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Cardiovascular effects of nicotine: Relation to deleterious effects of cigarette smoking
EDITORIALS
Cardiovascular effects of nicotine: Relation deleterious effects of cigarette smoking Sandeep Khosla, MD, Atul Laddu, MD, Seymour Ehrenpreis, and John C. Somberg, MD North Chicago, Ill.
Nicotine has been consumed in the form of tobacco for hundreds of years. Nearly 30% of Americans smoke despite that most desire to quit1 This is in large part because of the addicting properties of nicotine. Nicotine is a tertiary amine composed of a pyridine and a pyrolidine ring.2 It binds stereospecifitally to acetylcholine receptors at the autonomic ganglia, the adrenal medulla, neuromuscular junctions, and the brain.2 Nicotine readily crosses the blood brain barrier and is distributed throughout the brain.3 The absorption of nicotine across biologic membranes depends on the pH. The pH of smoke from cigarettes is acidic so that nicotine is primarily ionized and does not cross cell membranes rapidly, and hence no absorption from oral mucosa. When tobacco smoke reaches small airway and alveoli of the lung, it is rapidly absorbed regardless of the PH.~ Chewing tobacco, snuff, and nicotine gum are buffered into an alkaline pH to facilitate mucosal absorption. The amount of nicotine extracted from nicotine gum is incomplete and highly variable.4 Similarly, intake of nicotine during cigarette smoking varies from puff to puff depending on puff volume, depth of inhalation, dilution with room air, rate, and intensity of puffing.5 Because of the variable amounts of nicotine absorption by various routes, to estimate its dose, one should measure the blood levels and know how fast the smoke eliminates it.2 Nicotine is rapidly and extensively metabolized, mainly in the liver and to a smaller extent in the
From the Divisions Health Sciences/The Received
of Clinical Chicago
for publication
Pharmacology and Medical School.
Sept.
2, 1993;
accepted
Reprint requests: John C. Somberg, MD, Division cago Medical School, 3333 Green Bay Rd., North AM HEART
J 1994;127:1669-72.
Copyright @ 1994 0002-8703/94/$3.00
by Mosby-Year +O 4/l/63509
Book,
Inc.
Cardiology,
University
of
Oct. 15, 1993. of Cardiology, The ChiChicago, IL 60064.
to
PhD,
lung.2 Renal excretion depends on urine flow and its pH and accounts for 2 % to 35 % of total elimination6 The half-life of nicotine is approximately 2 hours, with a range of 1 to 4 hours7 The primary metabolites are cotinine and nicotine-N-oxide, neither of which is pharmacologically active. Because of cotinine’s long half-life (16 to 20 hours), it is used in surveys and treatment studies as a marker of nicotine intake.8 The most abundant urinary metabolite is 3’hydroxy-cotinine.g Blood concentrations sampled in the afternoon in smokers generally range from 10 to 50 pg/ml. The increments in blood concentration after smoking a single cigarette range from 5 to 30 pg/ml.2 Blood and urine levels of pipe smokers are similar to those of cigarette smokers.iO Transdermal nicotine, which provides 21, 14, or 7 mg of nicotine over a 24-hour period, has an average steady-state plasma concentration of 17, 12, and 6 pg/ml, respectively.ll Nicotine is described as a stimulant of autonomic ganglia and skeletal neuromuscular junctions (i.e., nicotine muscarinic receptors). However, the in vivo actions are very complex and depend on dose, target organ, prevalent autonomic tone, and prior exposure history. Nicotine appears to be the substance in cigarette smoke that causes activation of the sympathetic nervous system by stimulation of the adrenal medulla.12 This commentary is an attempt to define the cardiovascular effects of nicotine in humans, a subject about which considerable controversy exists. Systemic hemodynamic effects. In a healthy person, smoking a cigarette increases heart rate and contractility and systolic and diastolic blood pressures.12-17 Cardiac output increases predominantly because of the increase in heart rate; arterial pressure increases because of an increase in both cardiac output and systemic vascular resistance. Smoking or nicotine causes cutaneous vasoconstriction, systemic venoconstriction, and increased muscle blood flow. The cardiovascular effects can be prevented by 1669
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combined cy- and P-adrenergic blockade, which suggests that these effects are mediated by activation of the sympathetic nervous system.12! l3 However, it has been observed in a dog model that after adrenergic blockade with phenoxybenzamine and propranolol, there was still a significant increase in myocardial oxygen consumption, systemic arterial pressure, and peripheral vascular resistance during infusion of nicotine. However, in this model myocardial contractility declined. is These findings suggest a role of nonadrenergic mechanisms in the cardiovascular effects of nicotine. Local autoregulatory responses to increased myocardial requirements may be responsible for increased myocardial blood flow during nicotine infusion. A moderate increase in myocardial contractility during nicotine infusion in dogs with intact adrenergic receptors has been observed by some investigators,rg> 2owhereas others noticed no increase in myocardial contractility. I8 This discrepancy may be explained in part by use of higher dose of nicotine in the latter study. At higher doses nicotine appears to have cardiac depressant properties. Possible cardiac depressant mechanisms may be the activation of cardiac parasympathetic nerves2r or the release of vasopressin. 22 Vasopressin is released in response to smoking, and because vasopressin antagonists can blunt nicotine-induced vasoconstriction of blood vessels in skin, it may contribute to systemic vascular effects of smoking.23T 24 In patients with coronary artery disease, smoking may reduce left ventricular contractility and cardiac output,= 26 probably because of nicotine-mediated coronary vasoconstriction27 or the effects of carbon monoxide. In patients with depressed left ventricular function, increase in afterload can cause a decrease in stroke volume and an increase in the left ventricular filling pressure.28 Effects on coronary circulation. In patients with proximal coronary artery disease, cigarette smoke may not increase coronary blood flow and in fact may even decrease coronary blood flow despite an increase in myocardial oxygen demand because of increased heart rate and blood pressure.2gSeveral investigators have shown that in subjects with coronary artery disease, smoking does not increase coronary blood flow in response to increasing myocardial oxygen demand and that coronary vascular resistance increases
14,30,31
In a study by Martin et al. on 10 patients, when the heart rate times blood pressure (or double product) was held constant by atria1 pacing, smoking decreased coronary flow and increased coronary vascular resistance. When the double product was in-
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June 1994 Heart Journal
creased by 50% by atria1 pacing, there was a 57 % +: 16 % increase in coronary flow before smoking compared with only a 24 % -t 12 % (p < 0.01) increase after smoking.31 Thus the effects of smoking differ in subjects with normal coronary arteries from those with proximal coronary disease: the coronary vasodilation mediated by increased metabolic demand caused by smoking is counteracted by coronary vasoconstriction. A paradox exists between the in vivo and in vitro effects of muscarinic agonists on coronary vessels. In isolated blood vessel preparations acetylcholine induced vasoconstriction 32-34but in vivo elicited substantial vasodilation.35-37 This paradox was partly explained by Furchgott and Zawadski,38 who demonstrated that the ability of acetylcholine to dilate blood vessels depends on an intact endothelial cell layer. The mechanisms responsible for endothelium-mediated relaxation of coronary arteries involve the production of prostacyclin32 and a second vasorelaxants, endothelial-derived relaxant factor.3g Acetylcholine acts on receptors on endothelial cells to trigger release of endothelial-derived relaxant factor, which diffuses to adjacent smooth muscle cells to cause relaxation.40 Thus in cells with endothelial damage resulting from the arteriosclerotic process, the endogenous vasodilators are not released and coronary dilation does not occur. This may be what occurs during the cold pressor test, when immersion of the hand in ice water causes coronary vasodilation in normal subjects and constriction in those patients with coronary artery disease.41v 42 Other studies have indicated that even with intact endothelium, muscarinic stimulation by exogenous agents causes coronary vasoconstriction in both human and nonhuman primates as well as in bovine and porcine models.40T43~44 The presence of parasympathetic nerve endings in the adventitia of large and small coronary arteries has been demonstrated.45> 46 Reid et a1.47demonstrated that stimulation of the cervical vagus elicits vasodilation of small coronary vessels. Similar findings have not demonstrated control of large coronary arteries.4s It has been suggested that carotid-body chemoreceptor stimulation by nicotine can produce reflex a-adrenergic receptor-mediated constriction of both large and small coronary arteries and that the constriction of small vessels is balanced by vagally mediated dilation.4g It has been suggested that cigarette smoke increases platelet aggregation in vitro50 as well as plasma catecholamines, which in turn exacerbate platelet activity in vitro and in vivo.51, 52 Nicotine administered intravenously or absorbed from ciga-
Volume 127, Number 6 American Heart Journal
rette smoke increases plasma catecholamine levels by stimulating the release of epinephrine from adrenal medulla of dogs53 and humans.54 Epinephrine stimulates platelet aggregation and thrombus formulation by platelet adrenergic mechanisms involving activation of adenylate cyclase.55 Human platelets are believed to contain cw-adrenergic receptors on their membranes. Stimulation of these receptors can initiate aggregation. 52 Cigarette smoke may be a powerful stimulus for aggregation and thus result in formation of an occlusive coronary thrombus within a coronary artery already predisposed to thrombosis because of an ulcerated atherosclerotic plaque.5” Carbon monoxide, one of the most poisonous byproducts of cigarette smoke that constitutes approximately 2.7% to 6.0% of smoke, may cause damage by injuring the vascular endothelium and contributing to the thrombotic episodes related to smoking.57 Conclusion. Nicotine has major effects on the cardiovascular system. Nicotine and its long-acting metabolites can cause arterial vasoconstriction resulting in increased systemic vascular resistance, thereby causing a sustained increase in arterial blood pressure. This increase in systemic vascular resistance may lead to coronary dilatation, although the degree of dilatation is often attenuated. However, coronary flow is reduced because of nicotine vasoconstriction in patients with atherosclerotic coronary artery disease. The paradoxic effects are the result of the lack of an intact endothelium in patients with coronary artery disease, resulting in reduction of nitric oxide production. This, in combination with adjustments (reduction) in neurally mediated vasodilation, leads to a decrease in coronary flow. These adverse effects of nicotine combine with the proaggregatory action of nicotine on platelets that may lead to additional adverse coronary events. Clearly, smoking is highly deleterious, and the replacement of smoking by exogenous nicotine (patch, gum, etc.) reduces the adverse effects of carbon monoxide. Even under these circumstances platelet-aggregating effects and coronary constriction of nicotine remain major risk factors for patients with coronary artery disease. In summary, nicotine, the active ingredient in cigarettes, has complex actions on the cardiovascular system. In healthy persons, it increases the heart rate, blood pressure, myocardial contractility, and coronary blood flow. These actions are attributed to stimulation of the sympathetic nervous system. Nonadrenergic local autoregulatory mechanisms may also be operative in increasing coronary blood flow. In patients with proximal coronary artery disease, the coronary flow does not increase in proportion to the
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et al.
1671
increased metabolic demand during nicotine administration and may even decrease. This is because of nicotine-mediated coronary vasoconstriction. The paradoxic vasoconstriction may be caused by damaged endothelium because intact endothelium is required for vasodilation produced by nicotine. Nicotine also increases platelet aggregation and may enhance thrombus formation in already predisposed diseased coronary arteries. Thus nicotine can be hazardous in patients with proximal coronary artery disease. REFERENCES
1. Cigarette smoking in the United States, 1986. MMWR 1987;36:581-5. I 2. Benowitz NL. Pharmacologic aspects of cigarette smoking and nicotine addiction. N End J Med 1988:319:1318-30. 3. Hansson E, SchmiterlodCG. Physiological disposition and fate of Cr4, labelled nicotine in mice and rats. J Pharmacol Exp Ther 1962;137:91-102. 4. Benowitz NL, Jacob P III, Savanapridi C. Determinants of nicotine intake while chewing nicotine polacrilex gum. Clin Pharmacol Ther 1987;41:467-73. 5. Heming RI, Jones RT, Benowitz NL, Mines AH. How a cigarette is smoked determines blood nicotine levels. Clin Pharmacol Ther 1983;33:84-90. 6. Benowitz NL, Jacob P III. Nicotine renal excretion rate influences nicotine intake during cigarette smoking. J Pharmacol Exp Ther 1985;234:153-5. 7. Benowitz NL, Jacob P III, Jones RT, Rosenberg J. Interindividual variability in the metabolism and cardiovascular effects of nicotine in man. J Pharmacol Exp Ther 1982;221:368-72. 8. Benowitz NL. Kuvt F. Jacob P III. Jones RT. Osman AL. Cotinine disposition and effects. Clin Pharmacol Ther 1983; 34:604-11. 9.
10.
11. 12. 13.
14.
15. 16.
Neurath GB, Dunger M, Orth D, Pein FG. Trans-3’-hydroxycotinine as a main metabolite in urine of smokers. Int Arch Occup Environ Health 1987;59:199-201. Wald NJ, Idle M, Boreham J, Bailey A. Serum cotinine levels in pipe smokers: evidence against nicotine as cause of coronary heart disease. Lancet 1981;2:775-7. Gorsline J, Gupta SK, Dye D, Rolf CN. Nicotine dose relationship for Nicoderm (nicotine transdermal system) at steady state. Pharm Res 1991;1O(suppI):S299. Benowitz NL. Clinical pharmacology of nicotine. Ann Rev Med 1986;37:21-32. Cryer PE, Haymond MW, Santiago JV, Shah SD. Norepinephrine and epinephrine release and adrenergic mediation of smokingassociated hemodynamic and metabolic events. N Engl J Med 1976;295:573-7. Nicod P, Rehr R, Winniford MD, Campbell WB, Firth BG, Hillis LD. Acute systemic and coronary hemodynamic and serologic responses to cigarette smoking in long-term smokers with atherosclerotic coronary artery disease. J Am Co11Cardiol 1984;4:964-71. Koch A, Hoffman K, Steck W. Acute cardiovascular reactions after cigarette smoking. Arteriosclerosis 1980;35:67-75. Rabinowitz BD, Thorp K, Huber GL, Abelmann WH. Acute hemodynamic effects of cigarette smoking in man assessed by systolic time intervals and echocardiography. Circulation 1979;60:752-60.
Thomas CB, Bateman J, Lindberg E, Bornhold H. Observations on the individual effects of smoking on the blood pressure, heart rate, stroke volume and output of healthy young adults. Ann Intern Med 1956;44:874-92. 18. Crystal GJ, Downey HF, Bashour FA. Myocardial oxygen 17.
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26. 27. 28. 29. 30.
31.
32. 33. 34. 35. 36. 37.
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consumption and blood flow during nicotine infusion: effect of combined alpha and beta adrenergic blockade. J Cardiol Pharmacol 1981;3:317-27. Mjos OD, Ilebekk A. Effects of nicotine on myocardial metabolism and nerformance in dogs. Stand 3 Clin Lab Invest 1973; 32175-80. Ilebekk A, Lekven J. Cardiac effect of nicotine in dogs. Stand J Clin Lab Invest 1974:33:153-g. DeGeest, Levy MN, Zieske H, Lipman RI. Depression of ventricular contractility by stimulation of vagus nerves. Circ Res 1965;17:222-35. Schmid PG, Abboud FM, Wendling MG. Regional vascular effects of vasopressin: plasma levels and circulatory responses. Am J Physiol 1974;227:998-1004. Husain MH, Frantz AG, Ciarochi F, Robinson AG. Nicotine stimulated release of neurophysin and vasopressin in humans. J Clin Endocrinol Metah 1975;41:1113-7. Waeber B, Schaller MD, Nussberger J, Bussien JP, Hofbauer KG, Brunner HR. Skin blood flow and cigarette smoking: the role of vasopressin. Clin Exp Hypertens 1984;6:2003-6. Aronow WS, Cassidy J, Vangrow JS, March H, Kern JC, Goldsmith JR, Khemka M, Pugano J, Vantec M. Effect of cigarette smoking and breathing carbon monoxide on cardiovascular hemodynamics in angina1 patients. Circulation 1974;50:340-7. Pentecost B, Schillingford J. The acute effects of smoking on myocardial performance in patients with coronary arterial disease. Br Heart J 1964;26:422-9. Klein LW. Anbrose J. Pichard A. Holt J. Gorlin R. Teichholz LE. Acute effects of cigarette smoking on coronary vascular dynamics [Abstract]. Circulation 1983;68:165. Benowitz NL, Kuyt F, Jacob P III. Influence of nicotine on cardiovascular and hormonal effects of cigarette smoking. Clin Pharmacol Ther 1984;36:74-81. Winniford MD. Smoking and cardiovascular function. J Hypertens 1990;9(suppl 5):517-23. Klein LW, Ambrose J, Pichard A, Holt J, Gorlin R, Teichholz LE. Acute coronary hemodynamic response to cigarette smoking in patients with coronary artery disease. J Am Co11Cardiol 1984;3:879-86. Martin JL, Wilson JR, Ferraro N, Laskey WK, Kleaveland JP, Hirshfeld JW Jr. Acute coronary vasoconstrictive effects of cigarette smoking in coronary heart disease. Am J Cardiol 1984;54:56-60. Young MA, Vatner SF. Regulation of large coronary arteries. Circ Res 1986;59:579-96. Ito Y, Kitamura K, Kuriyama H. Effects of acetylcholine and catecholamine on smooth muscle cell of porcine coronary artery. J Physiol (Lond) 1979;294:595-611. Foley DH, Amsterdam EA, Mason DT. Interactions of vasoactive effects of adenosine and potassium ion on isolated feline coronary artery smooth muscle. Circ Res 1979;44:207-15. Blesa MI, Ross G. Cholnergic mechanisms on the heart and coronary circulation. Br J Pharmacol 1970;38:93-105. Gross GJ, Buck JD, Walties DC. Transmural distribution of blood flow during activation of coronary muscarinic receptors. Am J Physiol 1981;240:H941-H6. Cox DA, Hintze TH, Ratner SF. Effects of acetylcholine on large and small arteries in conscious dogs. J Pharmacol Exper Ther 1983;225:764-9.
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38. Furchgott RF, Zawaski JV. The obligatory role of endothelial cells in relaxation of smooth muscle by acetylcholine. Nature 1980;288:373-6. 39. Furchgott RF. Role of endothelium in response to vascular smooth muscle. Circ Res 1983;53:557-73. 40. Young MA, Knight DR, Vatner SF. Parasympathetic coronary vasoconstriction induced by nicotine in conscious calves. Circ Res 1988;62:891-5. 41. Mudge GH Jr, Grossman W, Mills RM Jr, Lesch M, Braunwald E. Reflex increase in coronary vascular resistance in patients with ischemic heart disease. N Engl J Med 1976;295: 1333-7. 42. Brown BG, Lee AB, Bolson EL, Dodge HT. Reflex constriction of significant coronary stenosis as a mechanism contributing to ischemic left ventricular dysfunction during isometric exercise. Circulation 1984;70:18-24. 43. Sakai K. Vasoconstriction produced by intracoronary cholinomimetic drugs in isolated donor perfused hearts of rhesus monkeys: comparison with pig, dog and rabbit hearts. J Cardiovasc Pharmacol 1981;3:500-9. 44. Ginsburg R, Bristow MR, Davis K, Dibiase A, Bellingham ME. Quantitative pharmacologic responses of normal and atherosclerotic isolated human epicardial coronary arteries. Circulation 1984;69:430-40. 45. Denn MJ, Stone HL. Autonomic innervation of dog coronary arteries. J Appl Physiol 1976;41:30-5. 46. Dolezel S, Gerova M, Gero J, Sladek T, Vasku J. Adrenergic innervation of coronary arteries and the myocardium. Acta Anat 1978;100:306-16. 47. Reid JVO, Ito BR, Huang AH. Parasympathetic control of transmural coronary blood flow in dogs. Am J Physiol 1985; 249:H337-H43. 48. Gerova M, Dolezel S, Gero J, Barta T. Role of vagus in control of major conduit coronary artery in the dog. Physiol Bohemoslov 1979;28:299-307. 49. Sobey CG, Dusting GJ, Woodman OL. Reflex epicardial coronary vasoconstriction elicited by nicotine in anesthetized doss. Naunvn Schmiedeberes Arch Pharmacol1989:339:464-8. 50. Grygnani G: Gamba G, As&i E. Cigarette smoking effect on platelet function [Abstract]. Thromb Haemostas 1977;37:423. 51. Levine PH. An acute effect of cigarette smoking on platelet function: a possible link between smoking and arterial thrombosis [Abstract]. Circulation 1973;48:619. 52. Drummond AH. Platelets in biology and pathology. Gordon JL, ed. Case report. Amsterdam: North Holland Publishing Co, 1976:215. 53. Watts DT. The effect of nicotine and smoking on the secretion of epinephrine. Ann New York Acad Sci 1960;90:79. 54. Kershbaum A, Bellett S. Cigarette smoking and blood lipids. JAMA 1964;187:32. 55. Folts JD. Bonebrake FC. The effects of cigarette smoke and nicotine on platelet thrombus formation instenosed dog coronary arteries: inhibition with phenotalamine. Circulation 1982;3:467-70. 56. Felts JD. Gering- SA, Laibly SW, Bertha BG. Effects of cigarette smoke and nicotine on platelets and experimental coronarv arterv thrombosis. Adv EXD Med Biol 1990:273:339-58. 57. C&e J, &let RW, Ball KP. Carbon monoxide absorption by cigarette smokers who change smoking cigars. Lancet 1973; 1:1033-5.
Cardiovascular effects of nicotine: Relation deleterious effects of cigarette smoking Sandeep Khosla, MD, Atul Laddu, MD, Seymour Ehrenpreis, and John C. Somberg, MD North Chicago, Ill.
Nicotine has been consumed in the form of tobacco for hundreds of years. Nearly 30% of Americans smoke despite that most desire to quit1 This is in large part because of the addicting properties of nicotine. Nicotine is a tertiary amine composed of a pyridine and a pyrolidine ring.2 It binds stereospecifitally to acetylcholine receptors at the autonomic ganglia, the adrenal medulla, neuromuscular junctions, and the brain.2 Nicotine readily crosses the blood brain barrier and is distributed throughout the brain.3 The absorption of nicotine across biologic membranes depends on the pH. The pH of smoke from cigarettes is acidic so that nicotine is primarily ionized and does not cross cell membranes rapidly, and hence no absorption from oral mucosa. When tobacco smoke reaches small airway and alveoli of the lung, it is rapidly absorbed regardless of the PH.~ Chewing tobacco, snuff, and nicotine gum are buffered into an alkaline pH to facilitate mucosal absorption. The amount of nicotine extracted from nicotine gum is incomplete and highly variable.4 Similarly, intake of nicotine during cigarette smoking varies from puff to puff depending on puff volume, depth of inhalation, dilution with room air, rate, and intensity of puffing.5 Because of the variable amounts of nicotine absorption by various routes, to estimate its dose, one should measure the blood levels and know how fast the smoke eliminates it.2 Nicotine is rapidly and extensively metabolized, mainly in the liver and to a smaller extent in the
From the Divisions Health Sciences/The Received
of Clinical Chicago
for publication
Pharmacology and Medical School.
Sept.
2, 1993;
accepted
Reprint requests: John C. Somberg, MD, Division cago Medical School, 3333 Green Bay Rd., North AM HEART
J 1994;127:1669-72.
Copyright @ 1994 0002-8703/94/$3.00
by Mosby-Year +O 4/l/63509
Book,
Inc.
Cardiology,
University
of
Oct. 15, 1993. of Cardiology, The ChiChicago, IL 60064.
to
PhD,
lung.2 Renal excretion depends on urine flow and its pH and accounts for 2 % to 35 % of total elimination6 The half-life of nicotine is approximately 2 hours, with a range of 1 to 4 hours7 The primary metabolites are cotinine and nicotine-N-oxide, neither of which is pharmacologically active. Because of cotinine’s long half-life (16 to 20 hours), it is used in surveys and treatment studies as a marker of nicotine intake.8 The most abundant urinary metabolite is 3’hydroxy-cotinine.g Blood concentrations sampled in the afternoon in smokers generally range from 10 to 50 pg/ml. The increments in blood concentration after smoking a single cigarette range from 5 to 30 pg/ml.2 Blood and urine levels of pipe smokers are similar to those of cigarette smokers.iO Transdermal nicotine, which provides 21, 14, or 7 mg of nicotine over a 24-hour period, has an average steady-state plasma concentration of 17, 12, and 6 pg/ml, respectively.ll Nicotine is described as a stimulant of autonomic ganglia and skeletal neuromuscular junctions (i.e., nicotine muscarinic receptors). However, the in vivo actions are very complex and depend on dose, target organ, prevalent autonomic tone, and prior exposure history. Nicotine appears to be the substance in cigarette smoke that causes activation of the sympathetic nervous system by stimulation of the adrenal medulla.12 This commentary is an attempt to define the cardiovascular effects of nicotine in humans, a subject about which considerable controversy exists. Systemic hemodynamic effects. In a healthy person, smoking a cigarette increases heart rate and contractility and systolic and diastolic blood pressures.12-17 Cardiac output increases predominantly because of the increase in heart rate; arterial pressure increases because of an increase in both cardiac output and systemic vascular resistance. Smoking or nicotine causes cutaneous vasoconstriction, systemic venoconstriction, and increased muscle blood flow. The cardiovascular effects can be prevented by 1669
1670
Khoslu et al.
combined cy- and P-adrenergic blockade, which suggests that these effects are mediated by activation of the sympathetic nervous system.12! l3 However, it has been observed in a dog model that after adrenergic blockade with phenoxybenzamine and propranolol, there was still a significant increase in myocardial oxygen consumption, systemic arterial pressure, and peripheral vascular resistance during infusion of nicotine. However, in this model myocardial contractility declined. is These findings suggest a role of nonadrenergic mechanisms in the cardiovascular effects of nicotine. Local autoregulatory responses to increased myocardial requirements may be responsible for increased myocardial blood flow during nicotine infusion. A moderate increase in myocardial contractility during nicotine infusion in dogs with intact adrenergic receptors has been observed by some investigators,rg> 2owhereas others noticed no increase in myocardial contractility. I8 This discrepancy may be explained in part by use of higher dose of nicotine in the latter study. At higher doses nicotine appears to have cardiac depressant properties. Possible cardiac depressant mechanisms may be the activation of cardiac parasympathetic nerves2r or the release of vasopressin. 22 Vasopressin is released in response to smoking, and because vasopressin antagonists can blunt nicotine-induced vasoconstriction of blood vessels in skin, it may contribute to systemic vascular effects of smoking.23T 24 In patients with coronary artery disease, smoking may reduce left ventricular contractility and cardiac output,= 26 probably because of nicotine-mediated coronary vasoconstriction27 or the effects of carbon monoxide. In patients with depressed left ventricular function, increase in afterload can cause a decrease in stroke volume and an increase in the left ventricular filling pressure.28 Effects on coronary circulation. In patients with proximal coronary artery disease, cigarette smoke may not increase coronary blood flow and in fact may even decrease coronary blood flow despite an increase in myocardial oxygen demand because of increased heart rate and blood pressure.2gSeveral investigators have shown that in subjects with coronary artery disease, smoking does not increase coronary blood flow in response to increasing myocardial oxygen demand and that coronary vascular resistance increases
14,30,31
In a study by Martin et al. on 10 patients, when the heart rate times blood pressure (or double product) was held constant by atria1 pacing, smoking decreased coronary flow and increased coronary vascular resistance. When the double product was in-
American
June 1994 Heart Journal
creased by 50% by atria1 pacing, there was a 57 % +: 16 % increase in coronary flow before smoking compared with only a 24 % -t 12 % (p < 0.01) increase after smoking.31 Thus the effects of smoking differ in subjects with normal coronary arteries from those with proximal coronary disease: the coronary vasodilation mediated by increased metabolic demand caused by smoking is counteracted by coronary vasoconstriction. A paradox exists between the in vivo and in vitro effects of muscarinic agonists on coronary vessels. In isolated blood vessel preparations acetylcholine induced vasoconstriction 32-34but in vivo elicited substantial vasodilation.35-37 This paradox was partly explained by Furchgott and Zawadski,38 who demonstrated that the ability of acetylcholine to dilate blood vessels depends on an intact endothelial cell layer. The mechanisms responsible for endothelium-mediated relaxation of coronary arteries involve the production of prostacyclin32 and a second vasorelaxants, endothelial-derived relaxant factor.3g Acetylcholine acts on receptors on endothelial cells to trigger release of endothelial-derived relaxant factor, which diffuses to adjacent smooth muscle cells to cause relaxation.40 Thus in cells with endothelial damage resulting from the arteriosclerotic process, the endogenous vasodilators are not released and coronary dilation does not occur. This may be what occurs during the cold pressor test, when immersion of the hand in ice water causes coronary vasodilation in normal subjects and constriction in those patients with coronary artery disease.41v 42 Other studies have indicated that even with intact endothelium, muscarinic stimulation by exogenous agents causes coronary vasoconstriction in both human and nonhuman primates as well as in bovine and porcine models.40T43~44 The presence of parasympathetic nerve endings in the adventitia of large and small coronary arteries has been demonstrated.45> 46 Reid et a1.47demonstrated that stimulation of the cervical vagus elicits vasodilation of small coronary vessels. Similar findings have not demonstrated control of large coronary arteries.4s It has been suggested that carotid-body chemoreceptor stimulation by nicotine can produce reflex a-adrenergic receptor-mediated constriction of both large and small coronary arteries and that the constriction of small vessels is balanced by vagally mediated dilation.4g It has been suggested that cigarette smoke increases platelet aggregation in vitro50 as well as plasma catecholamines, which in turn exacerbate platelet activity in vitro and in vivo.51, 52 Nicotine administered intravenously or absorbed from ciga-
Volume 127, Number 6 American Heart Journal
rette smoke increases plasma catecholamine levels by stimulating the release of epinephrine from adrenal medulla of dogs53 and humans.54 Epinephrine stimulates platelet aggregation and thrombus formulation by platelet adrenergic mechanisms involving activation of adenylate cyclase.55 Human platelets are believed to contain cw-adrenergic receptors on their membranes. Stimulation of these receptors can initiate aggregation. 52 Cigarette smoke may be a powerful stimulus for aggregation and thus result in formation of an occlusive coronary thrombus within a coronary artery already predisposed to thrombosis because of an ulcerated atherosclerotic plaque.5” Carbon monoxide, one of the most poisonous byproducts of cigarette smoke that constitutes approximately 2.7% to 6.0% of smoke, may cause damage by injuring the vascular endothelium and contributing to the thrombotic episodes related to smoking.57 Conclusion. Nicotine has major effects on the cardiovascular system. Nicotine and its long-acting metabolites can cause arterial vasoconstriction resulting in increased systemic vascular resistance, thereby causing a sustained increase in arterial blood pressure. This increase in systemic vascular resistance may lead to coronary dilatation, although the degree of dilatation is often attenuated. However, coronary flow is reduced because of nicotine vasoconstriction in patients with atherosclerotic coronary artery disease. The paradoxic effects are the result of the lack of an intact endothelium in patients with coronary artery disease, resulting in reduction of nitric oxide production. This, in combination with adjustments (reduction) in neurally mediated vasodilation, leads to a decrease in coronary flow. These adverse effects of nicotine combine with the proaggregatory action of nicotine on platelets that may lead to additional adverse coronary events. Clearly, smoking is highly deleterious, and the replacement of smoking by exogenous nicotine (patch, gum, etc.) reduces the adverse effects of carbon monoxide. Even under these circumstances platelet-aggregating effects and coronary constriction of nicotine remain major risk factors for patients with coronary artery disease. In summary, nicotine, the active ingredient in cigarettes, has complex actions on the cardiovascular system. In healthy persons, it increases the heart rate, blood pressure, myocardial contractility, and coronary blood flow. These actions are attributed to stimulation of the sympathetic nervous system. Nonadrenergic local autoregulatory mechanisms may also be operative in increasing coronary blood flow. In patients with proximal coronary artery disease, the coronary flow does not increase in proportion to the
Khada
et al.
1671
increased metabolic demand during nicotine administration and may even decrease. This is because of nicotine-mediated coronary vasoconstriction. The paradoxic vasoconstriction may be caused by damaged endothelium because intact endothelium is required for vasodilation produced by nicotine. Nicotine also increases platelet aggregation and may enhance thrombus formation in already predisposed diseased coronary arteries. Thus nicotine can be hazardous in patients with proximal coronary artery disease. REFERENCES
1. Cigarette smoking in the United States, 1986. MMWR 1987;36:581-5. I 2. Benowitz NL. Pharmacologic aspects of cigarette smoking and nicotine addiction. N End J Med 1988:319:1318-30. 3. Hansson E, SchmiterlodCG. Physiological disposition and fate of Cr4, labelled nicotine in mice and rats. J Pharmacol Exp Ther 1962;137:91-102. 4. Benowitz NL, Jacob P III, Savanapridi C. Determinants of nicotine intake while chewing nicotine polacrilex gum. Clin Pharmacol Ther 1987;41:467-73. 5. Heming RI, Jones RT, Benowitz NL, Mines AH. How a cigarette is smoked determines blood nicotine levels. Clin Pharmacol Ther 1983;33:84-90. 6. Benowitz NL, Jacob P III. Nicotine renal excretion rate influences nicotine intake during cigarette smoking. J Pharmacol Exp Ther 1985;234:153-5. 7. Benowitz NL, Jacob P III, Jones RT, Rosenberg J. Interindividual variability in the metabolism and cardiovascular effects of nicotine in man. J Pharmacol Exp Ther 1982;221:368-72. 8. Benowitz NL. Kuvt F. Jacob P III. Jones RT. Osman AL. Cotinine disposition and effects. Clin Pharmacol Ther 1983; 34:604-11. 9.
10.
11. 12. 13.
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