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~I:~rEMALs n.-rn Mrraons Subjects Five men and three women (ages, 18 to 30 years ) with a smoking history of 2 to 1S pack-years comprised the group under study. 'I'hi ey were free of' cardiopulmonary symptoms and hadl normal findings on physical examinations; spirome- •From the Jane and Edward Shapiro PuItnonary Suite Division of Pulmonary Disease, Department of InteQ! Medicine, Mount Sinai Medical Center,,MSami Beach, Fla. Supported in part by grant. HL.-10822 from the National Heart, Lung, and Blood Imstitute. Manuscript received January 30: accepted Febntary' 9. Reprint'reqeiestss Dr. Saeknrr, 4300Akon Road, Miarni Beach 33140 CHEST, 74: 3,, SEPTEMBER, 1978! lYoNee:Ilhis muerial may be protected bycopyrieht law. (Gtle 17 US code; VtRMAL Dt RST1A.7A11O1`!iS Hernodynamic Effects of Smoking Cigarettes of H igh and Low N icofiine Content* Leonard Tachmes; Roberto J: Fernandez, B.S.;, and biarvin A. Sackner, Nt.D:, F.C.C.P. We studied the hemodynamic effects of smoking cigar- ettes with, high and low contents of nicotine in young smokers free of coronary arteriati disease; The smokine, of one cigarette with a high content of nicotine produced a peak rise in cardiac output of 32 percent above baseline values, and! the effect persisted for one hour Smoking a cigarette with a low content of nicotine produced a peak rise of 13 percent above baseline values, with a duration of five minutes. The rise in cardiac output was almost A s a result of absorption of nicotine, the smoldng of cigarettes produces a rise in heart rate, am elevation of systemic blood pressure,,and cutaneous vasoconstriction. In some smokers, cardiac output is Increased, while in others, it is unchanged. Possibly this variability is related to the failure to control the 1 ~ In a t of nncotune in the cigarett snlokdl contenee. study of smokers wi th angina pectoris, the sznoking of cigarettes with a high content of nicotine ('2:00 mg), effected a greater elevation of' heart rate and' _.systemic blood pressure than satoldng, cigarettes with a low content of nicotine (0.3 mg).° The smok- Cing; of cigarettes with a high nicotine content was associated with a significant fall in stroke volume ": because the rise im heart rate took place without a change in cardiac output.' The dose-related hemo- dynamic effects of'srnroldng cigarettes with low and' high nicotine contents have not been investigated in y;oung;smokers free of'cardiac disease and constitute the basis of this report. entirely attributable to tachy,cardia, since stroke volume remained relatively constant The smoking of a cigarette ..dth high nicotine content also caused greater and more sustained!elevation in systemic blood pressure t5an smok•, ing,a cigarette with low nicotine content.'hhos, there was i a responsiveness to the dose of nicotine in cigarettes smoked by young, smokers free of' coronary arterial! dis- ease. trie testing, and resting electrocardiograms. AD gave in- forrned consent and received' financial remuneration for theirr participation in the study. Methods A modification of a previously described technique of rebreathing was utilLzed.s.' Briefly, the subject rebreathed 2 L of the tested mixture of gases at 24 breaths per minute from the i position for functional residiial' capacity ( FRC').. The mixture consisted of '013 percent radioactive 2sorygen- labelled carbon monoude,, U percent acetylene, 10 percent helium; 21 percent oxygen, and the balance nitrogen. Arsaly- sis of gases was performed'.vith a mass spectrometer (Perkin- Elmer.%{GA 1100), ancIthe analog signals were processed on- line by a digital computer (Digital Equipment Co. model. PDP-12). Diffusing capacity of carbon monoxide was calcu- lated from the curve for the disappearance of carbon monoz fde: 'I'he latter was also used to adjust the intercept of the curve for the diaappearance of acetylene to zero time, in order tor estimate the combined volume of blood in the pulmonary tissue plus capillaries. The curve for the disap- pearance of acetylene, together,.vith the absorption of acet+y- Iene in the tiasve andi blood, was used' to: calculate the flow of blood'an the pulmonary capillaries. ln normal subjects, where intrapuimonary shunting of blbod is negligible, the flow of' blood in the pulmonary capillaries can be considered to be equivalent to cardiac output The curve for helium equi- libration provided data for calculation of FFIC, and the curve for disappearance of oxygen provided data for calculating the consumption of; oxygen. The flow of' blood in the calf was determined by aa plethysmographic technique utilizing a mercury-in-Silastic strain gaugea0 Heart rate was estimated from a sing)b-lead. ECG, and blood pressure was estimated by auscultation after ' obliterating the brachial arteriall pulse with an occluded cuff. Procedure The subjects omitted lunch and refrained from smoking at HEMODYNAMIC EFFE4TS' OF SMOi(INl6' CIGAREI7ES 243

Bas.lin. 15 60 90 1210 . . ume - minutes FYcvaa L Flow of' blood in pulmonary capillaries (equivalent to cardiac output in normal subjects where intrapulmonary shunting of biood is negligible) after smoking one cigarette with high nicotine content (solid circles ), one cigarette with low nicotine content (open cir- cles), or one cigarette in sham fashiow (triangles). There was dose-relatecI increase in flow off blood in pulmonary capillaries. Significant differences of means from baseiine (IP < 0.05) are designated with asterisks. ~ least four hours prior to the study, which was' performed in intervals of time when the analysis of'variance was statistical- the middle of the afternoon. They first rested on a cot in a darkened' quiet room for 45 minutes. Then the procedure of. rebreathing was performed every ten minutes untiI' values for the consumptfow of oxygen became reproducible, a factor :: which generally took an additional! 30 to 60 minutes. Thee baseline values were measured' in duplicate, along wit;h, the - heart rate, blood pressure, and flow of blood in the calf, On each of three separate days, the subject smoked' a cigarette of high or low nicotine content in his usual' fashion -. : or feigned smoking a cigarette as a controi. The order of the different types of smoking was randomized. Cigarettes with a content'of nicotine of 2:4 mg (Players cigarettes) and,with a content of ' 0:1 mg, ( Cardeton ) were chosen as the cigarettes with high and low nicotine confents, respectively.1z Hemo- • dynamic measurements were repeated in duplicate and were averaged at 5, 15,, 80, 90, and' L0 minutes after the end of smokiagwhile the subject remained in the supine position. Data were tested for statistical'significance by means of an analysis of'variance and aNewman-Keu1s testl1='Stud'ent's i• • test was used to test differences from baseline at selected . C, Bcs.line 15 Tirrne - minutes i 90 12'0 F~cmz 2. Heart' rate after smoking one cigarette with high nicotine content (solid circles), one cigarette with low nicotine content (open circles), or one cigarette in sham fashion (triangles). There was dose-related increase in heart rate. Sigaificant differences of ineaas from baseline (P < 0.05) are designated with asteriaks. 244 TACHMES, FERN1A'NDEZ,' SACKNER •,lorkK 7`" ,+ ser-11 •,t be proteetad by capycight la+.. (rit,le 17'U1Seode).:;` ly significant. IRtsvzTS Sham srnokiitg of'a cigarette did not significantly affect any of the measurements. Smoking of the cigarette produced a graded increase in the flow of blood in the pulmonary capillaries (cardiac output), with~ the cigarette with the high nicotine content effecting a peak increase of 32 percent and the cigarette .vAh low nicotine content affecting a peak increase of 13 percent five miisutes after smoking (Fig,1) (P < 0.05). This increase persisted for 60 mihutes after smoking the cigarette with high nicta. tine content, with a subsequent decline to baseline. In contrast, the increase lrut'ed only five minutes after smoking the cigarette with low nicotine con- tent. The heart rate rose in a similar pattern (Fig 2), CHEST, 74: 3; SEPTEMBER, 19T&

. a Btu.lin. 15 ; ~0 90 120 . ~.,, . Tume - minutes ? FtcunE 3. Systolic (top) and diastolic (Fiottam) blood presaures: after smoling one dgarette with low nicotine content (solid circles);,,one cigarette with low nicotine content (opencircles)', and' one cigarette in sham fashion (triangles). Significant differences of ineans from baseline (P < 0.05) , are designated with esterislu. : such that it was the major factor in accounting for the increase in cardiac output„ since stroke volume remained nelatively constant. Systolic and diastolic blood pressures; increased according to the nicotine: content of the cigarette ( Fio 3). The eievati= of systemic blood pressure lasted' 15 minutes after smoking the cigarett'e with high nicotime content andi five minutes after smoking thei cigarette with low nicotine content. After smokino, there~were no statis- ticalliy sigqificant changes in the consumption of oxygen, the diffusing capacity, the volume of blood in the pulmonary tissue plus capillaries, the FIdQ, and the flow of blood in, the calE. Di=ssio:r - The present study dlemonstrated that' cardiac out> put increased immediately aftersmokimg in habitual young cigarette smokers, who were free of cardiac disease. Furthermore, the magnitude: and duration of this increase was directiy, related to i the : nicotine content of the cigarettes smoked. Heart rate and systemic blood pressure rose concomitantl'y, while stroke volume remained, relatively constant. These observations were qualitatively similar to those of Regan et al,s who foundl an increase in cardiac output of'1'4 percent by Fick's principle, and to those of' Kerrigan et al,4 who, reported an increase of' 1'5 percent by dye dilution after the smoddng, of ciga- rettes with an, unspecified nicotine content. In smokers with angina pectoris, smoking cigarettes with a lbigjn nicotine content of1'.8 mg; caused aa significant increase in systemic blood pressure and CHEST, 74: 1 SEPTEM'BER, 1978 r. . -r • r ~., , - 'bv' tir - Ttl heart rate but no change in, cardiac output becausa stroke volume decreased' In such, patients, eleva- tion of the carbon monoxide c•ontent of blood from the coronary sinus by breathing,carbon monoxide at 150 ppm, (.vhich1was comparable to Ievels achieved after smoking three cigarettes) increased the left ventricular end-diastolic pressure and decreased! the stroke volume." Thus„ the heart with coronary ar- terial disease mighf be more sensitive to the nega- tively inotropic effect of carbon monoxide than the normal heart. The increase in cardiac output,produced by smok- ing in our young smokers may be related'to a greaterr stianuSation: by nicotine of the ganglia of the sympa- thetic than the parasympathetic system. The former would lead to: the release of cstecholamiiaes from postganglionic fibers and the adrenal medulla, caus- ing variable degrees of positively cbaonotropic andl inotropic: cardiac actions, prednminant'vasoconstric- tion, and systemic hypertension,2' The diffusing capacity~d'zd not change in our sub- jects wdth the modest elevatiom of cardiac output ' after smoking. This is not surprising, since it has~ been shown that an elevati= in cardiac output of' 113 percent over baseline prodtirced by infusion of a combinatimn of norepinephrine and atropine does not alter the single-breath diffusing capacity. In con- trast, exercise sufficient to cause a~ comparable in- crease in casdiac output is associated with a 20 percent rise in diffusing capacity. The reason for the difference in the response of the diffusing,capacity to drug-elevated and exercise- HEMDD7NAMIC EFFECTS OFSMOKING CIGARETTES 245

administration of 0.5 mg of epinephrine, which caused greater hemodynamic effects, increased the flow of blood'in the calf. R$FERE.Y(ES I Thomas CB,, Bateman JL., Lidberg EF: Observations on the individuaL effects of' smoking on the bloimdl pressure, heart rate, stroke volume and cardiac output of healthy young adults. Ann Intern Med 44~8u4-892„1958. • 2' Comroe JH Jr: The pharmacologic actions of nicotine. Ann NY Acad'Sci'90t48+i1,1960 3 Regan TJ, Frank MJ, McCinty JF, et ali Myocardial response to cigarette smoking in normal subjects and patients with coronary disease. Circulation 23:316a469, 1981' '"4' Kerrigan R; Jain AC, Doyle JT: The circulatory response to cigarette smoking at rest and after exercise. Am J'Med Sci 255:113 -119, 1968 S Shepaniijt Physiology of the C'uculation1n Human Limbs In Health andi Disease. Philadelphia, NTrB Saunders Co, 1963,•.pp 381-389 . 24t TACHMES, FERNANDEZ, SACKNER N!ottacTfiii material maybe protcetrd by eopyr+giu law: (rde 117 US code) :' elevated cardiac outputs might be related to a fall in pulmonary arteriall pressure with administration of adrenergic agonHstsi+ and a rise with exereise.'s A1- though cigarette smoldng, produces cutaneous vaso- constriction,s the effects on the $ovc of' blood in the < muscles have been inconsistent Both Rottenstein et al1e and our group found a tendency towards an ~ Ancrease in the flow of blood' in i the muscles or to a - nediatribution of the flow of blood to the viscera. Sackner et a114 previously found that subcutaneous injection of 0.25 mg of epinephrine, which produced sLp elevation in cardiac output comparable to smok- img cioarettes with~ a high content of nicotine, did not affect the flo!w of blood in the calf, whereas 6' rlronow WS;, Dendinger J, Rokaw Sh:: Heart rate and carboa monoxide level after smoking high., low- and non. nicotine cigarettes. Ann Intern Med 74:697-702, 1971 7' Aronow WS,, Coitlsmith JR. Kern JC,, et' al: Effect of smoking cigarettes on cardiovascular hemodynanmics. Arch Environ Health 28:330-332, 1974 8' Sackner \4A; Greeneitch D, Heiman \fS; et ala Diffusing capacity, membrane diffusing capacity;, capillary bloadl .`;' ' volume, pulmonary tissue volume, and cardiac output' measured by a rebreathing technique. Aur, Rev Respir Dis 11i: i57 -1!6a,1975 91 Sackner MA, Friedman M; Silva G, et aI: The pulmonary hemodynamir effects of aerosols of Lsoprottrrenol'l andi a^ ipratropiurn in normal subjects and patients with revers- ible airway obstruction. Am Rev Respir Dis 116:1013- ible '' ;` 1022, 1977 10 Slason DT, Braunwald' E: A simplified pletlrysmognapbic system, for the measurement of systemic bloodl pressure, and peripheraI blood How. Arn Heart J' 64:79ta-804; 1962. 11' FederalTrade Commission, 1978' 12 BMD, Statistical Package: Health Sciences Computing, Facility, Department of Biomathematics, School of \'tedi- cine, University of California at Los Angeles, University ' of California Press, 1973 13 Aronow WS, Cassidy J, Vangrow JS, et aI: Effect of' cigarette smoking and breathing carbon monoxide on cardiovascular hemodynamics in anginal patients. Circn-, lation 50:340-347, 1974 14 Sackner MA, Dougherty R, Watson H, et a1: Hemody- namic effects of epinepltrine and' terbutaline in normal man. Chest 68:616-624, 1975 1'5' Bevegard S, Holmgren A, Jonsson~B: The effect of body position on the circulation, at rest and during exercise, with speciai' rekrence i to the influence on the stroke volume. Acta Physiol Scand'49:2779-298, 1960 16 Rottenstein H, Pierce G, Russ E, et al: Influence of nicotine ou the blood flow of resting'skeletal muscle and of the digits in normal subjects. Ann ; IY rlcad Sei 90:102- 110.5;,1B6o CHES'J•, 74: 31 SEPMBER, 1978 . "V