Review
Nitric oxide-mediated blood flow regulation as affected by smoking and nicotine

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Abstract

Cigarette smoking is a major risk factor for atherosclerosis, cerebral and coronary vascular diseases, hypertension, and diabetes mellitus. Chronic smoking impairs endothelial function by decreasing the formation of nitric oxide and increasing the degradation of nitric oxide via generation of oxygen free radicals. Nitric oxide liberated from efferent nitrergic nerves is also involved in vasodilatation, increased regional blood flow, and hypotension that are impaired through nitric oxide sequestering by smoking-induced factors. Influence of smoking on nitric oxide-induced blood flow regulation is not necessarily the same in all organs and tissues. However, human studies are limited mainly to the forearm blood flow measurement that assesses endothelial function under basal and stimulated conditions and also determination of penile tumescence and erection in response to endothelial and neuronal nitric oxide. Therefore, information about blood flow regulation in other organs, such as the brain and placenta, has been provided mainly from studies on experimental animals. Nicotine, a major constituent of cigarette smoke, acutely dilates cerebral arteries and arterioles through nitric oxide liberated from nitrergic neurons, but chronically interferes with endothelial function in various vasculatures, both being noted in studies on experimental animals. Cigarette smoke constituents other than nicotine also have some vascular actions. Not only active but also passive smoking is undoubtedly harmful for both the smokers themselves and their neighbors, who should bear in mind that they can face serious diseases in the future, which may result in lengthy hospitalization, and a shortened lifespan.

Introduction

Nitric oxide (NO) is an inevitably important molecule for the control of vascular tone, blood flow, peripheral vascular resistance, and systemic blood pressure. Endogenous NO was first discovered to be an endothelium-derived relaxing factor (Furchgott and Zawadzki, 1980) that transmits inhibitory information from vascular endothelial cells to smooth muscle cells. NO is constitutively synthesized by endothelial NO synthase (eNOS) (Marsden et al., 1992) and neuronal NOS (nNOS) (Bredt and Snyder, 1990). Endothelial dysfunction is one of the important factors responsible for hypertension, coronary and cerebral circulatory disorders, atherosclerosis, and diabetes mellitus. Reduced synthesis and action of NO derived from parasympathetic efferent (nitrergic) neurons are involved in hypertension (Toda et al., 1991, Toda et al., 2009a), renal circulatory disturbance (Toda et al., 2010), and erectile dysfunction (Toda et al., 2005).

Cigarette smoking is a pernicious risk factor for the pathogenesis of cardiovascular diseases (Rahman and Laher, 2007, Berger et al., 2009), and endothelial dysfunction is an important antecedent event in this process (Butler et al., 2001b). Nicotine is a major constituent of cigarette smoke. Although most of the effects of cigarette smoke are expected to be mediated by nicotine, other smoke constituents may also play some roles in the hemodynamic control either by acting directly on the synthesis and action of NO constitutively formed or by indirectly modifying the effect of nicotine. When acutely introduced, nicotine stimulates not only autonomic ganglia but also autonomic nerve (adrenergic, nitrergic, and cholinergic) terminals (Toda and Okamura, 2003), but if chronically administered, it appears to evoke detrimental actions such as those on endothelial cells.

This review article covers areas of research concerning the modification of regional blood flow or vascular tone (mainly forearm, cerebral, and placental circulation or intracavernous pressure) maintained by basal and stimulated release of NO from the endothelium and nitrergic nerves following acute and chronic exposure to cigarette smoke and nicotine in humans in vivo, human tissues, and experimental animals. Vascular effects of smoke constituents other than nicotine on NO bioavailability are summarized. Impairment of NO-mediated vasodilatation by passive smoking is also included.

Section snippets

Nitric oxide synthesis

NO is produced when l-arginine is transformed to l-citrulline by catalysis of NOS in the presence of oxygen and cofactors including calmodulin, tetrahydrobiopterin (BH4), reduced nicotinamide adenine dinucleotide phosphate (NADPH), heme, flavin adenine dinucleotide, and flavin mononucleotide. Ca2+ is required for the activation of neuronal and endothelial NOS (nNOS and eNOS) but not inducible NOS (iNOS). nNOS is constitutively expressed in the brain (Bredt and Snyder, 1990), peripheral nerves,

Forearm blood flow

Studies on forearm blood flow changes in response to NO-releasing substances and physical stimuli are commonly used to evaluate endothelial function in humans.

Flow-mediated brachial arterial dilatation was observed in all the nonsmoking subjects but was impaired or absent in the cigarette smokers; flow-mediated dilatation was inversely related to lifetime dose smoked; GTN-induced vasodilatation did not differ in control subjects and smokers, suggesting that smoking impairs endothelium-dependent

Regional blood flow regulation as affected by nicotine

Systemic administration of nicotine induces hypertension, vasoconstriction, and increased peripheral vascular resistance mainly mediated by activation of sympathetic nerves in the cardiovascular system. In isolated blood vessels, exposure to nicotine also results in contraction associated with stimulation of nicotinic receptors located in adrenergic nerve terminals, except for those in cerebral and coronary arteries, in which relaxations are induced by neuronal nicotinic receptor activation.

Cigarette smoke constituents

Although nicotine is undoubtedly a major molecule included in cigarette smoke, the effects of smoking on hemodynamics and NO metabolism are not solely associated with nicotine. Some other smoke components are expected to participate in the functional changes caused by smoking, either acting directly on blood vessels or indirectly by modulating vascular actions of nicotine. So far summarized in this article, modulations by chronic smoking of hemodynamic effects of endogenous NO have been usually

Conclusions

Endothelial dysfunction associated with chronic smoking is an important antecedent event in atherosclerosis, cerebral circulatory disorders, coronary vascular diseases, hypertension, and erectile dysfunction. Impaired NO synthesis in the endothelium and enhanced production of reactive oxygen species, such as superoxide anions, through decreased BH4 contents and NADPH diaphorase activity are involved in the smoking-induced pathogenesis. Cerebral vascular endothelial dysfunction results in brain

Acknowledgements

All authors thank Dr. K. Noda, Nippon-Shinyaku Company, for her assistance in arranging the references.

The authors have no potential conflicts of interest relevant to the contents of this article.

References (147)

  • C. Heiss et al.

    Acute consumption of flavanol-rich cocoa and the reversal of endothelial dysfunction in smokers

    J. Am. Coll. Cardiol.

    (2005)
  • W.E. Holden et al.

    Endothelium-dependent effects of cigarette smoke components on tone of porcine intrapulmonary arteries in vitro

    Toxicol. Appl. Pharmacol.

    (1990)
  • L.J. Ignarro et al.

    Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle

    Biochem. Biophys. Res. Commun.

    (1990)
  • H. Iida et al.

    Angiotensin II type 1 (AT-1)-receptor blocker prevents impairment of endothelium-dependent cerebral vasodilation by acute cigarette smoking in rats

    Life Sci.

    (2006)
  • D.J. Jiang et al.

    Involvement of DDAH/ADMA/NOS pathway in nicotine-induced endothelial dysfunction

    Biochem. Biophys. Res. Commun.

    (2006)
  • D. Jitsuiki et al.

    Effect of edaravone, a novel free radical scavenger, on endothelium-dependent vasodilation in smokers

    Am. J. Cardiol.

    (2004)
  • Z. Junhui et al.

    Nicotine-reduced endothelial progenitor cell senescence through augmentation of telomerase activity via the PI3K/Akt pathway

    Cytotherapy

    (2009)
  • P.A. Marsden et al.

    Molecular cloning and characterization of human endothelial nitric oxide synthase

    FERBS Lett.

    (1992)
  • W.G. Mayhan et al.

    Agonist-induced release of nitric oxide during acute exposure to nicotine

    Life Sci.

    (1999)
  • G.E. McVeigh et al.

    Effects of long-term cigarette smoking on endothelium-dependent responses in humans

    Am. J. Cardiol.

    (1996)
  • J.B. Michel et al.

    Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+-calmodulin and caveolin

    J. Biol. Chem.

    (1997)
  • J.H. Mudaliar et al.

    Combined exposure to cigarette smoke and hypercholesterolemia decreases vasorelaxation of the aorta

    J. Vasc. Surg.

    (1997)
  • R. Obwegeser et al.

    Maternal cigarette smoking increases F2-isoprostanes and reduces prostacyclin and nitric oxide in umbilical vessels

    Prostaglandins Other Lipid Mediat.

    (1999)
  • A. Onat et al.

    Reduced asymmetric dimethylarginine (ADFMA) levels mediate in the protection from metabolic syndrome by smoking

    Atherosclerosis

    (2008)
  • K. Alving et al.

    Pulmonary effects of endogenous and exogenous nitric oxide in the pig: relation to cigarette smoke inhalation

    Br. J. Pharmacol.

    (1993)
  • V. Ambrose et al.

    Tobacco particulate matter is more potent than nicotine at upregulating nicotinic receptors on SH-SY5Y cells

    Nicotine Tob. Res.

    (2007)
  • M.R. Andersen et al.

    Smoking cessation early in pregnancy and birth weight, length, head circumference, and endothelial nitric oxide synthase activity in umbilical and chorionic vessels: an observational study of healthy singleton pregnancies

    Circulation

    (2009)
  • K.E. Andersson

    Pharmacology of penile erection

    Pharmacol. Rev.

    (2001)
  • J.F. Argacha et al.

    Acute effects of passive smoking on peripheral vascular function

    Hypertension

    (2008)
  • J.F. Argacha et al.

    Acute effect of sidestream cigarette smoke extract on vascular endothelial function

    J. Cardiovasc. Pharmacol.

    (2008)
  • J.A. Barbera et al.

    Reduced expression of endothelial nitric oxide synthase in pulmonary arteries of smokers

    Am. J. Rspir. Crit. Care Med.

    (2001)
  • R.G. Barr et al.

    Impaired flow-mediated dilation is associated with low pulmonary function and emphysema in ex-smokers: the Emphysema and Cancer Action Project (EMCAP)

    Am. J. Respir. Crit. Care Med.

    (2007)
  • R.S. Barua et al.

    Dysfunctional endothelial nitric oxide biosynthesis in healthy smokers with impaired endothelium-dependent vasodilatation

    Circulation

    (2001)
  • J.A. Beckman et al.

    Atrovastatin restores endothelial function in normocholesterolemic smokers independent of changes in low-density lipoprotein

    Circ. Res.

    (2004)
  • J.S. Berger et al.

    Smoking, clopidogrel, and mortality in patients with established cardiovascular disease

    Circulation

    (2009)
  • F.M. Booyse et al.

    Effects of chronic oral consumption of nicotine on the rabbit aortic endothelium

    Am. J. Pathol.

    (1981)
  • D.S. Bredt et al.

    Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme

    Proc. Natl. Acad. Sci. U. S. A.

    (1990)
  • R. Butler et al.

    Cigarette smoking in men and vascular responsiveness

    Br. J. Clin. Pharmacol.

    (2001)
  • R. Butler et al.

    Lisinopril improves endothelial function in chronic cigarette smokers

    Clin. Sci. (Lond.)

    (2001)
  • D.S. Celermajer et al.

    Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults

    Circulation

    (1993)
  • D.S. Celermajer et al.

    Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults

    N. Engl. J. Med.

    (1996)
  • H.V. Clausen et al.

    The human placenta from heavy smokers: evaluation of vasoactive peptides by immunohistochemistry

    APMIS

    (2007)
  • S. Dimmeler et al.

    Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation

    Nature (Lond.)

    (1999)
  • V. Dishy et al.

    Sildenafil does not improve nitric oxide-mediated endothelium-dependent vascular responses in smokers

    Br. J. Clin. Pharmacol.

    (2004)
  • I. Edirisinghe et al.

    Cigarette smoke-induced oxidative/nitrosative stress impairs VEGF- and fluid shear stress-mediated signaling in endothelial cells

    Antioxid. Redox Signal

    (2010)
  • M. Fan et al.

    CYBA C242T gene polymorphism and flow-mediated vasodilation in a population of young adults: the Cardiovascular Risk in Young Finns Study

    J. Hypertens.

    (2007)
  • Q. Fang et al.

    Impairment of nitric oxide synthase-dependent dilatation of cerebral arterioles during infusion of nicotine

    Am. J. Physiol.

    (2002)
  • Q. Fang et al.

    l-arginine prevents impaired endothelium-dependent cerebral arteriolar dilatation during acute infusion of nicotine

    Nicotine Tob. Res.

    (2004)
  • Q. Fang et al.

    Inhibition of NADPH oxidase improves impaired reactivity of pial arterioles during chronic exposure to nicotine

    J. Appl. Physiol.

    (2006)
  • S. Feng et al.

    A new method for estimating the retention of selected smoke constituents in the respiratory tract of smokers during cigarette smoking

    Inhal. Toxicol.

    (2007)
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