European Journal of Clinical Pharmacology Volume 23 Issue 1 1982 [Doi 10.1007%2Fbf01061371] G. G....

8/19/2019 European Journal of Clinical Pharmacology Volume 23 Issue 1 1982 [Doi 10.1007%2Fbf01061371] G. G. Belz; P. E.…

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Eur J Clin Pharm acol 1982) 23 : 15-20European Journal of

linical Pharmacology© Springer-Verlag 1982

Sym pathom imetic Effects of mezinium on the Cardiovascular Systemand Plasm a C atecholamines in M an

G. G . Belz 1, P. E. Aust I G. B elz 1, E. App el 2, an d D. P alm2

l Insti tut f i ir Kardiovaskul~ire Therapie, Wiesbaden and 2Zentrum der Pharmakologie, Klinikum der Universit~it Frankfurt ,Frankfur t , Federa l Republ ic of Germ any

Summary The cardiovascular effects of the sympa-thomime t ic agen t amez in ium were invest iga ted in adouble-bl ind, placebo-co ntrol led, randomi zed t r ia l insix volunteers . Before and 2 h af ter oral administra-t ion of ame zin ium 30 mg or p lacebo the ca rd iovascu-lar responses to or thostat ic s t ress , induce d by 80 ° pas-sive head-up t i l t , were assessed by recording bloodpressure, systolic t ime intervals , and echoc ardiogram .Plasma ca techolamines were a l so de te rmined . Af te ramezinium treatment , the average supine systol icb lood pressure was increased by +3 0 m m Hg andafter t i l ting it remain ed above bot h the pre- tre atmen tand p lacebo va lues . Comp ared to p lacebo , amezini -um el ici ted only minor chang es in heart ra te and dia-s tolic blood pressure. The effect of ameziniu m on thepre-eject ion period corrected for heart ra te (PEPc)

and me an veloci ty of f iber shortening (VcFmean) in-dicated posi t ive inotro pic propert ies . I ts effects wered is tinc tly more pron ounc ed dur ing t il t than wi th thesubjec t s sup ine . P lasma concent ra t ions o fno radren a-l ine a nd adrena l ine were no t in f luenced by amezin i-um during rest or t il t. F rom these resul ts and previousresearch i t is concluded that amezinium induces i tssymp athom imeti c effects by preferent ial ly inhibi t ingthe re -up take of noradrena l ine wh ich i s re leased bythe drug i tself , or by sympathet ic act ivat ion duringt il t. This m echa nism o f act ion might explain the pro-noun ced sympathom imet ic e ffec t s o f the d rug , espe-cially durin g orth ostatic stress.

Key words: amezin ium; sympathomimet ic e ffec t s ,catecholamines, echocardiography, systol ic t ime in-tervals , or thostat ic s t ress, inhibi t ion of norad renal in euptake

Amezin ium (4-amino-6-methoxy-1-phenyl-pyridazi-n ium methyl su lpha te ) exer t s p ronou nced and longlast ing sympathom imet ic e ffec ts in an imals and man[4, 9, 14, 15, 16, 17, 31, 35]. Th e b ioav ailab ility of th edru g is high at 50~57% [12, 29, 31]. In anim al experi-

ments a- and f l -adre nocepto r blocking drugs an-tagonized the elevat ion of blood pressure a nd posi t ive

ino t ro p ic and chronot rop ic e ffec t s o f amezin ium [15 ,16, 17]. In an imal organs depleted of nerve terminalnoradrena l ine (NA) , the sympatho mimet ic ac tions o fame zinium were abol ished [17, 24] .

Therefore, the drug can be chara cter ized as act ingby an ind i rec t mechanism depend ent on the neurona ls tore of NA. A mez inium has some propert ies typicalof indirect act ing symp athom imeti c amines (e . g . tyra-min e as a pro toty pe; [10]), but it also has others tha tare dis t inctly different . Like other indirect ly act ingsympathomimet ics , amezin ium i s t ranspor ted in tothe noradrenerg ic nerve endings v ia the NA -uptakemechanism, thereby inh ib it ing up take and re -up takeof N A i tself [25, 28, 30] . The inhibi t ion of N A-u ptake

is muc h more pron ounc ed than tha t caused by ty ra-mine. The transport of amezin ium leads to a consider-able intraneuronal accumulat ion of the substance.This ac cum ulat ion is the pre-requisi te for i ts re lat ivelyselect ive and reversible inhibi t ion of intraneuronalmon oamin e ox idase (MAO), which is no t observedwith the classical indirect ly act ing sympa thom ime ticamines [24] . Furthermore, in contrast to tyramine,ame zinium i tself is not a sub s trate of M AO. I t re leasessmall amoun ts o f NA f rom the nerve endings in to thesynapt ic clef t , but a t a lower rate th an tyram ine [25,301

The aim of the present s tudy was to invest igate thecardiovasc ular effects of amezin ium in ma n af ter oraladministrat ion. The quant i ta t ive measurements wereper form ed exclusively by non-invasive techniques. Inaddi t ion , p lasma ca techolamines were measured inorder to e luc ida te i ts mech anism o f ac t ion in man .

Material and Methods

SubjectsThere w ere 6 volunteers , 4 females and 2 males , aver-age age 23.8 years (21-26 years), average height168 cm (160-175 cm), an d av erage body we igh t 56.4 kg

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16 G.G. Belz et al.: Cardiovascular Effects of Amezinium

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Fig. 1. Schematic presentation o f daily study protocol. Body posi-t ion is indicated as supine or 80 ° head-up ilt by the symbols. Onetilting experiment was performed without drug administration andanother 120 min following reatment with placebo or amezinium.+ indicates ime points of collection of blood for determination ofplasma catecholamines and measurement of the various pa-

rameters of cardiovascular unction

(48-62 kg). The volunteer s did not have any disease ora histor y of disease of the heart, lung, kidneys , or liver.On examinat ion four weeks prior to the test, all volun-teers had signs of symp athicoto nic dysregulation ac-cordi ng to the criteria of Thulesius [27]. In each sub-ject a clear echocardio gram o f the left ventricle wasmade in the supine and head-up positions. The sub-jects did no t take any other drug during the trial peri-od. Written informed consent was obtained fromeach volunteer.

Techniques

The echocardiogram, electrocardiogram (Lead IIECG), impedance cardiogram (ICG) and phonocar-diogram were recorded simulta neously using a Kon-tron Me dical IREX II ultrasonic unit. Five consecu-tive heart cycles from each recording were averagedto obtain a mean value. The impedance cardiogramwas obtained with a Minnesota Impedance Cardio-graph Model 400. Cardiograph Electrode Tape (In-strumentation for Medicine Inc., Greenwich, USA)was a ppli ed as descri bed else where [3, 13]. Pre-ejec-tion period (PEP) was measured from the Q-wave inthe E CG to the intersection of the d Z/ dt curve with itsstandar d zero-line [2], and was corrected for h eart rateaccording to Weissler et al. [32] and Weissler andSchoenfeld [33], resulting in PEPc. Left ventricularejection time was measured from the end of PEP tothe first high frequency component s of aortic closure[2, 31.

A 2.25 MHz transducer, 13 mm outside diameter,medium focus, was used to obtain the echocardio-grams. Echocardiography was performed by stand-ard technique s to obtain a simultaneo us record of the

interventricular septum and the epicardium and en-docar dium of the posterior wall of the left ventricle,

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just below the tip of the anterior leaflet of the mitralvalve [8]. The dist ances betwe en the endo card ial sur-faces of the left ventricular posterior wall and the in-terventricular septum were measured at end-diastole(R-wave in ECG) and end-systole.

The mean velocity of circumferential fibre short-ening (VcFmean) was cal culated fro m Vc~ mea n =

(EDD-ESD) The end-diastolic (VED) and end-EDD x LVETsystolic (VES) vol umes were c alculate d accord ing tothe form ula o f Teichholz et al. [26].

Stroke volume (SV) was tak en by subtracting VESfrom VED. Cardiac omp ut was calculated by SV xHR. Total peripheral resistance was calculated as-suming brachial artery me an pressure (BAPm):

BAPm = BPdiastolic + (BPsystolic-BPdiastol-ic) x 0.43 (Wezler an d B6ger [341). Brach ial arteryblood pressure was measure d using an ordin ary mer-cury manometer.

Plasma atecholarnines

Venous blood samples (5 ml) taken without venouscongestion from an antecubital vein into heparinized



G, G. Belz et al . : Cardiov ascular Effects of Ame zinium 17

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Fig.3. Velocity of mean circumferential f ibre shortening Vcvmean)and end-systolic and end-diastolic diameters of the left ventricleduring the second ti lt ing experiment 120 rain = 120 rain on thetime axis) following administration of placebo PL) 0--------0) orameziniu m 30 mg AM ) • • ) . For details see Fig. 2)

syr inges were imm ediately t ransferred into E ppen-do ff reaction vessels containing 20 ~1 of a freshly pre-pared, ice cold solut ion of 95 mg E GTA and 60 mg re-duced glutathione per ml , adjusted to pH 6.5. Plasmawas im med iately separ ated in a refrigerated centri-fuge and was stored at - 70 ° C until analysis. Quanti-ta t ive determinat ions of noradrenal ine and adrena-l ine in plasm a were perfo rmed essentia lly accordingto the me thod described b y Appel et al. [1].

Stud), Protocol and Meas uremen ts

Each of the volunteers was s tudied twice over a per i -od of 7 days. On each s tudy day the volunteers re-ceived, in a double-blind, randomized sequence,ame zinium metilsu lfate 30 mg (3 tablets of Regulton®,10 mg each) or an equivalent number of placebotablets. D uring the day s preced ing the study, the vo-lunteers were requir ed to adh ere to the following, in-structions: from noon no excessive physical activityor sport, and no co ffee, china tea, cola drinks, smok-ing, alcohol or drugs were allowed; fr om 10:00 p.m.the volunteers had to rest in bed an d to fast.

On th e study days the fasting volunteers arrived at

the laboratory at 7:30 a.m. A Vygoflon T persistentTeflon venous need le was inser ted in an antecubita l

vein in the lef t arm. The electrodes for EC G and ICGand the microphone fo r the phonocard iogram wereappl ied. The electrodes for the IC G rema ined in placeduring the ent i re s tudy per iod for each day.

The subject rested for 15 rain in the supine posi-

tion on a tilt table.After the resting period, two basic recordings werema de 5 min apart. T hereaf ter, the subjects were ti ltedto 80 ° he ad- up po sition w ithin 10 sec, and r ecordswere ma de 1, 5, and 10 min after t i lt ing. W hen at 80 °til t, 20 of the volunteer 's weight was supporte d bypadd ed arm supports unde r the axi lla and he sat on abycicle seat, while his legs dang led unsu ppor ted. Thesubject was returned to the supine posi tion an d themed ication was given with 100 ml wate r according tothe randomizat ion plan. Repeated recordings of theparameters and venous blood samples in the supineposition were m ade at 30, 60, 90,115 and 120 min afterdrug ad ministration. F ollowing this, the secon d tilt ingexperiment was done according to the protocol of thefirst one, with blood s amplin g after 1, 5, and 10 min oftilt ing. The co mplete plan of each stud y day is depict-ed in Fig. 1.

Statistical Evaluation

The ar i thmetic mean s and univar ia te 95 -confidenceintervals were calculated for each tim e point. 'Statisti-cally significant ' difference s (differences with confi-dence limits not including '0 ') between amezinium

and placebo are mar ked on the graphs by °* ' . Datashow n in the figures are mean values + SE M (n = 6).

e s u l t s

Effects of Tilt and A mezinium on Heart Rate HR)and Blood Pressure

As expected, t il t increas ed HR. At the end o f 10 mintilt ing, the rise was 20 and 40 beats/m in, respectively,compared with the values before and af ter placeboadministration (Fig.2). The decrease in systolic and

diastol ic blood pressures was more pron ounc ed dur-ing til ting following than before place bo a dministra-tion. These variations could be explained by in-creased orthostatic sensitivity of the volunteers d ue tothe 120 min resting period in supine position. Amezi-nium did not ch ange resting HR, a nd o nly slightly in-creased H R above placeb o value during til t. Systolicblood pressure was cont inuously enhanced by ame-zinium, reaching + 30 mm Hg by 120 min af ter admin-istration (Fig.2). Although the decrease in systolicblood pressure during t il t was more pr onou nced af teramezinium than as placebo, i ts level became stabi-lized above its pre-treatment level, and was about

+ 20 mm Hg above the corresponding placebo value.Similar behaviour af ter ame zinium was observed in



18 G.G . Belz et al . : Cardiova scular Effects of Ame zinium

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Fig.4, End-diastolic diameter of the left ventricle ED D; abscissa)versus pre-ejection period corrected for heart rate PEPc; o rdi-nate). Mea n values imm ediately before and 1 rain after t il t ing areshown for 4 experiments: O O before and ~ 120 rainfollowing placebo ; A A before and • • 120 rain follow-ing amezinium 30 mg For details see Fig.2)

turn secondar y to a shif t of blood into the caudal ve-nous system [18, 20] . The changes in ED D rema inedalmost unaffected by amezinium as compared toplacebo. ES D in the placebo phase was progressivelydiminished by 10 min of ti l t ing, from 3.1 to 2.2 cm.

ESD under the inf luence of amezinium during t i l trapidly fell from 3.0 to 1.8 cm, and th en beg an to ap-proach end values s imilar to those me asured 10 rainafter t i lt during p lacebo.

Compared to placebo, amezinium did not affectcardiac output average 4100 ml/ min ) during the120 min resting peri od results not shown). Duri ng til tunder placebo, there was a rapid initial drop in car-diac output of 1440 ml/m in to 2660 ml/min) , fol-lowed by gradual s tabi l izat ion o f output . However,amez inium l imited the reduct ion in cardiac output to670 m l/m in to 3430 ml/ mi n) and general ly main-taine d the ou tput at that level.

Nei ther t i lt nor the drug induced any s ignif icantchan ge in total periphe ral resistance results notshown).

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Fig.5. Plasma catecholamines follow ing oral administration ofplacebo PL; O, O) and amezinium 30 mg AM ; A, A) . Meanvalues _+ SEM for noradrena line NA) and adrenaline A) areshown

the diastol ic blood pressure, but the changes weresmaller and were not notably different f rom those o fplacebo.

Effects of Tilt and Amezin ium on Variables Determinedby M eans of Echocardiography

Throu ghout the 120 min for which the volunteers re-mained in the supine posi t ion af ter t reatment withplacebo and amezinium, no change was observed inED D, ESD, or in Vcv me an Fig.3) . Elevat ion ofVcvmean did occur during the 80 ° t i l t af ter placebo oramezinium, but , the ra te and extent of the changes dif-fered. After placebo, the VcFmean increased from 1.2to 2.t s -1 after 10 min, where as the incre ase duringame zinium was sudd en and larger f rom 1.3 to 2 .4 s -1

in 1 min Fig. 3). After both t reatments E DD was re-duced following til t , due to a decrease in venous re-

Effects o f Ti l t and Ameziniumon Systolic Time Intervals

Recent s tudies have shown that before and during t il tamez inium can induce dist inct , s ignif icant shorteningof the systolic time intervals corrected for heart rate[4] . These resul ts not depicted) were confirm ed andextende d in the present investigation. When values ofED D compar e Fig.3) as a measu re of preload werecorrelated with the s imultaneously determined PE Pc,as a me asure o f cardiac performance , the resul t waspart of a cardiac funct ion curve. This curve may giveinsight into ch anges in the inotro pic state. As depictedin Fig. 4 , in the supine posi t ion amezinium mark edlyred uce d PEPc by - 15 ms p < 0.05) in relation to thecontrols , whereas EDD was not affected. When thesubjects were placed under orthostatic stress by til t-ing, two changes occ urred:

1. Com pare d to placebo there was some addi t ion-al decrease in E DD fol lowing amezinium.

2. Despite this decre ase in preload , during amezi-

nium the PEPc under t i l t was lengthened by only30 msec, whereas during placebo i ts prolongat ion wasapproxim ately 50 ms.C omp ared to the placebo phasedurin g til t , PEPc was 30 ms shorter, wher eas in the su-pine posi t ion the difference due to the effect of thedrug w as on ly 15 ms.

Effects of Tilt and A mezinium on PlasmaCatecholamines

As expe cted [21 ], a pro nou nce d increase in no radr en-al ine concentrat ion in plasma mean values f rom267 ng /l to 619 ng/1) was fou nd 10 min following til t

Fig. 5). Adren al ine concentrat ion rema ined almostunaltere d. Up to 120 min after administration , amezi-



G.G. Belz et al.: CardiovascularEffects of Amezinium t9

n ium had no t a ffec ted ca techo lamine concen t ra t ionsat rest. Durin g ti l t, too, am ezi niu m did no t affect plas-ma n ora dren alin e (Fig. 5).

Discussion

The m ain resul ts of th is placebo-control led, double-bl ind s tudy indicate that am ezinium, in subjectsin su-pine position has a long-lasting effect of increasingbloo d pressure , especial ly i ts systol ic comp onen t . Inaddi t ion, i t i s a posi t ive inotropic drug in man. Thecardiac effects of amezinium are clarified by the sig-nif icant shor tening of the pre-eject ion per iod correct-ed for hear t ra te (PEPc; Fig.4) . In the supine posi t ion,ca rd iac ou tpu t , EDD, ESD, and VcFmean showedonly minor changes. M ore p ronoun ced d rug e ffec ts(with the exc ept ion of act ions on bloo d pressure , seebe low) compared to p lacebo were obse rvedafte r tilt-ing stress was induced . Card iac ou tpu t r emained en-hanced re la t ive to placebo, the cardiac performancein terms of Vcvmean, PE Pc, an d SV (which is indicat-ed by the re la t ion of ESD to EDD ) was dis t inct ly in-creased above the level dur ing placebo, and also part -ly above the value s before ti l t ing.

PEPc as a measure o f cardiac performan ce is in-f luenced by HR ( this inf luence is e l iminated byWeiss ler s equat ions) , preload, dias tol ic blood pres-sure, and ca rdiac contractil i ty. At any inotrop ic level,the P EP c is mos t sensitive to cha nge in pr eloa d [7]. In

normal hear ts , provided the ventr ic le is not over-loaded, according to the Frank-Star l ing pr inciple adecrease in prelo ad wil l lead to a decrease in cardiacperfo rman ce an d vice versa . Several technique s havebeen shown to a l ter preload; those which decreasepreloa d (and the refore len gthen PEPc) are t i lt ing [22,23], haemo dialy sis [5], nitroglyce rin [7], and furose-mide [6] . Buch et a l . , us ing EDD from echocardio-gram s as a m easu re of prel oad [6, 19], were the first tocombine E DD and PEPc fo r de riva t ion o f ca rd iacfunct ion curves . No te that in Fig. 3 there are dis t inctreduct ions in EDD induced by t i l t ing. Ti l t - inducedreduct ion in preload, when correla ted with prolonga-t ion of PEPc, a l lows comparison of cardiac perform-ance un der two different preloa d s i tuat ions. Amezini-um as com pare d to placebo did not inf luence preload,ra ther there was a s l ight diminut ion of EDD 1 minafter t i l t ing (see Figs. 3 and 4). Therefo re, the shorten-ing of PEPc by the drug observed here was not in-duc ed by a change in preload. The behaviour of dia-stolic blo od p ressure [11] has also to be tak en into con-s iderat ion in re la t ion to PEPc. Since, after amezin iumadminis t ra t ion, these values were not lower thanthose dur in g placebo, the changes may not be respon-sible for the observed shortening of PEPc. We can

conclude that , fol lowing amezinium, increased car-diac performa nce is not due to change in ventr icular

load, but rather, i t is the inotropic level that is en-hanced .

I t should be noted that , despi te the dis t inct in-crease in systol ic bloo d pressure in the supine posi-tion, a pronounced decrease in systolic pressure sti l l

occurred af ter t i lt ing, even though the level remaine ddis t inct ly above the control level. The la t ter ma y bedue to enhanced ca rd iac ou tpu t and inc reased con-tractility.

In exper iments with dogs an increase in per ipher-al resis tance and a redis t r ibut ion of blood volumefrom per ipheral compartments has been found [15]after amezinium. A positive inotropic effect has alsobeen demonstra ted. In contras t , the present s tudy inma n suggests that the cardiac effects pred omin ate un-der our condi t ions .

Mechanism of Act ion

Animal exper iments have shown tha t amez in iumelic i ts i t s symp atho mime tic effects indirectly, name lyvia endogenous noradrenal ine (NA). An increase inNA in plasma was expected to accompany the pro-nounced increase in systol ic blood pressure in thepresen t investiga tion (Fig. 2), as has prev iously be enshown for tyramine [10]. However, this has not beenobse rved (Fig. 5).

I t can be dedu ced from the resul ts of Steppeler e tal. [25], that after am ezin ium ad mini strati on m uc h lessrelease of NA is required than af ter tyramine to in-duce equieffect ive sympatho mime tic effects in isola t-ed perfus ed rabbit hearts.

In contras t to tyramine, amezinium is one of themost potent inhibi tors of NA-uptake into the nerveending; and, i t i s not a substra te of in t raneuronalMA O but r ather i t inhibits this enzym e [25, 28]. Thus,amezin ium may act by re leasing only a small amo untof ca techo lamines, which wo uld be p reven ted f rominact ivat ion by MAO, as well as by the re-uptake intothe neuron . Based o n the la t ter mechanism , i t i s con-ceivable why amezi nium is pharmacological ly effec-tive, especially whe n N A release is triggered by the or-thosta t ic ref lex mech anisms: the most pron oun ced ef-

fects were seen when body posi t ion was changedfrom the supine into the t i l ted posi t ion (compareFigs . 3 and 4). A drug w ith such a m echa nism of act ionappears not to have been avai lable unt i l now. Thistype of d rug is not only of theoret ical in teres t, butmight a lso be o f therapeut ic value, especial ly for treat-ment o f hypo tens ive a nd / o r o r thos ta ti c d i so rders.

Acknowledgements The statistical analysis evalua tionwas kindly done by the Biometr ic Grou p of Cl inicalResearch and Development , Operat ing Divis ionPharma, BASF Aktiengesel lschaf t , Ludwigshafen,FRG.

Ameziniummeti lsulfa te and placebo tablets wereprovid ed by courtesy of Dr. Oloff , Cl inical Research



20 G.G . Belz et al . : Cardiovasc ular Effects of Ame zinium

and Development Operating Division PharmaBAS F Aktiengesellschaft Ludwigshafen FRG.

We are grateful to the Dr. Robert Pfleger Stiftungfor its donation of the liquid scintillation spectro-meter.

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Receive d: Decem ber 19, 1981accepted in revised form: January 22,1982

Prof. Dr. med. Gusta v G. BelzInstitut ftir Kardiovaskul~ire TherapieWilhelmstral3e 16

D-6200 Wiesbaden, Federal Republic of Germany

European Journal of Clinical Pharmacology Volume 23 Issue 1 1982 [Doi 10.1007%2Fbf01061371] G. G....

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Transcript of European Journal of Clinical Pharmacology Volume 23 Issue 1 1982 [Doi 10.1007%2Fbf01061371] G. G....