ReviewNitric oxide-mediated blood flow regulation as affected by smoking and nicotine
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)
- et al.
Effect of cigarette smoke extract on neonatal porcine vascular smooth muscle cells
Toxicol. Appl. Pharmacol.
(2001) - et al.
The pathophysiology of cigarette smoking and cardiovascular disease: an update
J. Am. Coll. Cardiol.
(2004) - et al.
Reduced endothelial nitric oxide synthase activity and concentration in fetal umbilical veins from maternal cigarette smokers
Am. J. Obstet. Gynecol.
(2004) - et al.
Angioprotective action of calcium dobesilate against reactive oxygen species-induced capillary permeability in the rat
Eur. J. Pharmacol.
(1998) Folic acid says NO to vascular diseases
Nutrition
(2003)- et al.
Relationship between obesity, smoking, and the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine
Metabolism
(2004) - et al.
Potent and selective inhibition of human nitric oxide synthases. Selective inhibition of neuronal nitric oxide synthase by S-methyl-l-thiocitrulline and S-ethyl-l-thiocitrulline
J. Biol. Chem.
(1994) - et al.
Flow-mediated vasodilation of the femoral and brachial artery induced by exercise in healthy nonsmoking and smoking men
J. Am. Coll. Cardiol.
(2001) - et al.
Cessation of smoking rapidly decreases erectile dysfunction
Endocr. Pract.
(1998) - et al.
Endothelial progenitor cells participate in nicotine-mediated angiogenesis
J. Am. Coll. Cardiol.
(2006)
Acute consumption of flavanol-rich cocoa and the reversal of endothelial dysfunction in smokers
J. Am. Coll. Cardiol.
Endothelium-dependent effects of cigarette smoke components on tone of porcine intrapulmonary arteries in vitro
Toxicol. Appl. Pharmacol.
Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle
Biochem. Biophys. Res. Commun.
Angiotensin II type 1 (AT-1)-receptor blocker prevents impairment of endothelium-dependent cerebral vasodilation by acute cigarette smoking in rats
Life Sci.
Involvement of DDAH/ADMA/NOS pathway in nicotine-induced endothelial dysfunction
Biochem. Biophys. Res. Commun.
Effect of edaravone, a novel free radical scavenger, on endothelium-dependent vasodilation in smokers
Am. J. Cardiol.
Nicotine-reduced endothelial progenitor cell senescence through augmentation of telomerase activity via the PI3K/Akt pathway
Cytotherapy
Molecular cloning and characterization of human endothelial nitric oxide synthase
FERBS Lett.
Agonist-induced release of nitric oxide during acute exposure to nicotine
Life Sci.
Effects of long-term cigarette smoking on endothelium-dependent responses in humans
Am. J. Cardiol.
Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+-calmodulin and caveolin
J. Biol. Chem.
Combined exposure to cigarette smoke and hypercholesterolemia decreases vasorelaxation of the aorta
J. Vasc. Surg.
Maternal cigarette smoking increases F2-isoprostanes and reduces prostacyclin and nitric oxide in umbilical vessels
Prostaglandins Other Lipid Mediat.
Reduced asymmetric dimethylarginine (ADFMA) levels mediate in the protection from metabolic syndrome by smoking
Atherosclerosis
Pulmonary effects of endogenous and exogenous nitric oxide in the pig: relation to cigarette smoke inhalation
Br. J. Pharmacol.
Tobacco particulate matter is more potent than nicotine at upregulating nicotinic receptors on SH-SY5Y cells
Nicotine Tob. Res.
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
Pharmacology of penile erection
Pharmacol. Rev.
Acute effects of passive smoking on peripheral vascular function
Hypertension
Acute effect of sidestream cigarette smoke extract on vascular endothelial function
J. Cardiovasc. Pharmacol.
Reduced expression of endothelial nitric oxide synthase in pulmonary arteries of smokers
Am. J. Rspir. Crit. Care Med.
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.
Dysfunctional endothelial nitric oxide biosynthesis in healthy smokers with impaired endothelium-dependent vasodilatation
Circulation
Atrovastatin restores endothelial function in normocholesterolemic smokers independent of changes in low-density lipoprotein
Circ. Res.
Smoking, clopidogrel, and mortality in patients with established cardiovascular disease
Circulation
Effects of chronic oral consumption of nicotine on the rabbit aortic endothelium
Am. J. Pathol.
Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme
Proc. Natl. Acad. Sci. U. S. A.
Cigarette smoking in men and vascular responsiveness
Br. J. Clin. Pharmacol.
Lisinopril improves endothelial function in chronic cigarette smokers
Clin. Sci. (Lond.)
Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults
Circulation
Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults
N. Engl. J. Med.
The human placenta from heavy smokers: evaluation of vasoactive peptides by immunohistochemistry
APMIS
Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation
Nature (Lond.)
Sildenafil does not improve nitric oxide-mediated endothelium-dependent vascular responses in smokers
Br. J. Clin. Pharmacol.
Cigarette smoke-induced oxidative/nitrosative stress impairs VEGF- and fluid shear stress-mediated signaling in endothelial cells
Antioxid. Redox Signal
CYBA C242T gene polymorphism and flow-mediated vasodilation in a population of young adults: the Cardiovascular Risk in Young Finns Study
J. Hypertens.
Impairment of nitric oxide synthase-dependent dilatation of cerebral arterioles during infusion of nicotine
Am. J. Physiol.
l-arginine prevents impaired endothelium-dependent cerebral arteriolar dilatation during acute infusion of nicotine
Nicotine Tob. Res.
Inhibition of NADPH oxidase improves impaired reactivity of pial arterioles during chronic exposure to nicotine
J. Appl. Physiol.
A new method for estimating the retention of selected smoke constituents in the respiratory tract of smokers during cigarette smoking
Inhal. Toxicol.
Cited by (90)
Modulation of preeclampsia by the cholinergic anti-inflammatory pathway: Therapeutic perspectives
2021, Biochemical PharmacologyDeletion of nicotinic acetylcholine receptor alpha9 in mice resulted in altered bone structure
2019, BoneCitation Excerpt :To our knowledge it is not known whether the bone vascular system express nAChR subunits α9 and 10. However, application of nicotine leads to dilation in the most vascular systems [34] whereas in bone it enhances vascular constriction [35]. Since the pharmacological profile of α9α10 does not resemble the typical nAChR [36], not only the presence of these subunits but also their functional role remains unknown in the bone vascular system.
Elucidating Mechanisms of Long-Term Gasoline Vehicle Exhaust Exposure–Induced Erectile Dysfunction in a Rat Model
2019, Journal of Sexual MedicineDoes dietary nitrate say NO to cardiovascular ageing? Current evidence and implications for research
2018, Proceedings of the Nutrition Society