Reversal of the Cardiovascular Effects of Verapamil
by Calcium and Sodium: Differences Between
Electrophysiologic and Hemodynamic Responses
ROBERT J. HARIMAN, M.D., LUCIA M. MANGIARDI, M.D., R.G. MCALLISTER, JR., M.D.,
BORYS SURAWICZ, M.D., RALPH SHABETAI, M.D., HIROSHI KISHIDA, M.D.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
SUMMARY The reversibility of verapamil-induced hemodynamic and electrophysiologic changes by intravenously administered CaCI2 and NaCI was tested in 34 anesthetized open-chest dogs during verapamil infusions which produced plasma verapamil concentrations of 70-2042 ng/ml. An increase of serum calcium concentration (Ca). to an average 6.5 mEq/l abolished the depressive effects of verapamil on cardiac output and
left ventricular dp/dt and diminished drug-related hypotension by an average of 52%, but did not affect
verapamil-induced prolongation of AH interval and slowing of sinus rate. Further increase of (Ca). to an
average of 8.2 mEq/l decreased AH prolongation caused by verapamil from an average of 95% to 45% of control value, but had no effect on verapamil-induced slowing of sinus rate or second-degree atrioventricular (AV)
block during atrial pacing. Rapid intravenous injection of 40 ml 2 M NaCI, transiently raised serum Na+ concentration to 162 mE/l, decreased AH prolongation caused by verapamil to an average of 22% of control value,
decreased slowing of sinus rate from an average of 34% to an average of 19% of control value, and decreased
the severity of second-degree AV block, but had no effect on verapamil-induced complete AV block or sinus
arrest. Hypernatremia had no effect on AH interval and sinus rate without prior CaCl2 infusion. In the absence
of verapamil, neither increase of (Ca). to 8.2 mEq/l, nor NaCl injection following CaCl2 had any effect on AH
interval or sinus rate. This study suggests 1) that both Ca+ and Na+ compete with verapamil, but Na+ acts
only in the presence of hypercalcemia; 2) different verapamil effects differ in their reversibility; and 3) treatment with calcium may be useful in counteracting the negative inotropic effect of verapamil.
verapamil on the membrane current flowing through
the slow channel,2 on the slow channel-dependent
automaticity in guinea pig myocardium,'2 and on the
contractility in the mammalian myocardium at slow
heart rates.3 In vivo, Ca++ reversed the suppressive
effect of verapamil on digitalis-induced arrhythmias in
dogs."3 Similarly, an increase in extracellular Na+
concentration abolished the verapamil-induced second-degree AV block and restored 1:1 conduction in
the isolated rabbit heart.'"
Verapamil concentration in the body fluids has not
been measured in any of the previous studies. In our
laboratory, McAllister et al. have developed an assay
for verapamil in plasma,'3 studied the elimination
kinetics of the drug in dogs,"' and designed intravenous bolus-infusion regimens that enabled us to correlate various plasma verapamil concentrations with
the cardiovascular effects of the drug." In this paper
we report the reversibility of these effects in vivo by
CaCI2 and NaCl administration, at different plasma
verapamil concentrations.'7' 18
VERAPAMIL BLOCKS the slow inward membrane
current carried primarily by calcium, but also by
sodium ions.1-3 This current is believed to be an important factor in the depolarization of the sinoatrial (SA)
and atrioventricular (AV) nodes4-7 and in excitationcontraction coupling in the myocardium.1 8
Verapamil is useful in terminating reentrant supraventricular tachycardia and in slowing ventricular rate
in atrial fibrillation or flutter.9' 10 However, it can
cause AV block, sinus bradycardia, depression of
myocardial contractility and hypotension."
Previous studies have shown the Ca++ added to a
tissue bath reversed the suppressive effects of
From the Cardiovascular Division, Department of Medicine,
University of Kentucky College of Medicine, and Lexington
Veterans Administration Hospital, Lexington, Kentucky.
Supported in part by a grant from the Kentucky Heart Association and by the Medical Research Service of the Veterans Administration. Presented in part at the 49th and 50th Scientific
Sessions of the American Heart Association, Miami Beach,
Florida, November 1976 and 1977.
Dr. McAllister is a clinical investigator of the Veterans Administration.
Dr. Hariman's present address: Department of Pharmacology,
College of Physicians and Surgeons, Columbia University, New
York, New York 10032.
Dr. Mangiardi's present address: Department of Medicine,
University of Torino, Italy.
Dr. Shabetai's present address: Department of Medicine,
University of California, La Jolla, California 92093.
Dr. Kishida's present address: Department of Medicine, Nippon
University, Tokyo, Japan.
Address for reprints: Borys Surawicz, M.D., Department of
Medicine, University of Kentucky College of Medicine, Lexington,
Materials and Methods
We studied 34 open-chest dogs (17-25 kg),
anesthetized with sodium pentothal (30 mg/kg i.v.)
and mechanically ventilated using a respirator. Serial
determinations of arterial pH, PCO2, and Po2 at 30minute intervals were done to insure adequate ventilation. The methods of measuring hemodynamic parameters - cardiac output, dp/dt of the left ventricular
pressure, aortic blood pressure, and peripheral vascular resistance, and the electrophysiologic parameters (AH interval and AV nodal refractory periods)
- were described in our previous paper."' These
Kentucky 40506.
Received June 16, 1978; revision accepted November 8, 1978.
Circulation 59, No 4, 1979.
797
798
CIRCULATION
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parameters were measured during atrial pacing at a
constant rate and, except for the AV nodal refractory
periods, were expressed as an average value of five
complexes. His bundle pacing was used when secondor third-degree AV block developed. Throughout all
experiments, pacing rate was constant, and-the driving rate was the slowest required to suppress the spontaneous rhythm, usually about 2.5 Hz. PP interval was
determined as an average value of 10 consecutive
spontaneous complexes.
Verapamil (Knoll Pharmaceutical Co) was administered according to bolus-infusion method, where
each bolus was given at a rate of 3 mg/min." Ten dogs
received 3.0-4.2 mg bolus followed by constant infusion at 0.06 mg/min; 11 dogs received 7.0-8.5 mg
bolus followed by constant infusion at 0.15 mg/min;
and three dogs received 14.0-21.5 mg bolus followed
by infusion at 0.33 mg/min. In two dogs, verapamil
was given in excess of the above doses to produce
plasma concentrations of about 1000 and 2000
ng/ml.
We studied the effects of increased serum calcium*
and/or sodium serum concentrations in those 26
verapamil-treated dogs and in eight control dogs not
treated with verapamil. In eight of the verapamiltreated dogs, we monitored all hemodynamic and electrophysiologic parameters simultaneously, and in the
other 18 dogs, only the electrophysiologic parameters
and the arterial pressure. In those eight dogs, 10%
CaCl2 solution was infused at a rate of 3 mg/kg/min
for 15 minutes, while the rate of verapamil infusion
was unchanged. In 13 of the 18 dogs, similar CaCl2 infusion was followed by three successive intravenous injections made at 5-minute intervals in the following
order: first, 40 ml of 2 M NaCl solution; then 40 ml of
2 M Na lactate solution; finally, 40 ml of 2 M sucrose
solution. In the other five of the 18 dogs a similar
NaCI injection preceded the CaCl2 infusion by an interval of 15 minutes; this infusion was again followed
by similar injections of NaCl, Na lactate and sucrose.
The same method of administration of calcium and
sodium salt solutions was used in the eight control
dogs. Of these, four received CaCl2 infusion at a rate
of 3 mg/kg/min for 60 minutes; and the other four,
one NaCl injection, followed 15 minutes later by 15
minutes of CaCl2 infusion 3 mg/kg/min, and then
three successive injections of NaCl, Na lactate and
sucrose at 5-minute intervals.
Results
Plasma Verapamil, Calcium and Sodium Concentrations
In each experiment, plasma verapamil concentrations measured immediately before and after completion of CaCI2, NaCI, Na lactate, and sucrose infusions did not differ from each other by more than
15%.
Serum calcium concentrations (Ca)8 increased from
*We assume that the fraction of ionized calcium was constant in
our experiments because blood pH was kept constant"' and plasma
proteins were not expected to change.
VOL 59, No 4, APRIL 1979
O VERAPAMIL
1 5MIN. CaC2 15mg/kg
120
z 100
ua
80
z
60
15MIN
Ll
CaCI2 45mg/kg
T BOLUS 40m1 2M NaCt
$ 40
20
OL.
N
P1
P.s
I
L_I
19 19
-CONTROL
19
6
NS <0.001 <0.005
e-0.01
FIGURE 1. Effects of verapamil alone, after CaCI,, and
after CaCi, + NaCI administration on the percent change of
AH interval from control. Vertical bars are the average
values and the vertical lines at their tops, the mean ± SEM.
The numbers of dogs (N) are shown under each bar.
Statistical significance of p, relates to the comparison between values in the first bar, vs those in the other bars.
Statistical significance ofp2 is a comparison of values in the
third vs those in the fourth bar. Serum calcium concentrations (mean ± SEM.) from left to right are: 4.6 ± 0.2, 6.6
± 0.2, 8.2 ± 0.2, and 8.0 ± 0.3 mEqll.
an average control value of 4.6 ± 0.2 mEq/l to an
average of 6.5 ± 0.2 mEq/l after 5 minutes, and to an
average of 8.2 ± 0.3 mEq/l after 15 minutes of CaCI2
infusion. The latter concentrations did not change by
more than 1.0 mEq/l at the time of the subsequent
sodium salt and sucrose injections.
Serum sodium concentration immediately after the
rapid i.v. NaCl or Na lactate injections ranged from
162 to 185 mEq/l, and decreased to less than 155
mEq/l within 5 minutes after the injection.
AH Intervals in Verapamil-treated Dogs
The results are summarized in figure 1, which shows
the mean (± SEM) AH intervals during atrial pacing at
plasma verapamil concentrations varying from
70-377 ng/ml. The AH interval increased after verapamil administration by an average of 95% and did not
change significantly at an average (Ca). of 6.5 mEq/l,
i.e., after 5 minutes of CaCI2 infusion. However, at
(Ca)8 averaging 8.2 mEq/l, i.e., after 15 minutes of
CaCl2 infusion, AH interval shortened significantly,
reaching a value that was about 45% longer than the
control AH interval. Injections of NaCl during
sustained hypercalcemia produced further shortening
of AH interval to an average value which was still 22%
longer than the control AH interval.
In all experiments, the effects of CaCl2 on the AH
interval persisted for at least 45 minutes after the end
of calcium infusion, even though the verapamil administration was continued. However, the effect of
NaCl injection lasted only about 1 minute. The NaClinduced shortening of AH interval during hypercalcemia could be reproduced by repeated injections
VERAPAMIL, Ca++ AND Na+/Hariman et al.
0-
501
O AH INTERVAL
& PP INTERVAL
40-
0
w
FIGURE 2. Effects of CaCl2 infusion at a
rate of 3 mg/kg/min in a dog on the AH intervals during atrial pacing at a rate of 150
beats/min (AH) and during spontaneous
sinus rhythm (PP). The abscissa shows time
in minutes (min) and serum calcium concentration [Cal in mEq/l, the ordinate, changes
in percent.
0
4A 301
w
cr-
z
799
20
_t
10
0
?22
0
2Q
Alk
0 5 10 15 20
4.7 6.2 7.5 8.2 8.9
A
I
30
9.6
40
10.5
A
A
A
I
60 Time (min)
13.2 [Cal (mEq/l)
50
11.6
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
after 15 minutes of CaCl2 infusion and 86 ± 13 msec
SEM after the repeated NaCl injection. The differences
between these values were not significant. Administration of CaCl2 for 15 minutes did not change the AH
interval, but longer duration of infusion associated
with higher serum calcium concentrations increased
the AH interval. Figure 2 shows an experiment in
which the increase of AH interval occurred when (Ca),
reached 9.6 mEq/l. In the other three dogs, the onset
of AH prolongation occurred at (Ca)8 9.4 mEq/l, 10.9
mEq/l, and 11.0 mEq/l.
of NaCl or Na lactate. In this group of six dogs,
changes induced by second injection of NaCl or by injection of Na lactate after NaCl did not differ
significantly from those induced by the first injection
of NaCI.
The effects of NaCl and Na lactate were not due to
change in osmolality, because an iso-osmolar sucrose
solution had no effect on the AH interval. Rapid administration of larger than 40-ml volumes of NaCl,
Na lactate, or sucrose solutions caused atrial fibrillation.
NaCl injections not preceded by CaCl2 infusions
had no significant effect on the AH interval in four
dogs at plasma verapamil concentrations varying
from 100-270 ng/ml. In these animals, verapamil-induced AH prolongation averaged 67 ± 15% of control
value before and 63 + 18% of control value after NaCl
AV Nodal Effective and Functional Refractory Periods,
Second and More Advanced Degrees of AV Block
in Verapamil-treated Dogs
The effects of CaCl2 infusion on the AV nodal
refractory periods paralleled those on the AH interval. The verapamil-induced prolongation of the AV
nodal effective and functional refractory periods was
partly reversed after 15 minutes of CaCl2 infusion.
Figure 3 shows a representative experiment in which
verapamil increased the effective refractory period
from 140 to 315 msec, and the functional refractory
period from 230 to 400 msec. After 15 minutes of
CaCl2 infusion which increased (Ca). from 4.6 to 7.9
injection.
AH Intervals in Dogs Not Treated with Verapamil
Administration of NaCl had no effect on the AH in-
tervals before or after CaCL2 infusions. In the four
control dogs, AH interval averaged 85 + 8 msec before administration of sodium and calcium salts, 82 ±
12 msec after the first NaCl injection, 80 ± 10 msec
500
o CONTROL
* IVI=150 ng/ml,ICal2=4.6 mEq/l
u
E
x 15 min.Ca C2
11 AV block
0%
45mg/kg,ICal =79mEq/I
**
400[
-j
4
lxx
XX X x
x xxx
w
z
3001
0
0° 0
I
0
0
100000000 000
I
?nn
ZUUB--l
100
300
-%^ If%
-% - -
2uu
A1 A 2
I
NTE RVAL
(msec)
XX6
00
'
FIGURE 3. Effective andfunctional refractory periods of the A V node in a dog during
atrial pacing at a rate of 140 beats/min
before and after verapamil (plasma
verapamil concentration 150 ng/ml), and
after CaCl2 infusion during verapamil administration. On the abscissa, intervals between the nonpremature and the premature
atrial complexes (A1-A2) and on the ordinate, the corresponding H1-H2 intervals.
Serum calcium concentrations before and
after CaCl2 infusion are 4.6 and 7.9 mEq/l,
respectively.
VOL 59, No 4, APRIL 1979
CIRCULATION
800
TABLE 1. Effect of a 15-minute CaCl2 Infusion (45 mg/kg)
and a Rapid I. V. 40 ml 2 M NaCl Injection to Verapamilinduced Second-degree Atrioventricular Block
Atrioventricular block
[V]
V
V+Ca V+Ca+Na
Dog
(ng/ml)
4:3
7:6
1
4:3
455
2:1
2:1
3:2
2
480
2:1
2:1
6:5
3
262
5:4
2:1
2:1
4
315
3:2
2:1
2:1
5
272
a VERAPAMIL
M
E 15Min.CaCI2
L
4
LLJ
m
60
45mg/kg
B BOLUS 40ml 2M NaCI
40
z
; 20
IAvI
I I
§- .
N
24
24
NS
Abbreviations: [V] = plasma verapamil concentrations;
V = after verapamil administration; V + Ca = after a 15
minute CaCl2 infusion; V + Ca + Na = after a rapid injection of NaCl.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
mEq/l, the effective refractory period decreased to
225 msec and the functional refractory period to 335
msec. Similar results were obtained in other experiments. AV nodal effective refractory periods in these
six dogs averaged 189 ± 15 msec before verapamil,
350 + 27 msec after verapamil, and 245 + 24 msec
after CaCl2 administration. The latter value was
significantly shorter than the value after verapamil (p
< 0.05). AV nodal functional refractory periods in
these dogs averaged 218 ± 7 msec before verapamil,
377 ± 11 msec after verapamil, and 318 ± 7 msec
after CaCl2 administration. The last value was
significantly shorter than the value after verapamil (p
< 0.05). We could not test the effects of sodium salts
on the AV nodal refractory periods because of the
short duration of changes induced by NaCl injections.
In five dogs, second-degree AV block occurred at
plasma verapamil concentrations from 262-480
ng/ml. In these animals, CaCl2 infusion of 15 minutes
duration did not change the AV block, but the number
of conducted complexes increased when NaCl was injected during hypercalcemia (table 1). In two dogs
with the highest recorded plasma concentrations of
verapamil of 936 to 2043, ng/ml respectively, the AV
block was more advanced than 2:1. This block was
unchanged after the CaCl2 infusion, as well as after
the subsequent NaCl injection.
5Min.CaCI2 15mg/kg
P1
P2
C nNTDAn
24
NS
11
<0.01
<0.01
FIGURE 4. Effects of verapamil alone, after CaC12, and
after CaCl2 administration on the percent change of PP interval from control during sinus rhythm. Vertical bars are
the average values and the vertical lines at their tops, ± SEM.
The numbers of dogs (N) are shown under each bar.
Statistical significance of pi relates to the comparison
between values in the first bar vs those in other bars.
Statistical significance of P2 relates to the comparison between values in the third vs those in the fourth bar. Serum
calcium concentrations are as in figure 1.
Sinus Rate and Rhythm in Verapamil-treated Dogs
At the verapamil concentrations of 70-480 ng/ml,
the PP interval during sinus rhythm increased by an
average of 34% in 24 dogs (fig. 4). Figure 4 shows that
the PP interval did not change significantly after 5 and
15 minutes of CaCl2 infusion. However, after the subsequent NaCl injection, PP interval decreased
significantly to a value which was 19% greater than the
control PP interval. This shortening of PP interval
persisted for about 1 minute and could be reproduced
by repeated injections of NaCl or Na lactate solutions, but not by sucrose. NaCl injections not
preceded by CaCl2 infusions had no effect on the PP
intervals in four dogs at plasma verapamil concentrations of 100-270 ng/ml.
The two dogs whose plasma verapamil concentrations were 936 and 2043 ng/ml, respectively, had sinus
0 VERAPAMIL
60
0
5MIN. Ci 2C12 15mg/kg
4
20
(3 0
z
<
oNO-
-t
---
I-.
czo
1CONTROL
1~~2286±15(Oml /min)
b |
I-
-4
-60
.OU
I
I
I
a
I
100 300 500 700 900 1900 2100
PLASMA VERAPAMIL CONCENTRATION (ng/mi)
FIGURE 5. Effects of 5-minute verapamil
and CaCl+ + infusion on cardiac output in
eight dogs. The abscissa shows plasma
verapamil concentration; the ordinate, percent change in cardiac output. The average
control cardiac output is shown by the interrupted horizontal line. Average serum calcium concentrations are 4.6 ± 0.2 and 6.5 ±
0.3 mEqll, before and after CaCl2 infusion
respectively.
VERAPAMIL, Ca++ AND Na+/Hariman et al.
o VERAPAMIL
CO
801
LVdp/t MAP
PVR
* 5MIN.CaCI2 15mng/kg
LL
* 5MIN. CaC12 15mg/kg
CD
z 40
a-
OVERAPAMIL
< 20
0
z 20
---CONTROL
(1890 60mm Hg/sec)
20.
z
-40-
-
-60-80
100 300500 700 900 1900 2100
PLASMA VERAPAMIL CONCENTRATION (ng/mI)
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
FIGURE 6. Effects of S-minute verapamil and CaCl++ infusion on left ventricular dp/dt in eight dogs. On the
abscissa, plasma verapamil concentration and on the ordinate, percent change in left ventricular dp/dt. The average
control left ventricular dp/dt is shown by the interrupted
horizontal line. Average serum calcium concentrations before and after CaC12 infusions are 4.6 ± 0.2 and 6.5 ± 0.3
mEq/l, respectively.
arrest. The arrest persisted after 15 minutes of CaCl2
infusion and subsequent NaCl injection.
Sinus Rate in Dogs Not Treated with Verapamil
Administration of NaCI or Na lactate had no effect
on PP intervals before or after CaC12 infusions. PP interval did not change after administration of CaCl2 for
15 minutes, but became longer after longer CaCl2 infusions associated with higher (Ca)8. Figure 3 shows
an experiment in which PP interval increased when
(Ca). reached 10.5 mEq/l. In three other experiments, the onset of increase in PP interval occurred at
(Ca)8 10.1, 11.3, and 11.8 mEq/l.
Cardiac Output, Left Ventricular dp/dt, Aortic Pressure
and Peripheral Vascular Resistance
in Verapamil-treated Dogs
Cardiac output and left ventricular dp/dt increased
in all dogs after 5 minutes of CaCl2 infusion at plasma
verapamil concentrations varying from 150-2042
ng/ml. Figure 5 shows that verapamil alone decreased cardiac output in seven of eight dogs, and that
increase of (Ca)8 from 4.6 ± 0.2 to 6.5 ± 0.3 reversed
this effect and increased cardiac output to the levels
which were higher than those before verapamil administration. Figure 6 shows similar effects on the left
ventricular dp/dt which was depressed by verapamil,
but after 5 minutes of CaC12 infusion returned to control levels or higher.
CaCl2 administration increased, but did not reverse
the verapamil-induced decrease in mean aortic pressure (fig. 7). Figure 7 shows that the peripheral
vascular resistance (PVR) decreased after CaCl2 administration, because the increase of cardiac output
exceeded the increase in mean aortic pressure.
S -20 1-40
inI Ir
.
.
.. .. -
-60
Nj
8
8
8
p <0.001 <0.001 <o05
-V
-u EU KtIHI
_ .r
.
8
<OD5
FIGURE 7. Effects of S-minute verapamil and CaCl2 infusion on the mean ± SEM. percent changes in cardiac output
(CO), left ventricular dp/dt (LV dp/dt), mean aortic
pressure (MAP), and peripheral vascular resistance (PVR)
in eight dogs. The p values represent the statistical
significance of the differences between the values in the clear
and striped bars. A verage serum calcium concentrations
before and after CaCI, infusion as in figures 5 and 6.
We found marked differences in the reversibility of
certain hemodynamic and electrophysiologic effects of
verapamil. These differences could not be attributed to
differences in plasma verapamil concentration, because they were present when the hemodynamic and
electrophysiologic effects were recorded simultaneously. Figure 8 shows an example of such an experiment. In the experiment shown in this figure, the
verapamil-induced prolongation of AH interval
remained unchanged when (Ca)8 increased from 4.9 to
6.6 mEq/l (B, C), but decreased by 30 msec when
(Ca)8 reached 8.1 mEq/l. In contrast to this slow and
incomplete reversal of AH prolongation, cardiac output and left ventricular dp/dt increased to values
higher than control at (Ca),8 of 6.6 mEq/l (C); they increased further at (Ca)8 of 8.1 mEq/l (D). Figure 8
shows also that CaCl2 infusion increased, but did not
restore to control the systolic and diastolic aortic pressure.
Discussion
We previously reported the hemodynamic and electrophysiologic verapamil effects described in the dogs
used in this study."' The results of the present study
are: 1) an increase of (Ca)8 by 1-2 mEq/l reversed the
negative inotropic effect of verapamil, but had no
effect on AV conduction and sinus rate; 2) a greater
increase in (Ca)8 reversed, in part, the effects of
verapamil on AV conduction, but not on sinus rate; 3)
a rapid increase in (Na)8 concentration reversed partially the verapamil effects on both AV conduction
and sinus rate, but only after a prior increase in (Ca)8;
4) severe depression of AV conduction and SA node
function was irreversible, but severe depression of cardiac output and left ventricular dp/dt was reversible;
and 5) AV conduction became slower and sinus rate
decreased after a certain critical increase in (Ca)8 in
the absence of verapamil.
Our understanding of these phenomena is very
limited because of many unanswered questions concerning the sites of verapamil action and the
802
CIRCULATION
VOL 59, No 4, APRIL 1979
460 msec
AN 210msoc
4
LV dp/dt
1931 mml,g
mmHg
100 0CON T ROL, (Ca)= 5.0 mEq/1
AHN 2l0msec
(V):: 13 ng/ml, (Ca) 4.9mEq/1
A
lOmsec
LVdp dtl
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
g\ 256OmmHg
2804mmgsegI
mmU'
mmng
1000
(V) 194ng/ml,(Ca)-6.7 mEq
(V) 204ng ml,(Ca)- 8.lmEqt
Il
FIGURE 8. Effects of verapamil before and after infusion of CaCl+ +in a dog during atrial pacing at a rate
of 130 beats/min on the following parameters, shown from top to bottom: electrocardiogram, His bundle
electrogram, left ventricular dp/dt (L V dp/dt), aortic (Ao) and left ventricular (L V) pressure. Top left, control; top right, plasma verapamil and serum calcium concentrations are 213 ng/ml and 4.9 mEqll, respectively; bottom left, 5 minutes after starting CaCl2 infusion, plasma verapamil and serum calcium concentrations are 194 ng/ml and 6.6 mEq/l, respectively; bottom right, 15 minutes after onset of CaCl2 infusion
plasma verapamil and serum calcium concentrations are 204 ng/ml and 8.1 mEqll, respectively. The cardiac
output in this experiment was 2350 ml/min in control, 2030 ml/min after verapamil, 2470 ml/min after 5
minutes, and 2650 ml/min after 15 minutes of CaCl2 infusion.
mechanism of its interaction with Ca++ and Na+ at
the cellular and subcellular level.
Inotropic Effects
Verapamil decreased the steady-state isotonic contraction force in the isolated cat papillary muscle.3
This effect was caused primarily by the (-) optical
isomer of the drug.7 The negative inotropic effect
appeared to be caused, at least in part, by blocking of
the slow inward current.2 Kohlhardt et al. showed that
a fourfold increase of Ca++ concentration in the bath
neutralized or even overcompensated the effects of
verapamil on the slow current and contractility.2
However, the studies of Bayer et al.3 7 revealed more
complex interaction between verapamil and calcium.
These investigators found that within the range of
6-60 Hz the negative inotropic effect of verapamil
depended on the frequency of stimulation being more
pronounced at higher than at lower stimulation rates.
Thus, a three-fold increase in Ca++ concentration
restored or overcompensated the verapamil-depressed
steady-state isotonic contraction force at slow, but not
at rapid rates of stimulation.3 This may be explained
by the observations of Kohlhardt et al.2 that verapamil
not only decreases the steady-state slow current, but
also slows the recovery rate of this current.2 However,
other manifestations of the verapamil-calcium interaction were less readily explained by the effect of
the drug on the slow inward current. Thus, at a
verapamil concentration of 5 ng/ml and a Ca++ concentration of 2.5 mM/l, an abrupt change in the
stimulation rate from 60 to 6 Hz resulted in an
overshoot of the increase in contractile force.3 We attributed this phenomenon to the possible action of
verapamil on some intracellular time-dependent sites
believed to be responsible for the kinetics of Ca++
movement from the sarcoplasmic reticulum to the
"storage sites" in the lateral cysterns.3
The detailed studies by Bristow et al. in the isolated
rabbit atrium on the dose-response relationships of
different verapamil and D600 (the methoxyderivative
of verapamil) concentrations within a wide range of
Ca++ concentrations suggested a competitive antagonism between these drugs and calcium on the
dp/dt.'9 However, unlike the compound D600,
verapamil did not meet rigid criteria for the competitive antagonism, since the relative amount of antagonism decreased with increasing verapamil doses.'9
Therefore, we have suggested that a "pharmacologic
803
VERAPAMIL, Ca++ AND Na+/Hariman et al.
property of verapamil unrelated to calcium antagonism leads to an increase of the availability of intracellular Ca++.
Our findings suggest that relatively small amounts
of calcium are required to overcome the negative inotropic effect of therapeutic and toxic doses of
verapamil. The practical application of these results to
verapamil therapy in man must await the appropriate
clinical studies. In our study the reversibility of the
depressed left ventricular dp/dt persisted until the termination of the experiments, i.e., for not less than 45
minutes after the end of calcium infusion. In other
studies the positive inotropic effects of intravenously
administered calcium salts in intact animal and man
usually lasted less than 15 minutes.20 This observation
appears to favor the mechanism of competitive inhibition of verapamil effect by Ca++ rather than a nonspecific positive inotropic effect of increased (Ca),.
We found that increase in (Ca)8 increased cardiac
output but lowered PVR. These effects of increased
(Ca)8 concentration would be expected even in the
absence of verapamil. Stanley et al. reported that 10
mg/kg of CaCl2 decreased the PVR in unanesthetized
calves not treated with verapamil by an average of
19%.20 In our study, 15 mg/kg of CaCl2 decreased the
verapamil-depressed PVR by an additional 10%. In
the absence of control studies, we do not know if the
effects of calcium on PVR were influenced by pretreatment with verapamil, but our results show that Ca++
does not reverse the verapamil-induced decrease in
PVR. This suggests that the verapamil-calcium interaction in the smooth muscle may differ, at least
quantitatively, from that in the cardiac muscle. Such
differences are plausible, since Chiarandini and
Bentley reported that in the skeletal muscle an increase in extracellular Ca++ concentration did not
reverse the verapamil-induced inhibition of the
Solandt effect and of the acetylcholine-induced con19
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tracture.2'
Effects on AV Conduction and Sinus Rhythm
We found that an increase of (Ca), to an average of
7.9 mEq/l caused a modest but significant decrease in
the AH interval, but no change in the sinus rate. This
suggests some antagonism of Ca++ and verapamil
within the AV node, a finding not reported by previous investigators. Zipes and Fischer could not reverse verapamil effects by infusing calcium gluconate,
CaCI2 and saline into arteries supplying the AV node
and the SA node, respectively.4 The differences
between our results and those of Zipes and Fischer
may be caused by the doses and the methods of
calcium administration. Dogs may tolerate intravenous better than intra-arterial calcium administration since the latter produced atrial or ventricular fibrillation,4 while we did not observe serious
arrhythmias after intravenous CaCl2 administration.
The non-reversibility of sinus bradycardia induced
by verapamil can be explained by the studies of
Kohlhardt et al. on the rabbit SA node.2 They
reported that a threefold increase in extracellular
Ca++ concentration did not change the verapamil-
induced depression of action potential overshoot, upstroke velocity and conduction block,2 and contrasted
this lack of calcium effect on the SA node, with the
reversibility of verapamil-induced depression of contractility in the ventricular myocardium. They also
noted that the lack of Ca++ excess action on the SA
node was not due to an irreversible damage of the
node, because the drug effect could be washed out, and
postulated the presence of unidentified differences
between properties of the slow membrane channel in
pacemaker cells and ventricular myocardium.2
The failure of hypernatremia to affect the
verapamil-induced changes on the AH interval was
surprising for two reasons: 1) The inward Na+ current is believed to participate in the depolarization of
the AV nodal fibers through both the rapid22 and the
slow channel;23 therefore, high Na+ concentrations
would be expected to improve conduction by influencing one or both of these mechanisms; 2) Watanabe
reported that verapamil-induced AV block in the
isolated rabbit hearts could be abolished by increasing
the extracellular Na+ concentration from 145 to 172
mEq/1.14 The ineffectiveness of hypernatremia in our
experiments could be due to an insufficient increase in
Na+ concentration, or to an insufficient duration of
high Na+ action. Unfortunately, we could not examine the effects of larger volumes of hypertonic Na+
solutions because they caused atrial fibrillation.
Effect of Hypernatremia in the Presence of Hypercalcemia
We found that NaCl and Na lactate injections
significantly decreased the AH interval and increased
the sinus rate in the verapamil-treated animals only
after a previous CaCI2 infusion. It appears, therefore,
that the action of Na+ may require some prior
calcium-verapamil interaction. Further studies must
clarify the mechanism of this phenomenon and establish its practical applicability in the treatment of
verapamil toxicity.
Effects of Calcium on AV Nodal Conduction
and Sinus Rhythm in the Absence of Verapamil
Our study confirmed the previously reported
prolongation of PR interval and slowing of sinus rate
in animals and in man with hypercalcemia.9 24, 25 The
effects of verapamil-calcium interaction in this study
were confined to (Ca)8 concentrations that were lower
than those which had independent effect on the AH interval and the sinus rate. However, higher Ca+ + concentration may be expected to have a synergistic effect
with verapamil on the AV nodal conduction and the
sinus rate.
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Reversal of the cardiovascular effects of verapamil by calcium and sodium: differences
between electrophysiologic and hemodynamic responses.
R J Hariman, L M Mangiardi, R G McAllister, Jr, B Surawicz, R Shabetai and H Kishida
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Circulation. 1979;59:797-804
doi: 10.1161/01.CIR.59.4.797
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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