The Action of Norepineplrine, - Homepage | Circulationcirc.ahajournals.org/content/6/2/238.full.pdfThe Action of Norepineplrine, Epinephrine and Isopropyl Norepinephrine on the Rhythmic

The Action of Norepineplrine, Epinephrine

and Isopropyl Norepinephrine on theRhythmic Function of the Heart

By MORRIS H. NATHANSON, M.D., AND HAROLD MIILLER, 'M.D.

The actions of norepinephrine and isopropyl norepinephrine on the rhythnic plroperty of the heartwere studied and compared with that of epinephrine. Norepinephrine does not abolish cardiac stan(1-still byr carotid sinus stimulation, has no effect on the ventricular rate of heart block and induces a

sinus bradyeardia. Isopropyl norepinephrine acts similarly to epinephrine in that it abolishes theinduced cardiac standstill, increases the ventricular rate of heart block and produces a sinus tachy-cardia. In the treatment of cardiac arrest, the isopropyl compound appears to possess optimumfeatures as it is very potent in the prevention of cardiac standstill and does not predispose to ven-tricular fibrillation.

T HE PROPERTY of rhythmicity orautomaticity, the pacemaking functionof the heart, is essential to normal car-

diac activity. If a pacemaking mechanism isabsent, cardiac or ventricular arrest follows ina heart which may be completely competentin its contractile function. In a previous report'utilizing the cardiac standstill induced by stim-ulation of the carotid sinus in man, it wasshown that epinephrine and related compoundswere the only substances which increased car-diac rhythmicity. Recently two relatively newepinephrine-like compounds have received con-siderable attention. They are norepinephrineand isopropyl norepinephrine (Isuprel). Norepi-nephrine differs from epinephrine in the ab-sence of a methyl group on the terminal nitro-gen of the side chain and Isuprel hasan isopropyl group substituted for the methylgroup of epinephrine.The recent studies on norepinephrine are anl

important development in the study of thechemistry and physiology of the sympatheticnervous system. It is now known that theadrenal medulla secretes considerable amountsof the nonmethylated compound.2 There is alsoconsiderable evidence that norepinephrine is

From the University of Southern California,School of Medicine and Medical Services, Los AngelesGeneral and Cedars of Lebanon Hospitals. Aided by3 grant from the Dorothy H. and Lewis RosenstielFoundation.

D)r. Nathanson died April 24, 1952.

238

an important chemical transmitter of sympa-thetic nerve impulses.' Isopropyl norepi-nephrine (Isuprel) has recently been introducedas a substitute for epinephrine in the treatmentof asthma. This compound differs from norepi-nephrine and epinephrine chiefly in its vasculareffect, producing a vasodilatation and adepressor reaction. In the present study, theaction of norepinephrine and isopropyl nor-epinephrine was observed in (a) patients inwhom carotid sinus pressure induced cardiacstandstill, (b) patients with complete heartblock, and (c) patients with sinus rhythm. Theeffects of these sympathomimetic compoundswere compared with those produced by epi-nephrine.

ACTION ON INDUCED CARDIAC STANDSTILL

Norepinephrine was administered to six pa-tients with a hyperactive carotid sinus cardio-inhibitory reflex. Levo-norepinephrine hydro-chloride was used in all cases. The procedurewas as follows: an electrocardiogram was firstmade to record the induced cardiac standstill.A blood pressure reading was also made at thistime. Levo-norepinephrine hydrochloride, 0.03mg., was then administered rapidly by intrave-nous injection and blood pressures recordedand electrocardiograms made with carotid sinuscompression at one-minute intervals. Follow-ing the administration of the drug, there wasan abrupt rise in blood pressure which rangedfrom an increase of 30 mm. systolic and 10

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MORRIS H. NATHANSON AND HAROLD MILLER

mm. diastolic to 100 mm. systolic and 30 mm.diastolic. The duration of the pressor effectvaried from five to eight minutes. Pressure on

the carotid sinus consistently reproduced thestandstill following the administration of thenorepinephrine.

In a previous study,4 it was shown thatIsuprel in doses of 0.14 to 0.2 mg. subcutane-ously consistently abolished the cardiac stand-still which could be induced by carotid sinuspressure. It was considerably more potent thanepinephrine in this respect. In the present study,Isuprel was administered intravenously to sixpatients in whom cardiac standstill could beinduced. The dose was 0.02 mg. After theadministration of the drug, the standstill was

prevented in each instance. Isuprel consistentlyproduced a drop in diastolic pressure but sys-

tolic pressure was not significantly modified.When compared with the action of epineph-

rine on the carotid sinus standstill as observedin previous studies' Isuprel showed the fol-lowing differences: (a) Isuprel did not producea pressor effect, (b) Isuprel was more potentin its action, and (c) it prevented the standstillby restoring the activity of the sinus node or

by initiating rhythmic foci in the auricles or

high in the ventricles. Epinephrine more fre-quently abolished the standstill by stimulatinglower ventricular foci.

ACTION OF NOREPINEPHRINE, EP1NEPHRINEAND ISOPROPYL NOREPINEPHRINE ON THE

VENTRICULAR RATE OF HEART BLOCK

Effects of Intravenous A dministration of theThree Substances

The effect of an intravenous injection of thethree compounds was studied in eight patientswith complete heart block. Levo-norepi-nephrine and synthetic levo-epinephrine were

administered in doses of 0.03 mg. by rapidinjection and the dose of Isuprel was 0.02 mg.The smaller dose of Isuprel was used because,in an earlier study, the activity of Isuprelappeared to be greater than that of epinephrine.The procedure was as follows: A control elec-trocardiogram was made and the blood pres-sure recorded. The compound was then injectedand a continuous electrocardiogram made. The

blood pressure was recorded at 30 seconds andthereafter at one-minute intervals. The obser-vations were followed for several minutes afterthe ventricular rate had returned to the pre-

injection level.Following the administration of norepineph-

rine, there was only a slight and very transitoryincrease in the ventricular rate. There was a

return to the preinjection rate usually withinone minute. In contrast, there was a definiteand sustained rise in the ventricular rate afterthe injection of epinephrine. Isuprel also in-duced a sustained increase in the ventricular

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FIG. 1. Patient I. H. Effect of the three compoundson blood pressure and ventricular rate in heart block.Norepinephrine produced the more intense pressorreaction but only a slight and transient increase inthe ventricular rate. The nonpressor drug Isuprelinduced a sustained increase in the ventricular rate.

rate, which, considering the smaller dose em-ployed, was comparable to that produced byepinephrine. Typical responses of the bloodpressure and ventricular rate to these com-pounds are shown in figure 1. In table 1 isshown the maximum increase in the ventricu-lar rate following the administration of thethree compounds. The superiority of epineph-rine and Isuprel is considerably greater thanis shown in this table, since, as has been men-tioned, the ventricular stimulation followingnorepinephrine was of very brief duration.

In addition to the quantitative variationsof ventricular rhythmicity, the drugs appearedto differ in the localization of their efects.

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ACTION OF COMPOUNDS ON RHYTHMIC FUNCTION OF HEART

TABLE 1.-Maximum Increase in the VentricularRate (Beats per Minute) in Eight Patients withComplete Heart Block Following the Intravenous Ad-ministration of the Three Compounds

Case Norepinephrine Epinephrine IsopropylNorepinephrine

1 3 22 162 4 20 173 3 26 104 11 38 205 7 29 116 9 40 327 3 22 288 9 47

Although norepinephrine showed only a slightand transient action on the basic ventricular

FIG. 2. The induction of multiple ectopic veicomplete heart block.

pacemaker, it did cause transient excitationof lower ventricular foci resulting in multifocalectopic beats (fig. 2). This effect was usuallyobserved in the first minute after the adminis-tration of the drug. In contrast, the stimulatingaction of Isuprel was predominantly on thebasic pacemaker. Epinephrine also induced ec-topic ventricular beats in the early phase ofits action. The following observations in a

patient with complete heart block suggest thata drug which activates ectopic ventricular foci1may produce the serious arrhythmia, ventricu-lar fibrillation.

The patient was a woman, 84 years of age, whoentered the hospital because of attacks of syncopeand convulsions of two days duration. She wasknown to have had hypertension for many yearsand the blood pressure on admission was 240/90.The heart rate was noted to be 40 beats per minuteand the electrocardiogram showed complete auricu-loventricular block (fig. 3, strip 1). During the firstminute after an intravenous administration of 0.03mg. of epinephrine, many multifocal ventricularpremature beats were present (fig. 3, strip 2). Onanother occasion, the patient received 0.03 mg. ofnorepinephrine intravenously. Within one minutethe electrocardiogram showed a ventricular tachy-

cardia (fig. 3, strip 3), and this passed into a definiteventricular fibrillation (fig. 3, strip 4). The durationof the arrhythmia was about four minutes, whenthe electrocardiogram again showed complete heartblock. On the following day, the patient received0.02 mg. of Isuprel by vein, which resulted in adefinite increase in the ventricular rate arising froma single pacemaker high in the ventricles (fig. 3,strip 5). There was no indication of excitation oflower ventricular centers after the latter.

Effects of Subcutaneous Administration of Epi-nephrine and Isuprel

Since the usual mode of drug administrationin heart block is by subcutaneous injection,the effect of Isuprel, given by this route, onthe ventricular rate of five patients with heart

.tricua .1beat bL noplin:eph: inein: I. l: ae wi

mtricular beats by norepinephrine in a patient with

FIG. 3. Strip 1 is the electrocardiogram of a patientwith complete heart block, ventricular rate 40.Strip 2 shows multiple ectopic ventricular beatsduring the first minute after an intravenous injectionof 0.03 mg. of epinephrine. Strips 3 and 4 show thedevelopment of transient ventricular fibrillation fol-lowing an intravenous dose of 0.03 mg. of norepineph-rine, Strip 5 shows a ventricular rhythm from a singlefocus, rate 60, after an intravenous injection of 0.02mg. of Isuprel. Isuprel induced no ectopic beats.

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MORRIS H. NATHANSON AND HAROLD MILLER

block was studied. In three patients a com-parison was made of the effects of epinephrineand Isuprel. Since our observations on carotidsinus standstill indicated that Isuprel was con-siderably more active than epinephrine, thedose of Isuprel used was 0.2 mg. and the re-sponse compared with that following theadministration of 1 mg. of epinephrine. The pro-cedure was as follows: after a control electro-cardiogram was made, the drug was adminis-tered and electrocardiogram was then made atfive-minute intervals for 15 minutes and there-after at 15-minute intervals. Table 2 showsthe results of these experiments. Following thesubcutaneous injection of 0.2 mg. of Isuprel,there was a definite and sustained increase inthe ventricular rate in each instance. In thethree patients in whom both drugs were used,the smaller dose of Isuprel produced a greatereffect than the larger dose of epinephrine.

Effect of the Sublingual Administration of IsuprelThe effect of the sublingual administration

of Isuprel was observed in four patients withcomplete heart block. The drug was given toeach patient in a 15 mg. dose on one occasionand in a 30 mg. dose at another time. After acontrol electrocardiogram was made and thedrug administered, electrocardiograms were re-corded at five-minute intervals for from oneto two hours. In two patients, the response toboth doses was slight but well sustained (table3, patients 2 and 4). In two patients, there wasa definite sustained increase in the ventricularrate (table 3, patients 1 and 3). The onset ofthe effect was from 15 to 30 minutes after theadministration of the drug and the durationvaried from 45 minutes to two hours. The 30mg. dose produced only a slightly more intenseaction than did the smaller dose; however, theeffect of the larger dose was more sustained.In three of the four patients, a comparisonwas made of the effects of intravenous andsublingual administration. In two patients, anintravenous dose of 0.02 mg. resulted in a moreintense response than that induced by 30 mg.given sublingually. In one patient, the increasein ventricular rate resulting from 30 mg. sub-lingually was greater than that which followedan intravenous dose of 0.01 mg. The duration

of the action following intravenous adminis-tration varied from 10 to 15 minutes while theeffect lasted up to two hours after the sub-lingual application of the drug.

TABLE 2.-Effect of the Subcutaneous Administrationof Epinephrine and Isuprel on the Ventricular Rate(Beats per Minute) in Complete Heart Block

Initial Ventric-ular Rate/Min. ......

After5 Min...10 Min..15 Min...30 Min..45 Min..60 Min..75 Min...90 Mill....105 Min...120 Min...

Max. Increasein Vent. Rate

Patient

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TABLE 3.-The Effect of the Sublingual Administrationof Isuprel on the Ventricular Rate (Beats per Minute)of Four Patients with Complete Heart Block

Maximum Duration ofPatient Dose Increase in Increase inVentricular Ventricular

Rate Rate

1 15 mg. 32 45 min.1 30 mg. 47 1 hrs.2 15 mg. 5 1 hr.2 30 mg. 8 1 hrs.3 15 mg. 17 1 hrs.3 30 mg. 19 2 hrs.4 15mg. 3 1 hr.4 30 mg. 4 1 hr.

ACTION OF NOREPINEPHRINE, EPINEPHRINE ANDISOPROPYL NOREPINEPHRINE ON HEART

RATE IN NORMAL SINUS RHYTHM

The effect of the three compounds wasstudied in eight patients with sinus rhythm.After a control electrocardiogram was madeand the blood pressure recorded, the drug was

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ACTION OF COMPOUNDS ON RHYTHMIC FUNCTION OF HEART

administered intravenously and a continuouselectrocardiogram was made. The dose of nor-epinephrine and epinephrine was 0.03 mg. andthat of Isuprel, 0.02 mg. Blood pressures wererecorded at 30 seconds and thereafter at inter-vals of one minute. Following norepinephrine,there was a transient increase in rate of from4 to 10 beats per minute, for a period of oneminute or less. Following this reaction, therewas either a drop in rate to the preinjectionlevel or to a level 2 to 10 beats per minutebelow the preinjection rate. Following epineph-rine, there was a moderate increase in rate of

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MINUTES AFTER INJECTION

FIG. 4. Patient F. G. Action of the three compoundsin a patient with sinus rhythm. Note the marked andsustained tachycardia following Isuprel and theinactivity of norepinephrine on heart rate, althoughthis compound induced the most intense pressorresponse.

8 and 16 beats per minute in two patients, thereaction subsiding in one minute. In six pa-

tients, epinephrine produced a greater increasein rate of from 26 to 67 beats per minute, thetachycardia subsiding usually within two min-utes. However, in three patients a rise in rateof from 15 to 30 beats per minute persisted for10 minutes. The increase in rate followingIsuprel was comparable to that induced byepinephrine but was of longer duration. Themaximum increase in rate varied from 25 to

62 beats per minute. The period of tachycardiawas five minutes in two instances and the dura-tion was 15 minutes or longer in six patients

(fig. 4). The blood pressure responses weresimilar to those observed in the experimentsin heart block.

DISCUSSION

The present studies show by several methodsthat norepinephrine does not have any sus-tained action on the rhythmic property of thehuman heart. Isopropyl norepinephrine, al-though a drug without pressor action, is verypotent in its effect on cardiac rhythmicity andappears to act predominantly on higher centersand nodal tissues. Norepinephrine exhibits atransient activation of lower ventricular foci,while epinephrine stimulates both the higherand lower rhythmic centers. The recent studiesof Greiner and Garb5 further indicate thatIsuprel is less disposed to produce ectopicrhythms. These observers found that the threecompounds increased irritability (lowered theirritability threshold) of heart muscle. Follow-ing the application of norepinephrine and epi-nephrine, automatic rhythm supervened at levelsat which the increase in irritability was slight.Isuprel, while affecting a far greater loweringof the irritability threshold, did not produce acorresponding effect on automaticity.The introduction of a new sympathomimetic

compound requires an evaluation of its placein practical therapy and particularly an estima-tion of its activity as compared with that ofepinephrine. In cardiac therapy, the applica-tion of the sympathomimetic compounds hasbeen limited almost entirely to the therapyand prevention of cardiac arrest, especiallythat associated with heart block. The presentstudies show that norepinephrine has little orno action on the basic ventricular pacemakerand thus would be of no value in the preventionof cardiac standstill. From another standpoint,it is probable that there is a definite dangerin the administration of this compound topatients who are susceptible to sudden cessa-tion of cardiac activity. It has generally beensupposed that the chief mechanism for theAdams-Stokes syndrome is ventricular stand-still. However, it has become increasinglyevident that varying degrees of ventricular ac-celeration and ventricular fibrillation are fre-quently the basis for this syndrome.6 Recently

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MORRIS H. NATHANSON AND HAROLD MILLE 24'3

Gallb an(1 Chenoweth7 produced ventricularfibrillation consistently in cats during hydro-carl)ol1 inhalation by the administration of nor-epiniephrinie and epinephrine while Isuprel didnot inlduce this serious arrhythmia under thesame conditionls. It is frequently difficult todetermine which mechanism, ventricular stand-still or fibrillation, is the basis for a suddencessation of effective cardiac action. If transientventricular fibrillation is the mechanism, theadmi istration of norepinephrine or epinephrinewould tend to perpetuate this arrhythmia, witha possible fatal termination. It is of interestthat in the patient described earlier, who wassusceptible to the development of ectopic ven-tricular beats and ventricular fibrillation, Isu-prel stimulated only a single rhythmic focusin the ventricles. It would appear that Isuprelpossesses optimum features for the prevenltionand therapy of sudden cessation of cardiacfunict~ion, in that it is potent in the treatment ofcardiac standstill and yet does not dispose toventricular fibrillation.

There appears to be a difference in the rela-tive potencies of Isuprel and epinephrine, de-pending on the mode of administration. Bythe subcutaneous route, on the carotid sinusstandstill and on the ventricular rate of heartblock, Isuprel is about, five times more activethan epinephrine. By intravenous administra-tion, Isuprel does not show this degree ofsuperiority. In part, the greater effectivenessby the subcutaneous route may be due to thefact that Isuprel possesses a local vasodilatingaction in contrast to the vasoconstrictor effectof epinephrine, and thus a more favorable ab-sorption of Isuprel is to be anticipated. Forthe prevention of cardiac standstill in heartblock, drugs are usually administered by thesubcutaneous route. The present studies indi-cate that a dose of from 0.14 mg. to 0.2 mg. ofIsuprel. will effectively increase the activity ofthe ventricular pacemaker and thus lessen thetendency to ventricular standstill.The activity of Isuprel by the sublingual

route is of interest in the therapy of conditionsin which cardiac standstill may occur, the hy-peractive carotid sinus reflex and completeheart, block. When attacks are frequent,, the

patient is usually under observation in a hos-pital and the drug may be administered by thesubcutaneous route. However, in the treatmentof patients who are having infrequent attacksand who are ambulant, a drug which can beself administered is desirable. The orally activesympathomimetic compounds, Paredrine andephedrine may be effective in such instances.8The sublingual administration of Isuprel is anaddition to the therapy of these conditions byself medication. Our studies indicate that theventricular rate may be increased by a sub-lingual dose of 15 mg. of Isuprel. It is suggestedthat this dose be used three or four times a dayor every two hours if indicated.

CONCLUSIONS

1. The effects of norepinephrine, epinephrineand isopropyl norepinephrine (Isuprel) on car-diac rhythmicity have been studied by thefollowing methods, (a) the action ott cardiacstandstill induced by carotid sinus pressure,(b) the response of the ventricular rate of heartblock, and (c) the effect on sinus rhythm.

2. As compared with epinephrine and Isuprel,norepinephrine, a potent pressor compound,shows little or no effect on cardiac rhythmicity.

3. Isuprel, having little or no pressor action,produces a potent and sustained increase inrhythmic function.

4. Norepinephrine is of no value in the ther-apy of cardiac arrest. There may be a definitehazard in the use of this drug in cardiac andvascular conditions because of its dispositionto produce ventricular fibrillation.

5. Isuprel appears to possess optimum fea-tures for the prevention and therapy of suddeninactivity of the heart in that the drug is veryeffective in cardiac standstill and yet it doesnot seem to dispose to ventricular fibrillation.

ACKNOWLEDGMENTSWe are indebted to Dr. Gordon A. Alles of Pasa-

dena for the l-norepinephrine and to the Sterling-Winthrop Research Institute of Rensselaer, NewYork, for the synthetic l-epinephrine and the iso-propyl norepinephrine.We wish to express our appreciation to D)r.

George C. Griffith, chief of the department ofcardiology, for his cooperation in this study.

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ACTION OF COMPOUNDS ON RHYTHMIC FUNCTION OF HEART

REFERENCES'NATHANSON, M. H.: Further observations on the

effect of drugs on induced cardiac standstill.Arch. Int. Med. 54: 111, 1934.

2GOLDENBERG, M., FABER, M., ALSTON, E. J.,AND CHARGOFF, E. C.: Evidence for the occur-rence of nor-epinephrine in the adrenal medulla.Science 109: 534, 1949.

3VON EULER, U. S.: A specific sympathomimeticergone in adrenergic nerve fibers (sympathin)and its relations to adrenaline and nor-adrena-line, Acta physiol. scandinav. 12: 73, 1946.

NATHANSON, M. H., AND MILLER, H.: Effect of 1-(3,4, dihydroxyphenyl)-2-isopropylaminoethano1(isopropyl-epinephrine) on the rhythmic prop-

erty of the heart. Proc. Soc. Exper. Biol. & Med.70: 633, 1949.

GREINER, T. H., AND GARB, S.: The influence ofdrugs on the irritability and automaticity ofheart muscle. J. Pharmacol. & Exper. Therap.98: 215, 1950.

6SCHWARTZ, S. P., AND JEZER, A.: Transient ventric-ular fibrillation. Arch. Int. Med. 50: 450, 1932.

PARKINSON, J., PAPP, C., AND EVANS, W.: Theelectrocardiogram of the Stokes-Adams attack.Brit. Heart J. 3: 171, 1941.

'GARB, S., AND CHENOWETH, M. B.: Studies on

hydrocarbon-epinephrine induced ventricularfibrillation. J. Pharmacol. & Exper. Therap.94: 12, 1948.

8 NATHANSON, M. H.: The action of parahydroxy-phenylisopropylamine (Paredrine) on the heartAnn. Int. Med. 12: 1855, 1939

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MORRIS H. NATHANSON and HAROLD MILLERRhythmic Function of the Heart

The Action of Norepinephrine, Epinephrine and Isopropyl Norepinephrine on the

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1952 American Heart Association, Inc. All rights reserved.

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