documented in many previous reports, several hundred micromolar to several millimolar concentrations of 4-AP are necessary to block Kv4.3 and Ito. The potency of nicotine to block Kv4.3 was ∼4×104 –fold higher than that of 4-AP (IC50=40±4 nM for nicotine versus 1.7±0.2 mM for 4-AP).56 Thus, nicotine can be potentially a useful pharmacological probe to study the role of A-type channels in cardiac electrical activity and the outcome of pharmacological interventions on A-type channels.

Decreases in inward rectifier K+ currents (Kir) have been implicated in a variety of disease states of the heart, including myocardial infarction and ischemia, cardiac hypertrophy, and heart failure.70 This decrease is often accompanied by cell membrane hyperpolarization and generation of arrhythmias, such as ectopic beats, early after-depolarization, and triggered activity.71 Depression of Kir can lead to increased susceptibility to activation of cells from an ectopic focus, due to increased input impedance and reduced current threshold. Wang et al56 reported that nicotine could block inward rectifier K+ channels. It is not unreasonable to speculate that nicotine could worsen heart diseases by promoting arrhythmias in part by directly blocking cardiac Kir. Simard and Li72 demonstrated that nicotine exposure caused a decrease in bioavailability of endogenous NO, as well as block of endogenous NOS activity and oxidative endothelial injury, resulting in a significant increase in Ca2+ channel availability. Nicotine increased availability of Ca2+ channels and decreased availability of KCa channels in cerebral arterioles.73 Nicotine altered NO signaling of L-type Ca2+ channels by a mechanism undescribed, causing blockage of the down-regulation of Ca2+ channels by NO and cGMP without altering normal up-regulation of Ca2+-activated K+ channels by NO and cGMP. Moreover, Gerzanich et al73 reported the significance of these ion channels by showing reduced pial vasorelaxation in response to NO in animals chronically exposed to nicotine.

In guinea pig ventricular cardiomyocytes, nicotine (100 μM and 30 μM) has been shown to inhibit Ca2+ and Kv channels, respectively.74 At 1 mM, nicotine blocked Ca2+ currents by approximately 90%. The responses to nicotine were not significantly modified by atropine (muscarinic receptor antagonist), hexamethonium (ganglion blocker), and nicotine receptor antagonists (d-tubocurarine and benzoquinonium). Nicotine also strongly inhibited the Kir channels in these cells. The cardiac actions induced by nicotine results from the modulation of ion channels across the cell membrane. The Kir channels possessed higher sensitivity to nicotine than Ca2+ and Kv channels. In rabbit SA nodal cells with no existence of Kir channels, nicotine inhibited Ca2+ channels but had less or no effect on Kv channels.75 The Kir channels mostly contributes to the resting potential, and the Kir channels inhibition might be expected to lead to partial depolarization of the membrane. However, nicotine did not affect the resting potential in guinea pig ventricular muscles and rabbit SA cells.76


The Canadian and American governments require that cigarette packages and advertisements caution consumers as to the potential health risks associated with smoking. Specifically, the product must carry the surgeon general's warning: smoking causes lung cancer, heart disease, and may complicate pregnancy. Nonetheless, Tobacco Company advertising still attempts to associate smoking with athletics, virility, and sex appeal. Despite the fact that the epidemiological evidence linking cigarette smoking with cardiovascular disease is overwhelming, the precise components of cigarette smoke responsible for this relationship and the mechanisms by which they exert their effect have not yet been elucidated. It is now known that the endothelium has a vastly more important role than was ever thought to be the case a decade ago. There is considerable evidence that cigarette smoking can result in both morphologic and biochemical disturbances to endothelium both in in vivo and in cell culture systems. Absorbed nicotine stimulates the release of catecholamines, while other products (perhaps nicotine) injure the arterial endothelium and promote atherogenesis. Free radicals and aromatic compounds diminish the endothelial synthesis of nitric oxide, causing impaired endothelium-dependent relaxation of arteries, the earliest clinical sign of endothelial dysfunction. Smoking alters the shear forces rheology at the endothelial surface, and these changes enhance the effects of products of tobacco combustion to up-regulate leukocyte adhesion molecules on the endothelial surface. The increased oxidation of low-density lipoprotein in smokers has synergetic effects to promote monocyte adhesion and monocyte migration into the subintimal space. Continued stimulation of intimal cells by oxidized low-density lipoprotein leads to the development of atherosclerosis. Many of these effects are ameliorated by high concentrations of vitamin C.

Disease of the cardiovascular system and their final or lethal states (acute myocardial infarction, apoplectic stroke, congestive heart failure) occur 3 to 4 times more frequently than lung cancer in heavy smokers. Proposal of the cessation of smoking and for the use of nicotine replacement (patch, chewing gum) were offered because the inhaled tobacco smoke mainly damage health whereas the smokers are addicted only by nicotine. A less restrictive distribution of nicotine preparations for replacement therapy should enable the heavy smoker in his first phase of smoking cessation to combine the nicotine administration with reduced cigarette smoking. Each decrease in the carbon monoxide content of the expired air with subsequent decrease in the carboxyhemoglobin content of the blood possibly diminishes the risk of cardiovascular events. This type of treatment gives new opportunities for the treatment of the smoking patients for every physician.


Completion of this article would not have been possible without the encouragement of Dr Roger Pierson at the University of Saskatchewan. S. T. Hanna is supported by a post-doctoral fellowship of Saskatchewan Health Research Foundation (SHRF).


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