EFFECTS OF Ca ANTAGONISTS ON SA AND AV NODES/Kawai et al.

vulsive syncope. Ann Intern Med 75: 919, 197124. Rubin SA, Brundage B, Mayer W, Chatterjee K: Usefulness of

Valsalva maneuver and cold pressor test for evaluation ofarrhythmias in long QT syndrome. Br Heart J 42: 490, 1979

25. Schwartz PJ, Wolf S: QT interval prolongation as predictor ofsudden death in patients with myocardial infarction. Circula-tion 57: 1074, 1978

26. Ebihara A: Clinical pharmacology of f-adrenoreceptor block-ing drugs and therapeutic use in hypertension. J Jpn Soc InternMed 69: 1, 1980 (in Japanese)

27. Shand DG, Rangno RE: The disposition of propranolol. 1.Elimination during oral absorption in man. Pharmacology 7:159, 1972

28. Bourdillon PJ: Prolonged QT interval to predict sudden death.Circulation 59: 1079, 1979

29. Randall WC, Thomas JX, Euler DE, Rozanski GJ: Cardiacdysrhythmias associated with autonomic nervous system in-balance in the conscious dog. In Neural Mechanisms in CardiacArrhythmias, edited by Schwartz PJ, Brown AM, Malliani A,Zanchetti A. New York, Raven Press, 1978, p 123

Comparative Effects of Three Calcium Antagonists,Diltiazem, Verapamil and Nifedipine, on the

Sinoatrial and Atrioventricular Nodes

Experimental and Clinical Studies

CHUICHI KAWAI, M.D., TOMOTSUGU KONISHI, M.D., EIICHI MATSUYAMA, M.D.,

AND HITOSHI OKAZAKI, M.D.

SUMMARY Diltiazem, verapamil and nifedipine suppress sinoatrial (SA) nodal function in the excised rab-bit heart. Clinically, however, their suppressive effect on the SA node is modified considerably by the reflex in-crease in sympathetic tone as a result of the fall in blood pressure caused by the vasodilating action of thecalcium antagonists.

Diltiazem, verapamil and nifedipine suppress atrioventricular (AV) nodal conduction and prolong refractoryperiods in the excised rabbit AV node. Clinically, diltiazem and verapamil exert a similar suppressive effect onthe AV node and are useful for treating and preventing AV nodal reentrant tachycardia. Nifedipine, inclinically practical doses, has no antiarrhythmic properties, probably because of reflex activation of the sym-pathetic system secondary to its hypotensive effect, which is greater than that of the other two calcium an-tagonists.

Diltiazem and verapamil may sometimes worsen AV conduction, especially in patients with conduction dis-turbances. Nifedipine, on the other hand, can be used as a coronary vasodilator with the least untoward effecton AV conduction.

THE CELLS of the sinoatrial (SA) and atrioventric-ular (AV) nodes show no evidence of a fast compo-nent. The entire action potential appears to resultfrom a slow inward current.1 Recent investigationshave suggested that the calcium-antagonistic proper-ties of some coronary therapeutic agents might alsocontribute to their antiarrhythmic effects by inhibit-ing slow inward currents. The antiarrhythmic effectsof verapamil have been reported,2 3 but nifedipineappears to have no antiarrhythmic effect4' 5 despite itshigh activity in antagonizing the effect of calciumions.6 Diltiazem, also a potent coronary vasodilator,

From The Third Division, Department of Internal Medicine,Faculty of Medicine, Kyoto University, Kyoto, Japan.

Presented in part at the Symposium on Slow Responses of theMyocardium at the First Meeting of the Japanese Section of theInternational Society for Heart Research, Tokyo, Japan, 1977.Address for correspondence: Chuichi Kawai, M.D., The Third

Division, Department of Internal Medicine, Kyoto UniversityHospital, 53 Kawaracho Shogoin, Sakyo-ku, Kyoto 606, Japan.

Received February 1, 1980; revision accepted September 3, 1980.Circulation 63, No. 5, 1981.

suppresses epinephrine- and ouabain-induced ar-rhythmias in guinea pigs.7 However, very few sys-tematic comparative studies have reported the effectof these three calcium antagonists on the SA and AVnodes.

In this report we present experimental and clinicalstudies of the effects of diltiazem, verapamil andnifedipine on the SA and AV nodes.

Methods

Experimental SetupUnder pentobarbital anesthesia (30 mg/kg) and ar-

tificial respiration, the rabbit right atrium was excisedand cut into two portions: preparation 1, with the SAnode and the crista terminalis, and preparation 2, withthe crista terminalis, the interatrial septum, the AVnode and the His bundle (fig. 1). Forty-seven rabbitswere used for preparation 1 and 12 for preparation 2.The experimental setup has been partly described.8The tissues were superfused in Tyrode solution

equilibrated with 95% 02 and 5% CO2. The

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FIGURE 1. Experimental preparations in excised rabbitright atrium. (I) Sinoatrial node (dotted area) and crista ter-

minalis (CT). (2) Atrioventricular node (designated as 1.)and His bundle (designated as 2.) App = appendage;SVC = superior vena cava; IVC = inferior vena cava;lAS = interatrial septum; CS = coronary sinus; A 0 = aor-

ta; PA = pulmonary artery; TV = tricuspid valve.Reprinted with permission of Excerpta Medica from NewDrug Therapy with a Calcium Antagonist.8

temperature was maintained at 34.0 + 1.0°C.Transmembrane resting and action potentials wererecorded with glass microelectrodes with resistancesof 10-20 MQ from the cells in preparation 1 and fromthose in preparation 2 (fig. 1).

The recording equipment consisted of a

preamplifier (WPI model 750), a cathode-ray oscillo-scope (Nihonkohden VC-9) and a photographicrecorder (San-ei Co.). The recordings were taken at apaper speed of 25 mm/sec for preparation 1 and 200mm/sec for preparation 2. For the intracellularrecording from the crista terminalis, a close bipolarsurface lead was sometimes used in place of intra-cellular recordings using two silver wire electrodeswith a 1-mm interelectrode distance and a differentialpreamplifier (WPI DAM-5A). The preparations weredriven with rectangular pulses of twice-diastolic-threshold voltage and l-msec duration, generated byan electronic stimulator (Nihonkohden MSE-40) andapplied with an isolation transformer and platinumwire electrodes. The modes of stimulation were: 30-second overdrive from the crista terminalis at a rate of120-240 beats/min for determining sinus recoverytime (SRT), and one premature stimulus (S2) withvaried coupling intervals in every eighth basic stimulus(S,) from the atrial site to determine refractoryperiods of the AV node.SRT was the time interval between upstrokes of the

last stimulated and the first recovering spontaneousaction potentials. SRT was the maximum time inter-val among three trials of overdrive at each rate, rang-

ing from 120-240 beats/min, with increments of 30beats/min and expressed in percentage of spontaneouscycle length (table 1).

In the measurements of effective and functionalrefractory periods (ERP and FRP), the basic cyclelength (S,-Sj) was set as 400 or 500 msec, long enoughto dominate over the automaticity of the preparation.

TABLE 1. Effects of Diltiazem, Verapamil and Nifedipine in Different Concentrations on the Sinoatrial NVode in the Rabbit

Spontaneous cycle length Overdrive stimulationAverage sinus %SRT

Concentration No. of slowing (%7) No. of Control After(g/ml) experiments (mean SD) experiments (mean SD) (mean so)

Diltiazem 1 X 10-7 6 12.0 - 4.9 3 114.0 7.0 188.7 48.6)t

5 X 10-7 3 37.0 5.3 * 3 125.0 *6.0 284.4 25.7

1 X 10-6 6 46.8 - 13.9 4 116.0 2.8 > 5001

Verapamil 1 X 10-7 4 13.0 8.7 3 124.4 - 0.6 229.6 - 70.0)t

5 X 10-7 9 20.3 10.5 * 3 126.6 - 4.8 325.0 - 35.5

2 X 10-6 9 57.5 24.8t - -

Nifedipine 1 X 10-7 3 8.0 2.0 3 117.3 - 9.5 173.7 - 27.1'

5 X 10-7 3 25.7 ^7.1 * 3 118.3 - 8.4 269.1 - 30.0

1 X 10-6 4 55.0 6.6§ 3 117.0 1 1.4 > 500**

Analysis of variance:*p <0.01.tP < 0.001.

Complete arrest in:$seven experiments.§one experiment.¶two experiments.**one experiment.

Abbreviations: %SRT = sinus node recovery time expressed in percentage of spontaneous cycle length.

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The coupling interval (S1-S2) was decreased by 10-msec steps from the basic cycle length until AV con-duction block occurred. Then the ERP was soughtfrom the last conducted S1 S2, decreasing the couplinginterval by 1 msec. All measurements were repeated15 minutes after the addition of diltiazem, verapamilor nifedipine.

Patients

Each patient gave written consent to the study. Dur-ing diagnostic cardiac catheterization and/or His bun-dle study in 31 patients (16 with secundum atrial sep-tal defect, 12 with preexcitation syndrome, two withparoxysmal supraventricular tachycardia and onewith accelerated idioventricular rhythm), the SRT wasmeasured after 30-second overdrive at a rate that in-duced the longest SRT, ranging from 100-150 perminute, and ERP and FRP were measured by the ex-trastimulus method. The modes of stimulation werethe same as for the isolated rabbit heart experimentsexcept for the use of quadripolar electrode catheters(Elecath, #6F) and an electronic stimulator (ME537V, Metro Electric Co.). High right atrial and Hisbundle electrograms, together with standard electro-cardiographic leads (I, aVF, V1) were displayed andrecorded at a paper speed of 100 mm/sec (Electronicsfor Medicine, VR-12). The measurements wererepeated after i.v. administration of 10-20 mg ofdiltiazem in 10 patients, 10 mg of verapamil in 13, and1 mg of nifedipine in eight. Each dose was injectedover 3 minutes. The AH and the HV intervals and theminimal right atrial pacing rate to produce AHWenckebach block were also measured before andafter administration of the calcium antagonists. Theserum concentration of diltiazem was determined invenous blood obtained from the antecubital vein op-posite that of the injection site in seven patients. It wasalso determined in two patients who were taking oralmedication who were not studied electrophysio-logically.The t test was used to assess the statistical

significance in both experimental and clinical studies.The statistical significance of changes was tested by

analysis of variance according to Newman-Keuls'multiple comparison.

ResultsEffect on the SA Node

After 3 minutes a solution of 2 X 10-6 g/ml,diltiazem suppressed the frequency of spontaneous fir-ing, the amplitude and the rate of rise of the actionpotential and the slope of diastolic depolarization inthe excised rabbit SA node preparation. After 4minutes, intermittent sinus arrest or intra-SA nodalblock developed (fig. 2). There was no essential changein the resting potentials. Verapamil and nifedipine hadsimilar effects on the SA nodal action potential. Thenumber of experiments, average sinus rate slowingand rate of prolongation of SRT (expressed as percentof basic cycle length) before and after diltiazem,verapamil and nifedipine in different concentrationsare shown in table 1. The effects of these agents aredose-dependent. Changes of the average sinus rateslowing (p < 0.01) and rate of prolongation (%SRT)(p < 0.001) with different concentrations of each drugare statistically significant. At the same concentra-tion there was no significant difference among thethree agents. A representative example of prolonga-tion of the SRT after nifedipine is shown in figure 3.

In clinical cases, however, diltiazem, verapamil andni'fedipine tended to increase the sinus rate andshorten the SRT (table 2). Among these variables, theincrease in the sinus rate (p < 0.05) and the shorten-ing of the SRT (p < 0.01) by nifedipine werestatistically significant. The following differences werestatistically significant: changes in the sinus rate,diltiazem vs nifedipine (p < 0.005), verapamil vsnifedipine (p < 0.05); in the SRT, diltiazem vs nifedi-pine (p < 0.05), verapamil vs nifedipine (p < 0.05);and in the systolic blood pressure, diltiazem vsnifedipine (p < 0.01), verapamil vs nifedipine (p <0.05).

Effect on the AV Node

In the excised rabbit AV nodal preparation, elec-trically stimulated at a basic cycle length of 400 msec,

c

- -SOmV

DOitiazem 2xlOgknL 3 min.

-5=mV

I

C 4 min

100 s

1 sec

FICJURE 2. Effct of' diltiazemii 2 X 10 6gltkil on sinoatrial (SA) node in the rabbit.Three minutes ajter addition of diltiaZem,frequency of spontaneous firing, amiiplitudeand rate of rise in action potential, and slopeof diastolic depolarization decreased (Jast-speed recording). After 4 minutes, internit-tenit sinius arrest or intra-SA nodal block oc-curred (slow speed recording). C = control.

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110°/0Fm

SAA!JA 2 V b'V1

nifedipine 107g/ml

1 1A 111 1- A 1- 1 1-

11 sec

15 min.

1 80/lo

r X

FIGURE 3. Effect of nifedipine on sinusrecovery time (SRT) in an excised rabbitsinoatrial (SA) nodal preparation. Over-drive stimulation at a rate of 180 beats/mmnwas given to the crista terminalis (CT)for 30seconds. The SRT of 110% basic cyclelength in controls was prolonged to 180%after addition of nifedipine in a concentra-tion of 10`' g/ml. The overdrive tests wererepeated by moving the position of the ex-ploring (SA) electrode in an area of 2 X 5mm. No full-sized action potentials arerecorded between the last driven beat andthe first recovery beat that precedes the CTfiring. Thus, the presence of intra-SA blockduring the prolonged recovery period wasalmost ruled out. Voltage calibration on theright end is 50 m V.

180/Imin x 30sec

an extrastimulus to the AV node with a coupling inter-val of 85 msec (S1-S2: 85 msec) was propagated to theHis bundle. However, an extrastimulus with a cou-

pling interval of 84 msec (S1-S2: 84 msec) was not con-ducted to the His bundle. After the administration ofdiltiazem at a concentration of 10-7 g/ml, an ex-

trastimulus with a coupling interval of 140 msec

(S1-S2: 140 msec) was propagated to the His bundle.An extrastimulus with a coupling interval of 138 msec

(S1-S2: 138 msec) was already blocked (fig. 4).In the same experimental settings, verapamil and

nifedipine also prolonged refractory periods of the AVnode (table 3). Thus, diltiazem, verapamil andnifedipine equally prolonged ERP and FRP of the AVnode in the excised rabbit heart at a concentration of

T.ABLi.' 2. Effects of Diltiazu nti, Verapamil cot \ ifXlipiac on

Clinical Cases

10-7 g/ml (fig. 5). We used this concentration becausethe human plasma concentrations of diltiazem andverapamil given for antiarrhythmic purposes were

3.30 X 10-7 to 5.10 X 10`8 g/ml (table -4) and2.52 X 10-8 to 7.10 X 10-8 g/m19, respectively. Thechanges of the values before and after administrationof these calcium antagonists were statistically signifi-cant.

Clinically, the AH interval determined during spon-taneous cycles was lengthened by i.v. diltiazem or

verapamil, while nifedipine shortened the AH interval.The slowest rate of right atrial pacing required toproduce Wenckebach-type AH block was decreasedafter the administration of diltiazem or verapamil.Nifedipine, in contrast, increased the slowest rate

thc Sinus Riatc, Sinuxs ATode I&COv(cry Time and 1Blood( Pressure in

Syst bloodSinus rate SI{T pressure

Age Sex (beats/min) (msec) (mm Hg)(years) (M/F) C A C A c A

Diltiazem (n = 10) 21.6 /2 83.9 84.5 1067 1008 110 105

+ SD -14.4 -12.1 283 i248 --12 14

p NS NS NS

Verapamil (ii = 13) 33.1 S/5 81.2 88.4 1113 1062 119 108- SD -14.8 15.9 ) - 165 -291) * 16 -14) t

p NS * NS * < 0.001 *

Nifedipine (n = 8) 30.3) 3/5 78.0 98.4 1331 1001 113 93SSD -17.4 -=23.3~-93 -379 -16 =11

p < 0.03 < 0.01 < 0.001

Significance of change (atialysis of variance):*p < 0.05.tP < 0.01.tp < 0.005.

Abbreviationis: SRT = sinus ILode recovery time; C = control; A after drug adminiistration.

control

CT -A 1 1 1 1 A -1 -A -1 -1 -A -1 -A

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BCL 400msec

82

A V 11

H I s -_S1-S2 85H14e 190

82S 1

1aZ (_)

I1-Fe (-)

0.1 SEC.

lBizem hydroctiorde tOrj/rM

81 2

A V N _

H i s -

S1-S2 140111-fQ 214

FIGURE 4. Effect of diltiazem on atrio-ventricular nodal (A VN) refractory periodsin excised rabbit A VN preparation drivenelectrically at a basic cycle length (BCL) of400 msec. His = His bundle action poten-

tial; S1 = stimulus artifact; S2 = extra-

stimulus artifact; H1 = His bundle electro-gram; H2 = His bundle electrogramresponded to extrastimulus S2. Figuresdenote time in milliseconds. Voltage calibra-tion on the right end in each panel is 50 m Vfor His bundle action potential. Calibrationfor A VN is not shown because of unstableimpalement.

S1-S2 138HIs4 (-)

(table 5, fig. 6). The HV interval was unchanged afterthe administration of calcium antagonists.

Diltiazem or verapamil prolonged the ERP andFRP of the AV node; nifedipine shortened the ERPand FRP (table 5, fig. 7).

DiscussionSince Kohlhardt et al.'0 demonstrated that slow

ionic currents are blocked by verapamil and com-pound D600, the suppressive effects of verapamil onthe electrical activity in the SA and AV nodes havebeen reported by Zipes and Fischer,3 Wit andCranefield,'1 and Okada and Konishi.'2 The presentstudy demonstrates that diltiazem, verapamil andnifedipine exert similar suppressive effects on the SAnodal action potentials in the excised rabbit atrium.

TABLE 3. Effects of Diltiazem, Verapamil and Nifedipine onEffective and Functional Refractory Periods of the Atrioventricu-lar Node in the Rabbit

No. of ERPAVN (msec) FRPAVN (msec)experiments Control After Control After

Diltiazem 4 106 161 209 243= SD -15 -437 128 -4=28

p < 0.05 < 0.01

Verapamil 4 125 224 232 3134 SD 47 -76 =12 -= 46

p < 0.01 < 0.02

Nifedipine 4 99 152 198 244d SD 19 ---17 '10 ---14

p < 0.01 < 0.01

Abbreviations: ERP = effective refractory period; FRIP= functional refractory period; AVN = atrioventricular node.

The finding that the effects were dose-related is consis-tent with previous reports.3 11 These calcium an-tagonists, in identical concentrations, equally pro-longed the SRT of the SA node cells.The effects of diltiazem, verapamil and nifedipine

on the sinus rate and the SRT in clinical cases aredifferent from those in excised rabbit SA nodepreparations. The tendency toward an increase in thesinus rate and a shortening of the SRT is most promi-nent with nifedipine, which has the greatest hypoten-sive effect among the three calcium antagonists. Onlyone-tenth as much nifedipine can be toleratedclinically because of this hypotensive action. It isassumed that the effects of diltiazem, verapamil andnifedipine on the human SA node in situ are modifiedby reflex activation of the sympathetic tone secondaryto their different degrees of hypotensive effect. Thishypothesis is supported by Breithardt et al.l3 demon-strating prolongation of sinus node spontaneous cycle

TABLE 4. Plasma Concentration of Diltiazem in ClinicalCases

Age Dose Plasma levelPt (years) Sex (mg) (g/ml)

KO 15 M 20 i.v. 1.13 X 10`7

YS 19 F 19 2.03 X 10-7

MI 36 M 20 1.25 X 10-7

TO 41 M 10 3.30 X 10-7

MN 15 M 10 1.68 x 10-7

HI 16 M 10 8.20 X 10-8

HN 17 M 10 5.10 X 10-8

SM 63 M 60 p.o. 1.10 X 10-7

TU 70 M 30 6.20 X 10-8

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msec

4001

ERP 300

200

1 00-

msec

4001

FRP 300-

diltiazem

P<0 05

P<0 0 11 oo

verapamilmsec

rnsec

400-

300-

200-

1 001

CDI

P< 0.02

msec

400 -

300-

200-

1 00 .

nifedipine

FIGURE 5. Effects of diltiazem (D)verapamil (V) and nifedipine (N) in an iden-tical concentration of 10` glml on effectiveand functional refractory periods (ERP andFRP) in an excised rabbit atrioventricularnodal preparation. Prolongation ofthe ERPand FRP by these agents is statisticallysignificant. Thick lines denote mean values.Reprinted with permission of ExcerptaMedica from New Drug Therapy with a

Calcium Antagonist.8

P<0 01

(I

length and recovery time when autonomic blockersare given before verapamil. As a result, the calciumantagonists may not suppress the SA node clinicallyas much as they do in the excised rabbit SA nodepreparation. However, in patients with sick sinus syn-

drome, calcium antagonists may cause prolongedsinus arrest or SA block due to the original sup-

pressive effects on the SA node in the absence ofproper response of the sick sinus node to the hypoten-sion induced by these agents.'4

Verapamil in a concentration of 5 X 10-7 g/ml sup-

pressed the spontaneous firing rate of the AV nodalaction potential, and in a concentration of 2 X 10 6

g/ml it reduced the overshoot markedly withoutsignificantly reducing the maximum diastolic poten-

tial.l2 Raschack demonstrated that both verapamiland nifedipine cause a dose-dependent prolongation ofFRP in the isolated left atrium of the guinea pig4 andof ERP of the AV node in the rabbit." Verapamil alsodepressed AV nodal conduction in the dog.3 The pres-ent study provides direct evidence that diltiazem,verapamil and nifedipine in identical concentrationsprolonged ERP and FRP of the AV node equally inthe isolated rabbit right atrium.

Diltiazem and verapamil suppress AV nodal con-duction in the human as well as in the excised rabbitAV nodal preparation.The action of nifedipine on AV conduction in

clinical cases is different from that of diltiazem andverapamil. Nifedipine appears to facilitate rather than

TABLE 5. Effects of Dtltiazem, Verapamil and Nifedipine on Atrioventricular Conduction, and Effective and Functional RefractoryPeriods of the Atrioventricular Node in Clinical Cases

Slowest RAPrate to produceWenckebach

AH AH block HV ERPAVN FRPAVN(msec) (beats/min) (msec) (msec) (msec)

C A C A C A C A C A

Diltiazem (n = 10) 80 97 154.4 137.3 47 47 297 361 409 449sD -'i26 -4-34 - 19.5 =i=20.3 5 5 45A 77 41 48

p < 0.01 < 0.01 NS < 0.05 < 0.05

Verapamil (n 13) 90 114 142.8 121.9 42 42 287 388 417 466= SD -27 -39 -7.6 -21.0 -6 -6 -36 =71 -52 468

p < 0.01 < 0.05 NS < 0.05 < 0.05

Nifedipine (n = 8) 92 88 129.2 139.5 44 44 40,9 339 480 417SD s12 -11 -25.6 -17.8 a 5 134 -97 -150 i100

p < 0.05 < 0.05 NS < 0.05 < 0.05

Abbreviations: RAP = right atrial pacing; ERP = effective refractory period; FRP = functional refractory period; AVN- atrioventricular node; C = control; A = after drug administration.

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msec200

A-H150

100

50

beats/min

200Slowest RAPrate to produce -sA-H Wenckebach15block

100

50

C

dilt;azem

P'O. 01

Pc<0.01D

rnsec200

150

100

50

beats/min

200

15%p100

50

C

verapamil

P<0.01

P<0.05V

msec200

150

100

50

beatsimin

200

150 _

100,

50 _

C

nifedipine

P<0.05

p< 0.05

FIGURE 6. Effects of diltiazem (D),verapamil (V) and nifedipine (N) on AH in-tervals and slowest rate ofright atrialpacing(RAP) to produce Wenckebach type AHblock (minimum RAP rate to produceWenckebach) in clinical cases. Thick linesdenote mean values. C = control.

diltiazem

P<0.05

P' 0.05

msec

500

400

300

200

600

500

400

300D

verapamil

(1 vP<0.05

P'0.05C V

msec

500

400

300

200

600

500

400

300

C

suppress AV conduction. The direct suppressive effectof nifedipine on AV nodal conduction seems weakbecause of low dose (one-tenth that of diltiazem orverapamil) and is overcome by a reflex increase insympathetic tone as the result of a fall in blood pres-sure. Nifedipine seems to be a more potent hypoten-sive agent than diltiazem or verapamil, so should alsoinduce a more pronounced reflex activation in thesympathetic system. The increase in sympathetic toneafter nifedipine was confirmed by the increase inplasma norepinephrine concentration determined bythe method of high-performance liquid chromatog-raphy'5, 16 in our laboratory. The results were partlyreported in a preliminary paper (The Fourth Inter-national Adalat symposium in Paris, October 1979).These clinical findings are consistent with those of ex-

periments in open-chest dogs by Taira et al.17

FIGURE 7. Effects of diltiazem (D),< verapamil (V) and nifedipine (N) on effec-

'<o.os tive and functional refractory periods (ERPand FRP) in clinical cases. Thick linesdenote mean values. C = control; < = casesin which failure of atrial capture by extra-stimulus preceded; therefore, actual value islower than that shown in the figure.

< 0.05N

Nifedipine, therefore, can be used as a coronaryvasodilator with the least untoward effects on AV con-duction.The difference of response between the SA and AV

nodes to the hypotensive effect of these calcium an-tagonists is probably because the nodes have adifferent sensitivity to reflex release of sympathetictransmitters.

Verapamil has been reported to be highly effectivein the treatment of paroxysmal supraventriculartachycardia,"8 and more recently of hypertrophic car-diomyopathy.'9, 20 Beneficial effects of diltiazem onreentrant tachycardia involving AV conduction havealso been reported.21 Our experience supports theseresults. However, besides their antiarrhythmic effects,diltiazem and verapamil suppress AV conduction andtherefore aggravate AV block; thus, caution should be

msec

500

ER P400

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used when these agents are considered for patientswith ischemic heart disease associated with latent ormanifest AV block of any degree.

Nifedipine does not have the antiarrhythmicproperties of diltiazem and verapamil. The beneficialeffect on arrhythmia secondary to improved coronaryperfusion, however, is beyond the scope of the presentstudy.

AcknowledgmentWe thank Eisai Pharmaceutical Company, Tanabe Seiyaku

Company and Bayer Yakuhin Company for supplying us withverapamil, diltiazem and nifedipine, respectively. The authors arealso indebted to Dr. Alice S. Cary for pertinent advice on themanuscript and Dr. T. Sakurai for statistical analysis.

References1. Cranefield PF: The conduction of the cardiac impulse. The slow

response and cardiac arrhythmias. Mt Kisco, NY, FuturaPublishing, 1975, p 97

2. Cranefield PF, Aronson RS, Wit AL: Effect of verapamil onthe normal action potential and on a calcium-dependent slowresponse of canine cardiac Purkinje fibers. Circ Res 34: 204,1974

3. Zipes DP, Fischer JC: Effect of agents which inhibit the slowchannel on sinus node automaticity and atrioventricular con-duction in the dog. Circ Res 34: 184, 1974

4. Raschack M: Differences in the cardiac actions of the calciumantagonists. Verapamil and nifedipine. Arzneim Forsch 26:1330, 1976

5. Kawai C, Konishi T, Matsuyama E, Okazaki H: Effect ofnifedipine on atrioventricular (A-V) conduction. Clinical andexperimental studies. In International Adalat Panel Discussion,edited by Lichtlen PR, Kimura E, Taira N. Amsterdam, Ex-cerpta Medica, 1979, p 7

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C Kawai, T Konishi, E Matsuyama and H Okazakithe sinoatrial and atrioventricular nodes. Experimental and clinical studies.

Comparative effects of three calcium antagonists, diltiazem, verapamil and nifedipine, on

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