The of Norepinephrine, Epinephrine, Methoxamine …circ.ahajournals.org/content/circulationaha/22/6/1125.full.pdfEpinephrine was administered in the same dose as norepinephrine in

The Direct Effects of Norepinephrine, Epinephrine, andMethoxamine on Myocardial Contractile Force in Man

By LEON I. GOLDBERG, PH.D., M.D., ROBERT D. BLOODWELL, M.D.,EUGENE BRAUNWALD, M.D., AND ANDREW G. MORROW, M.D.

A LTHOUGH the direct effects of sympa-thomimetic aminies on myocardial con-

tractile force have been well documented inthe experimental animal 1-7 such data haven:ot previously been obtained in man. Theeffects of these agents on the cardiac outputand arterial pressure of man have frequentlybeen measured.8t14 However, these two fune-tions may be profoundly modified by numer-ous other hemodynamic and reflex influences.Accordingly, any conclusions concerning theirdirect effect on myocardial contractility, basedoni such measurements alone, must be viewedwith caution. Indirect measurements in manhave led to diverse and conflicting conceptsof the myocardial actions of sympathoniimeticamines8 10, 15 and to speculations that theseagents, particularly norepinephrine, mayhave different cardiac effects in man and inexperimental animals.'6 17 Aviado'8 and Sel-zer and Rytand,19 in recent comprehensivereviews of the cardiovascular effects andtherapeutic indications of sympathomimeticamines, concluded that more definitive studiesof these agents in man were needed in orderto permit their rational clinical use.In the present study, the direct effects of

norepinephrine, epinephrine, and methoxa-mine on human myocardial contractile forcewere studied by means of the Walton-Brodiestrain-gage areh20 in patients undergoingthoracotomy. This instrument has been ex-tensively utilized in the study of the effectsof drugs on the heart in the dog,5' 7 and hasbeen found useful in monitoring myocardia]contractility during cardiac operations inman. 21, 22

From the Clinic of Surgery and the Section onExperimental Therapeutics, National Heart Institute,Bethesda, Md.

MethodsSympathomimetic ainines were admuinistered dur-

ing operation to 16 patients. They ranged in agefromii 4 to 40 years, and the average age was 25yTears. Eleven of these patients had atrial septa]defects, 3 had ventricular septal defects, and 2 hadpuliinonic stenosis. None had a history of heartfailure or severely dinminished cardiac reserve. Pre-anesthetic medications included meperidine (25 to75 mg.), scopolaminie (0.1 to 0.4 mg.) and pro-inethazine (15 to 50 wig.). After intravenousthiopental induction, all patients were maintainedunder light general anesthesia with nitrous oxide,oxygen, and a muscle relaxant, either succinvl-choline or d-tubocurarine. Thiopental and nleperi-dine were adnministered in small doses to all pa-tients for imiaintenance of anesthesia. Atropinewas given intravenously in doses of 0.2 to 0.4 nag.to 3 patients prior to thoracotomy.After a mnedian sternotomy had been performed

and the pericardiunm opened, the strain-gage archwas sutured to a convenient area on the rightventricle and the segment of myocardiulmi betweenthe 2 feet of the arch was stretched to about 50per cent of its diastolic length. Arterial bloodpressure was nmeasured through a polyethylenecatheter in the left radial artery by means of aStatham pressure transducer. Continuous record-ings of blood pressure and nmyocardial contractileforce were made simultaneously with a multi-ehannel oscillograph.

I-Norepinephrine bitartrate (Levophed, Win-throp), I-epinephrine bitartrate (Suprarenin, Win-throp), and nmethoxanaine hydrochloride (Vasoxyl,Burroughs-Wellcome) were administered intraven-ously either by rapid injection or by infusion.Norepinephrine was administered at least once toall 16 patients. In 5 patients methoxamine wasadministered in a dose sufficient to approximatethe diastolic pressure increment produced by nor-epinephrine. In 6 patients norepinephrine andepinephrine were injected in succession in equaldoses. Metaraminol bitartrate (Aramine, Merck,Sharp and Dohme) and mephentermine sulfate(Wyamine, Wyeth) were also used in several pa-tients. All amines, unless stated otherwise, wereinjected before institution of cardiopulmonarybypass or cannulation of the venae cavae, generally

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GOLDBERG, BLOODWELL, BRAUNWALD, MORROW

at a time when the femiioral artery was being pre-pared for cannulation and the heart was not beingmnanipulated. Contractile force and arterial pres-sure were recorded during a control period beforeeach administration of an amine. The doses of theamines were calculated as the base except forinethoxamine, which was calculated as the hydro-chloride salt.

ResultsThe effects of norepinephrine, epinephrine,

and methoxamine on right ventricular con-tractile force (CF), arterial pressure (BP),and heart rate (HR) are shown in table 1.The amplitudes of the contractile force re-cordings, which are directly proportional tothe force applied by the myocardium to thestrain-gage arch, were measured in millime-ters. Since the height of the contractile forcerecording depends upon such variables as thedirection of placement of the strain-gage arch,the depth of the sutures and the degree ofinitial tension placed on it,23 no attempt wasmade to convert the deflections inito grams offorce. The amplitude of the oscillographicdeflection during the control period was ad-justed arbitrarily in each patient and thesecontrol values are not, therefore, comparablein the different patients. The percentagechange, however, from the control value fol-lowing the injection of a drug into an indi-vidual patient permits meaningful compari-sons.

Norepinephrine

The intravenous administration of norepi-nephrine increased ventricular contractileforce in all 15 patients in whom valid meas-urements were made (figs. 1 and 2). The re-sponse was always transient, lasting about 5minutes. In 1 additional patient (M.T.), noincrease in contractile force was observed, butshe developed atrial fibrillation during thenorepinephrine injection, and the irregularityof the ventricular contractions made accuratemeasurements of contractile force impossible.This patient continued to have transient epi-sodes of this arrhythmia during the operation,so that its development may not have beenrelated to administration of the amine. Asmay be noted in table 12 there was consider-able variation in the contractile force, arterialpressure, and heart rate responses in the dif-

ferent patients. Similar variability of responseto norepinephrine and other amines has beennoted in anesthetized animals5 and probablydepends upon such factors as the differentresponses of patients to the same dose perkilogram of body weight, variations in thedepth of anesthesia, the level of circulatingcatecholamines, the amount of blood loss, andthe activity of the sympathetic nervous sys-tem. Although there was some correlation be-tween thecontractile force and pressure in-crements produced by norepinephrine, thisrelationship also varied among patients(fig. 3).

It is interesting that the 3 youngest pa-tients, aged 4 to 8 years, had relatively smallincreases in contractile force per unit increasein arterial pressure, suggesting that in chil-dren the arteriolar bed is relatively moresensitive to sympathomimetic amines than themyocardium. The patient (A.C.) in whom thecontractile force rose only 5 per cent in re-sponse to norepinephrine, apparently had anelevated contractile force level at the time itwas administered, since the contractile forcegradually decreased by 40 per cent duringthe subsequent period of observation. It ispossible that this weak response to norepi-nephrine was related to a high endogenouslevel of circulating catecholamines, since atypical response to epinephrine was obtainedat a later time when the initial contractileforce value was lower. The changes in heartrate in the 14 patients with sinus rhythmranged from an increase of 18 beats per min-ute to a decrease of 18 beats per minute.These changes in rate were undoubtedly influ-enced by the variable state of vagal block thatresulted from the pre-anesthetic and anes-thetic medications, because norepinephrine isknown almost always to result in bradyeardiain unanesthetized subjects.

EpinephrineEpinephrine was administered in the same

dose as norepinephrine in 6 patients. In 4instances, myocardial contractile force in-creased to approximately the same extent aswith the norepinephrine injections (figs. 1and 2). Systolic pressure also inereased in

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1128 ~~~~~~~~~GOLDBERG. BLOODWVELL, IANAL,MRO

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5 of- the, patients, huit the eliaiu-c iti dliastoliclIli,essur.e xxasvarJablie. ranigfrom1- a declinleof 7 nun. ITg. to an. in(11(crase of 20 nun11. Ha.This differ-en.ce is, apjpare.nt Ini figure,s 1- an-d2 ; in one Iiisstane, thte diastolic, pr-essure fellapp)roxi.mate]> 5" miim. Hgc iii thie 9riesci/ee of a

contractile force increment oif 38 p)er cent;in the other pat.jent (fig:. 2). however, afteran. unstable iniitial periodI the diastolic pres-sure rose, 20 nun. Jig and the, contr-act ile forcetincreased 50 percent. The hieart rate either-increasedi up t-o 24 beats per nuinnte or- re-

nxiainced un chaii ged after cpinej)hrinc admiim-istration. The, du-rationi of the eff-ects of this

HIIIiiii xvas Similar to timhse produced Inv 11/OP

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T1his din-iit was administered to 7 p)atients(figrs. 2 atiul 31. 1in 5 of thiese, contractile forceeither did ntot chang.ce significantly or- (Iccrieased slighttly (-6 to -9 per ceiiil ) in therenmainmg 2 I)atieiits, there wNer-e slighft in-creases in contractileforce (13 anid 1-8 percent) . The hiear-t ratle fell by 4 to 18 heats per-minute ini 4 of thie patienits anid the rate (lidniot elhaige or- iiicreased slightly (6 aii(l 12heats per minuiite) in the others. The durationof the pressor effect, following( a single inljee


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MYOCARDIAL CON'T'RACTTTiE FORCE

t1o1 (of llletioXtioxallile W usiuially betweeii 10to 15 mllilnUteS. Pil1e 1IloIIotilIucc( diffeirelcesbetwe-eni thlie effeets of iieftloxaitiie aiid( I0-

ej)ilLe_l)llt'ile oil coiitractile for(ce are shiownill figure 3. A.s shlowvn in fig-ure 2 0.25/1g. perKg. of loloep)illep)lihrlin iieircast(l imyoardialcontractile for ce 46 pet cenlt and the arl'terialjwt'essutC rose by 40/25 niu. 11gr. M\eth1oxam-iiiine(iil a (lo0se olf 2, mg-.) inl tlis, StallI p)atielnt J)l'o--(1(3e0(1 Can identical 1ieenellnlt in (1Ist ol i(artrial] pressure hut (co1traileic 1'01(c ill-cr,eased only 13 per conejtt.

Mephentermine anid Metaraminiol

2[ephlienterlilie (5 jn1W.) w1a1 ac1nlillisteiredintravenousiwl to platient l.ii. 1(1u1 conitractileforce inlcre(ased 71 per cent; tlle arter---ial bloo)0pressuie rease( 1 r01o 100 /70 to 1 /de)mmOn.IJJY. Thisf atine Atis also gi-ven i tt(ldose of15 ing. to ani addit ionial pat lent wilo bad p)1r(-I'01lld( llviI)(otllsioIi (652;-5 imn. Mg) tld Ahliois niot ilmelllded in table 1 'lThe bloodl pressurelose to 110/85 811(1 contractilc force ilcrecase(130 peim (eIlt. rTlhe (hliratioll of 1t1(50 effects of'itieplienteintitie exceeded 1o niinut es in e(1lpatienit.

Metaramitnol was adniiiinist ered to 2 patientspirior to cardioplulhtonaryv bypass. nl patientD.A. a dose of 1 mug". illnreased eontraetileforce bv 75 per ecutt while the ariteril pr es-sure rose fromi 90/60 to 160 /95 miomi. 11gy. TIna seconid patient, not inelucled inl thle tablelthe adm-inlistrationi of 1 ning. of miietaraminmolriesulted in a eontractile froi'e imicreirie,it of43 per cent Awith all illeiV8s5 in arterial pres-sure froni 8050 t-o 125 /75 nun. JTI. T'liis (ImIg(0.5 111g.) wvas a,1ilso adininiiis-erc to patientS.G. followvillng tl-he repatir of anl atnial septaldefect when hiyp)otciis,tioii (50 /30 nun,. 11hg)suddenly developed. Coiitriactile for(ce ini-cea'ekse(I 90 per ceiit cand tllew airterial pressurelose to 1l08 76 mm. IT%. The duirationi of theeffect-s of thlis amniiet also exceed1ed 15 miiin-utes.

DiscussionThe results of the cliieial stiudies described

al)ove demitonistrtte that epinephrine, iiorepi-neplirine, uleplienterminie, ttnd metaI'aiintinolsubstantially inierease myocardial contractileforce in man. Injectiomis of norepiuephriueCirculation, Volume XXII, December 1960

Lt P"VENTRICULARCONTRACTILE FORCE

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Figure 2The ff(el(S (o1/ 0-..J /o[.. nolfJ)(j)rl9)phrl1 ondC JJil{llJ)llli/c 110(1 (1/ 2 mqi. (of }{i i-y.) o] atef loll 110 ht/f 71ricfli1/01 (cntra1c1 ile fI)'tr11)1(/I ( f 1I t i lII , i? t i ) I '1) -t(I ) (c- titp 1tY( itvI/ h

atid of epi)ncpli_itie, ill the samice patients aiid(i111 CI('qul (doses, riesiulted in aliliost ideni-ticali ltcin'llellt>11S il;11\lSoettil'ditil eutraelcltile force1.\Lctlioxaiiiniet, on11 the othter lhitnd bad Vi'tii-tdly ito ('fleet (iii iiivotctiJll tuiltruattil e forceill (doses that lplr(oued pr'otiotmo 'ecl incretsesinl arteriiail l)l'cssure. These reXsultsIate s.inmlilarto those, I)i'cviously reported in anesthetized

11and mnianesthetized (logs6taind demnonistiateli(lt then' are no qulditative differences inthe effects of these amiiles oni contraectite forein ian1iand the log.

Prev-ious st udies in nlili liaxve coinsistently(leilionstrat(edl thiat el)inellhrine augmuents cfar-dc iacI oiitlmit501(1 andc that ]morepinephritie(itlIer (does inot lictulge or (limlnliishes this fune -

i-ionll.>S 1 13 14 'These results have led to tieerroleous coniclusion that lorepinecphriie isani amine with a purely pressor action anidwith nlo efect on myocardial conitractility,

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Figure 3Relationships between the changes in diastolic ar-terial blood pressure and myocardial contractileforce that occurred after each administration ofsympathonmimetic amines in 16 patients.

but that epinephrine is a stimulant of myo-cardial contractility. It is apparent from thepresent investigations that the different effectsof these agents on cardiac output are not theresult of any dissimilarity in their actionson myocardial contractility, but are probablyrelated to different effects on the peripheralvascular bed. The changes in cardiac outputmay be explained as follows: norepinephrineaugments systemic vascular resistance,8 whichin turn tends to result in reflex bradyeardiaand diminished cardiac output, despite theinereased myocardial contractile force. Epi-nephrine, on the other hand, tends to dimin-ish peripheral resistance,9 and its positivechronotropic effect is unopposed by a stimu-lation of baroceptors. Cardiac output thusrises with increments of myocardial contrac-tile force of a similar magnitude to thoseproduced by norepinephrine. A similarity inthe cardiac actions of these catecholamines inman had been previously suggested by thedata obtained by Wilber and Brust,24 whichshowed that norepinephrine increased cardiacoutput after atropine or tetraethylammoniumbromide had prevented reflex bradyeardia.Although the longer acting sympathomi-

metic amines, mephentermine and metarami-nol, were administered oni relatively few

occasions in the present study, they alwaysproduced increments in contractile force ofa magnitude similar to those following non-epinephrine, but of longer duration. It ap-pears, therefore, that sympathomimetic am-ines that increase arterial blood pressure inman may be divided, as in the dog, into 3classes :5 Class I amines, such as norepineph-rine and epinephrine, increase myocardialcontractility and have a short duration ofaction; Class II amines, such as methoxamine,have little or no effect on myocardial contrac-tility and act longer; Class III amines, me-phentermine and metaramiinol, increase con-tractility and have an action of long duration.Additional studies are being conducted withother amines to ascertain whether these agentsmay be similarly classified.The strain-gage arch, as a method for meas-

uring myocardial contractile force, was foundto be applicable in man as in the experimentalanimal. No complications arose from its usein the present investigation, and the presenceof the arch did not interfere with the surgicalprocedure. It should be emphasized that inorder for the strain-gage arch to measure thedirect effects of drugs on the contractile forceof the heart, the segment of myocardium be-tween the 2 legs of the strain-gage must bestretched to approximately 50 per cent of itsinitial length. As Cotten and associates23' 25, 26previously demonstrated in the dog, this pro-cedure eliminates significant changes in con-tractility produced by extracardiae effects ofdrugs, such as alterations in peripheral re-sistance, which would modify the end-diastolicfiber length and consequently the force ofcontraction. Other possible effects of increasedsystemic vascular resistance on myocardialcontractile force measurements were furthernminimized in this study, since the strain-gagearch was placed on the right ventricle. Theaugmentation in contractile force producedby norepinephrine and other sympathomi-metic amines cannot, therefore, be attributedto increases in peripheral resistance. With thestrain-gage arch the effects of at least 2 agentson myocardial contractile force should be com-pared in the same patient, since it has beendemonstrated that considerable variability


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exists in the magnitude of the contractileforce increments produced by the same agentin different patients. If oiie agent is consid-ered as the standard of reference, as nonepi-nephrine was in this study, the effects of allother drugs may be compared with those ofthe standard and individual responses in vari-ous patients can be analyzed.The results of the present study are im-

portant in any consideration of the therapeu-tic indications for the administration ofarniines. They emphasize that the cardiovas-cular actions of these drugs differ strikinglywhen equipressor doses are given. It is nowapparent that although norepinephrine andmethoxamine both elevate the blood pressureand diminish the heart rate, these 2 agentsshould not be considered to be interchange-able, as has previously been suggested.27' 28For example, if a patient is hypotensive be-cause of impaired myocardial contractility, asin shock that may accompany myocardial in-faretion, the administration of an amine withonly a pressor effect, such as methoxamine,would appear to be contraindicated. The aug-mentation of peripheral resistance producedby this amine, in the absence of a direct car-diac action, could result in cardiac dilatationand in pulmonary venous hypertension. Am-ines such as norepinephrine and metaraminolincrease both myocardial contractility andperipheral resistance and would appear to bemore suitable in this clinical situation. Onthe other hand, if a patient is hypotensiveprimarily because of a fall in peripheral re-sistance but has no impairment of myocardialcontractility, as may occur during spinal anes-thesia, methoxamine may be more applicable.These concepts had been presented previouslyon the basis of extensive animal experimenta-tion3' 5 6 and a few preliminary clinical ob-servations.6 Perhaps because of the mistakenimpression that these amines do not have thesame actions in animals and man, these prin-ciples have not been widely applied in clinicalpractice. It is hoped that a more rationalbasis for clinical use has been provided bythe present comparative studies of the directeffects of these drugs on the contractility ofthe human heart.Circulation, Volume XXII, December 1960

SummaryThe effects of 5 sympathomimetic amines

on myocardial contractile force were deter-mined with the Walton-Brodie strain-gagearch in 16 patients undergoing operations forcongenital heart disease. Equal doses of nor-epinephrine and epinephrine produced almostidentical increments in myocardial contractileforce; equipressor doses of methoxamine re-sulted in little or no change in the force ofcontraction. Mephentermine and metaraminolproduced increments in myocardial contrac-tile force similar to those following norepi-nephrine administration but the duration ofaction was longer. The results of these studiesindicate that there are no qualitative differ-ences in the actions of these amines on cardiaccontractile force of dog and man and providea basis for the rational clinical use of theseagents.

AcknowledgmentThe authors appreciate the cooperation of Drs.

N. S. Braunwald and J. W. Gilbert of the NationalHeart Institute, Clinic of Surgery, and Drs. R. C.Brown, G. R. Christenson, and C. L. Hebert of theClinical Center Department of Anesthesia.

Summario in InterlinguaLe effectos de 5 aminas sympathomimetic super le

fortia del contractilitate myocardial esseva determi-nate per medio del areo de Walton-Brodie in 16patientes subjicite a operationes pro congenite morbocardiac. Doses equal de norepinephrina e de epi-nephrina produceva quasi identic augmentos in lefortia de contraction del myocardio. Doses equipres-sori de methoxamina resultava in pauc o nullealteration del fortia de contraction. Mephenterminae metaraminol produceva augmentos del fortia decontractilitate myocardial simile a illos occurrentepost le administration de norepinephrina, sed leduration del effecto esseva plus longe. Le resultatosde iste studios indica que il existe nulle differentiasqualitative in le action de iste aminas super le fortiade contraction cardiac in canes o in humanos. Illosprovide le base pro le utilisation rational de isteagentes in le practica clinic.

References1. GARB, S.: Inotropic action of epinephrine, nor-

epinephrine and N-isopropylnorepinephrine onheart muscle. Proe. Soc. Exper. Biol. & Med.73: 134, 1950.

2. MELVILLE, K. I., AND Lu, F. C.: Effects of ephe-drine, phenylephrine, isopropylarterenol, andmethoxamine on coronary flow and heart ac-tivity as recorded concurrently. Arch. int.Pharmacodyn. 92: 108, 1952.

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3. SARNOFF, S. J., CASE, R. B., BERGLUND, E., ANDSARNOFF, L. C.: Ventricular function V:Circulatory effects of aramiine. Mechanism ofaction of "'vasopressor"' drugs in cardiogenieshock. Circulatioin 10: 84, 1954.

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ANDREW G. MORROWLEON I. GOLDBERG, ROBERT D. BLOODWELL, EUGENE BRAUNWALD and

Myocardial Contractile Force in ManThe Direct Effects of Norepinephrine, Epinephrine, and Methoxamine on

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