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The effect of lignocaine on myocardial function, high energy phosphate stores, and oxygen consumption: A comparison with propranolol
The effect of lignocaine on myocardial function, high energy phosphate stores, and oxygen consumption: A comparison with propranolol Winifred 0. Nayler, D.Sc. I. Mdnnes, F.R.C.S., F.R.A.C.S. Valerie Carson, M.Sc. J. Stone, B.Sc. T. E. Lowe, D.Sc., M.D., F.R.C.P., Melbourne, Australia
F.R.A.C.P.
R
ecently Jewitt, Kishon, and Thomas’ investigated the value of intravenous lignocaine (2-diethylamino-2’,6’-aceto-xylidide) (Xylocaine)* as an antiarrhythmic agent and concluded that it is “the antiarrhythmic drug of choice in the management of ventricular arrhythmias after acute myocardial infarction.” The effectiveness of lignocaine as an antiarrhythmic agent in the treatment of ventricular arrhythmias and atria1 ectopic beats which may occur after cardiac surgery, and in the treatment of digitalis-induced arrhythmias is well established.2-6 Other investihave advocated that gators, however, propranolol, an adrenergic P-receptor blocking drug, should be used for this purpose6-s but this view should perhaps be modified by subsequent investigationss-10 which have shown that propranolol impairs the ability of the left ventricle to perform mechanical work over a wide range of left atria1 filling pressures, and hence over a wide range of left ventricular end-diastolic fiber lengths. From the Baker Medical These investigations were Received for publication *American generic name.
338
Research Institute. Commercial supported by a Grant-in-Aid Dec. 6. 1968. lidocaine.
American Heart Journal
In addition, propranolol has been shown to cause vasoconstriction in the ‘coronary circulation.1° As it had not been established that lignocaine is free from these undesirable effects the following experiments were carried out to determine the effect of lignocaine on myocardial function, high energy phosphate stores, oxygen consumption, and coronary blood flow. Methods
Efect of lignocaine on myocardial contractions. The direct effect of lignocaine on cardiac contractions was determined using either small papillary muscles excised from exsanguinated dogs or discarded from patients undergoing open-heart surgery, usually for mitral valve replacement. The muscle preparations used were approximately 1.5 mm. in diameter and were suspended isometrically in aerated (95 per cent 02 and 5 per cent CO4 modified Tyrode’s solution10 maintained at 37 f Rd., Prahran. from the National
Victoria Heart
3181, Australia. Foundation of Australia.
September, 1969
Vol. 78, No. 3, pp. 338-345
Comparison
0.5” C. Stimulation was effected with suprathreshold rectangular pulses of 10 milliseconds’ duration delivered from a Tektronix square wave stimulator assembly at a rate of 38 pulses per minute. Preliminary experiments have shown that under the present experimental conditions high energy phosphate stores in strips of human and dog heart muscle are not significantly (p > 0.5) changed after 4 hours’ stimulation at this rate. Diastolic tension was adjusted until maximum tension developed during regular contractions. The contractions were detected with microsensor semiconductor strain gauges (type MS 132-120) arranged to form a wheatstone bridge, the output from which was displayed on an ultraviolet light optical recorder (S. E. Laboratories, type 200s). Preparations were equilibrated in Tyrode’s solution for 60 minutes before any drugs were added and the diastolic tension applied at the end of the equilibration period was maintained throughout the remainder of the experiment. The tension developed during contraction was recorded continuously for 30 minutes before and for at least 60 minutes after lignocaine had been added to provide the required concentration. These apparently long periods of recording were used to ensure that any delayed action of the drug would not be missed. The Tyrode’s solution was prepared in all-glass distilled water using Merck analytical reagent grade chemicals. Effect of lignocaine on left ventricular function. In previous studieslOnll dogs on right-sided cardiac bypass, in which inflow to the left ventricle and hence cardiac output is controlled, have been used to determine the effect of various drugs, including dl-propranolol, on ventricular function, high energy phosphate stores, coronary blood flow, and myocardial oxygen consumption. In the present experiments this same technique has been used to determine the effect of lignocaine on ventricular function and to establish whether the effect of this drug on the heart is accompanied by a change in coronary blood flow, myocardial oxygen consumption, or in the level of high energy phosphate stores in the myocardium. Healthy mongrel dogs (12 to 16 Kg.)
of lignocaine and propmnolol
339
were premeditated with 30 mg. morphine sulfate given intramuscularly 1 hour before anesthesia was induced with 20 mg. per kilogram sodium thiopental given intravenously. An intermittent positive pressure respirator delivered oxygen to the dog through a cuffed endotracheal tube. Arterial blood pressure in the left femoral artery was detected by a Statham strain gauge transducer (P23Db). Left ventricular function curves were established and left ventricular “work per minute” (IV) at a particular flow was calculated in gram-meters per minute, as previously described,‘@ as the product of total flow (Q, milliliters per minute) multiplied by the pressure difference between the systemic arterial (PAN, in centimeters of HzO) and left atria1 pressures (PLA, in centimeters of HzO): W= Q X (PAN - PLA). Although the term “work” is commonly used for this product, it is a measure of pow-er, i.e., work per unit time. In the control, as in the experimental series, the output from the pump (and hence left atria1 pressure) was increased in increments of approximately LO ml. per kilogram per minute. As soon as stable conditions were established after each increment in flow mean atria1 and arterial pressures were noted. The calculated left ventricular work per minute was plotted against left atria1 pressure. After a ventricular function curve had been established for each preparation and a ventricular biopsy taken (see below) to provide control observations, lignocaine was added intravenously either as a single bolus to provide a concentration within the range 0.2 to 5 mg. per kilogram, or as an infusion at a rate of 0.5 to 1.0 mg. per kilogram per minute. After lignocaine had been added as an infusion for 10 minutes, or 10 to 20 minutes after it had been added as a single bolus, both a left ventricular function curve and a ventricular biopsy were repeated. These biopsy samples were analyzed for adenosine triphosphate (ATP) and creatine phosphate (CP). Throughout these experiments samples of arterial and coronary sinus blood were taken when required and their percentage oxyhemoglobin saturation estimated spectrophotometrically as previously described.lOsl” Biopsy technique and assay procedure for
340
.4m. Hcavt J. .sc~~tcvnhrl~, 1Y 6Y
Nnyler et al.
high energy phosphates. A description of the method used to ensure that the biopsy tissue was rapidly frozen has been described in detail elsewhere.” Briefly, a small piece of muscle was drawn into a stainless steel tube, which had been precooled with liquid nitrogen, placed in close contact with the tissue. Liquid nitrogen was then poured into the tube and the frozen biopsy tissue snipped off with a tonsil snare and immediately dropped into liquid nitrogen in which it was stored until analyzed, usually on the same day. Successive biopsies were taken from closely adjacent areas. Preliminary studies showed that the levels of ATP, CP, and IP in any one biopsy sample were not significantly (p < 0.001) different from the levels found in biopsies taken from closely adjacent areas. ATP in a trichloracetic acid (TCA) extract of the biopsy was determined chromatographically as previously described,12CP was determined by the method of Furchgott and de Gubareff.13 Statistical analysis. The significance of results was determined by the Student t test, taking p = 0.05 as the limit of significance. Drugs. Dilutions were prepared in 0.9 per cent saline. Lignocaine was used as Xylocaine. Results
Efect of lignocaine on cardiac contractions. The mean results of experiments designed to study the effect of lignocaine on the tension developed by isolated isometrically suspended strips of human and dog papillary muscle are summarized in Fig. 1, where each point represents the mean f S.E.M. of six separate experiments. Cumulative doses of lignocaine were not used and the dose range studied was chosen to include the therapeutic range. In these experiments the negative inotropic effect of lignocaine was evident 2 or 3 minutes after it had been added to the Tyrode’s solution in the organ bath, and was fully developed within approximately 20 minutes. The data shown in Fig. 1 relate to the fully developed response and show that the effect of lignocaine on the tension developed during contraction in dog muscle is not significantly different from that
which occurs when human heart muscle is used. Since these muscle preparations were stimulated to contract at a constant rate, the depressant effect of lignocaine on cardiac contractions is not due to a change in the duration of the time interval separating successivecontractions. If after the negative inotropic effect of lignocaine was fully developed the Tyrode solution in the organ bath was replaced with lignocaine-free solution, then the tension developed during subsequent contractions increased gradually until control conditions were re-established. Recovery was usually complete within 20 minutes. The negative inotropic effect of lignocaine on these electrically stimulated muscle strips was accompanied by a decline in the rate at which tension developed during individual contractions. For example, when the negative inotropic effect caused by adding 3 pg per milliliter of lignocaine was fully developed, an additional 82 f 12 msec.* (6 experiments) was required after the onset of contraction before the maximum or “peak” tension was developed for that contraction. This difference was significant (p < 0.001). The negative inotropic effect of lignocaine on human and dog heart muscle is dosedependent, as is shown by the data in Fig. 1, and although the negative inotropic responsecaused by adding 1 I*g per milliliter of lignocaine lacked significance (p > O.S), the negative inotropic effect of doses of lignocaine of, or in excess of, 1.75 pg per milliliter was significant (p = 0.01). Effect of lignocaine on left ventricular function, high energy phosphate stores, coronnry bloodjkw, myocnrdial oxygen consumption, and ventricular ejkiency. Previous studies have established that in control left ventricular work function studies increasing the output from the pump to provide small increments in left atria1 filling pressure, and hence in left ventricular end-diastolic fiber length, results in comparatively large increments in left ventricular power so that when left atria1 pressure is plotted against left ventricular work per minute the resultant curve has a steep slope.1° In addition, these preliminary studies showed that successive *Results
presented
as mean
f S.E.M.
Comparison
Stin rate
38 beatslmin human paplllary dog
o-a
1
x--x
muscle
n:6
3 oz+I 6 -lO& 6 9 ?
-2o-
5 .E -3oY 5 J -4o%
diastolic fiber lengths, uT;asnot signiticantl~ different from that recorded from the same preparation before lignocaine \vas added. Left ventricular function curves recorded from a typical preparation before and 10 minutes after the addition of 1.0 and 5.0 mg. per kilogram lignocaine, as a single bolus, are shown in Fig. 2. Left ventricular \vork per minute performed Iq- six other preparations at indicated left atria1 pressures before and after adding lignocaine, either as a bolus or as an infusion as indicated, are listed in Table 1. The data in Table I relating to f)reparations SOS. 9 and 10 show that a dose of 5.0 mg.
PO001 I
p(0001
I
I
I
1
to
20
30
40
,ug/ml
p(Ooo1 I
5-O
LIGNKAINE
1. Dose-response curve for the effect of 1.0 to 5.0 pg per milliliter of lignocaine on the tension produced by dog and human papillary muscle during isometric contraction. Per cent change in tension B-A 100 calculated ~ X -, where B refers to tension Fig.
B
1
produced before and A after the addition of lignocaine. Each point represents mean + S.E.M. from 6 experiments. 4 = not significant at level of p = 0.05.
curves established during 90 minute control perfusion do not differ significantly (p > 0.5) from one another and that the addition of 0.1 to 0.3 mg. per kilogram dl-propranolol to the perfusion system results in the curve being significantly flattened and displaced to the right. This effect of dl-propranolol on ventricular function was found to be accompanied by coronary vasoconstriction, bradycardia, and a diminution in the rate at which oxygen is extracted from the coronary circulation.1° lIespite these changes in ventricular function the concentration of high energy phosphates stores in the myocardium remained unchanged.12 When, in the present experiments, lignoCaine was added either as a single bolus to provide a final concentration of from 0.2 to 4.0 mg. per kilogram or infused at a rate of 0.5 to 1.0 mg. per kilogram per minute, left ventricular function over a range of left atria1 filling pressures, and hence over a range of left ventricular end-
34 1
0J’ 1ignocciin.c~rind ~roprt~nolol
per
kilogram
lignocaine
given
as
a single bolus did depress ventricular work per minute at the indicated left atria1 filling pressure (4 cm. of H20) ,md the left ventricular function curve displayed in Fig. 2 ~110~s that in contrast to tlie result otjtained \I-hen tile smaller dose tbf lignoCaine M-as used, a dose of 5.0 nlg. per kilo-
gram of lignocaine flattened the luft ventricular b\:ork function curve, partic.ularl!. at higher left atria1 filling pressures (6.5 to 10.5 cm. of HrO), and displaced ii to the right.
Five
other
preparations
wielded
similar results. Other data listed iu ‘i’able 1 show that the infusion of 0.2 to 1.0 rng. per kilogram per minute of lignocaine or the injection of 0.1 to 5.0 mg. per kilogranl of lignocaine as a single I)olus caused the heart rate to slo~v from a mean value (8 experiments) of 119 & 9.6 to 1OX.T + 10.6 I)eats
per
nlinute.
Althougll
lignocaine
reduced the heart rate, coronar\’ I)lood How \vas maintained. Thus, in tllv x experiments listed in Tattle I the coronary l)lood flow tjefore lignocaine was added was 16.25 i
After kilOgriln1
1.1 nil.
per kilogram
per niinute.
adding either 2.0 to 5.0 jug. per of
lignocaine
as
;I single
I~olus
or
a ten minute infusion of 0.2 to 1.O mg. per kilogrant per nlinute of lignocaine, tllc. coronary I)lood flow in these same l)rcparations \las 16.73 f 1.6 nil. per kikqranl per minute. This difference \vas not signitic;tnt. The conclusion that 0.2 to 3.0 mg. per kilogranl of lignoraine does not c;~ust! any significant
fall
in
coromr\~
11lood
tlow
iii
these studies is supported 1:)~. t ho dat.;l slio\vn in PYg. 2, IS, \vhich iudicirtes th;lt coronary blood flow \\.‘lS mailttaitied throughout
the
whole
range
0i Irit vcri-
342
Nayler
Am. Heart I. September. 1969
et al.
l a
x -x o l -•
5E
o
Ccfbtrd I.0 mg/Kg 5.0 mq/Kg
Lignccahe Lignocaine
x0*
700
Y 5
600 t
%
400-
l20-
500-
Xo@
B i
100
l -
l
ElO-
l
300-X0@
2 9
200-
6
‘T
8 d >
X0.
A
1 LEFT
:,
A
A
ATRIAL
to
40-
24
’
’
’
IO
12
14
PRESSURE
60-
0
0 X
l
0
l X
X
,
uB
01
’
LEFT
(cmH201
’
’
200
VENTRICULAR
’
400 WORK
’
’
600
’
’
800
/ min cgm M/ minute)
Fig. 2. Effect of lignocaine on left ventricular work/minute and coronary blood flow. A, Left ventricular function curve recorded from a typical preparation before and after 1.0 and 5.0 mg. per kilogram of lignocaine was added, as indicated (preparation no. 15). B, Relationship between left ventricular work per minute and coronary blood flow in a typical preparation (no. 15) before and after adding either 1.0 and 5.0 mg. per kilogram of lignocaine, as indicated.
Table I. Efect of lignocaine on ventricular function, coronary bloodJEow,and heart rate*
Dog NO. 1 2 4 5 7 8 9 10
Lignocaine 0.2 mg./Kg./min. (infusion) 2.0 mg./Kg. (single bolus) 1.0 mg./Kg./min. (infusion) 2.0 mg./Kg. (single bolus) 3.0 mg./Kg. (single bolus) 4.0 (single bolus) fiigle 5.0 bolus)
(single bolus) Mean * S.E.M.
B A B A B A B A B A B A B i BA A
Left atrial pressure (cm. HeO)
Left venkicle work/m&. (gmM./min.)
2 2 2 2 2 2 4 4 2
740 750 790 800 860 750 860 840 820 815 1,210 1,162 92.5 660 1,006 790 901.4 * 53.1 820.9 * 52.3
Et 122 114 119.1 * 9.6 108.5 f 10.6
17 1.5 21 27 16 15 16 15 20 19 17 13 14 15 13 15 16.3 * 1.1 16.8 * 1.6
4
4
4
z 5 4 4 4 4
Coronary blood Heart rate (beats/n&.) 126 108 156 1.56 152 140 x 125 110 96 88
sow
(ml./Kg./min.)
*Where + = not significant at level of D - 0.05, B refers to before and A after adding lignocaine at the indicated dose as either a single bolus or an infusion. When given as an infusion. the infusion was maintained for 10 minutes before the ventricular function curve was m-established.
Comparison
tricular function after either 1.0 or 5.0 mg. per kilogram lignocaine had been added as a single bolus to the circulation. Myocardial oxygen consumption was determined for eight preparations before and after adding lignocaine and the results obtained, summarized in Table II, show that in these experiments the addition of this drug failed to cause any significant change in myocardial oxygen consumption. Before lignocaine was added the mean rate of myocardial oxygen consumption was 10.21 f 1.59 compared with a rate of 11.20 f 1.23 ml. per kilogram per minute (8 experiments) after adding lignocaine. This difference was not significant (p= 0.6).
Table II. Effect of lignocaine high energy phosphate stores* Dog Dog no.
weight (IQ.)
on myocardial
Left atrial ptez.srure (cm. I&O)
Lignocaine
343
of lignocaine and propran.
When the ventricular was calculated for these dividing left ventricular ute (in gram-meters per ventricular
oxygen
efficiencv index preparations, by “work” per minminute) by left
consumption
(milli-
liters
per minute), the results indicated that, within the dose range studied, lignoCaine failed to cause any significant change (p > 0.01) in the efficiency with which left ventricular work was performed. In these eight preparations the efficiency index
before
lignocaine
was
added
was
32.4 f 1.1 compared with an efficiency of 32.2 f 1.3 after the drug had been added. Analysis of the muscle biopsies for ATI’ and CP showed (Table II) that lignoraine
oxygen consumption,
Left ventricle work/min. (gmM./min.)
MyocardialO2 (ml./min./lOO Gm. heart wt.)
ventricular
e&dewy,
and
Left ventricle 02 (mI./min.)
Ve&riudar eigidcncv ins
ATP bmW Gm.)
CP bd4 Gm.)
1
16.0
0.2 mg./Kg./min. (infusion)
B A
6 6
1,280 1,300
15.5 15.4
47.7 47.4
26.8 27.4
7.3 7.2
7.6 7.0
2
15.5
2.0 mg./Kg. (single bolus)
B A
4 4
1,002 1,116
10.3 11.3
31.7 34.8
31.6 32.0
6.7 5.9
5.6 6.2
3
10.5
1 .O mg./Kg./min. (infusion)
B A
2 2
790 825
8.2 6.6
25.3 26.9
31.2 30.6
6.6 5.0
9.6 8.2
4
15.0
1.0 mg./Kg./min. (infusion)
B A
4 4
1,206 1,080
11.9 10.0
36.7 30.7
32.8 35.1
7.4 7.6
5.8 6.4
5
12.0
2.0 mg./Kg. (single bolus)
B A
5 5
940 1,180
9.3 11.3
28.7 34.7
32.8 34.0
8.8 7.8
6.8 7.2
6
17.5
1.0 mg./Kg./miu. (mfuaion)
B A
6 6
1,788 2,002
14.9 17.7
49.0 58.1
36.4 34.5
5.4 7.5
7.3 7.8
7
15.0
1 .O mg./Kg. (single bolus)
B A
1,000 1,002
8.7 8.3
27.2 25.5
36.7 39.4
6.3 6.8
7.4 8.6
10
15.5
5.0 mg./Kg. (single bolus)
B A
1,006 790
10.9 9.4
32.8 28.1
30.7 28.1
6.5 6.9
7.6 7.9
B A
1,126.5 f 109.1 lJ61.9 f 58.2
Mean
Sig.
* S.E.M.
4 (p = 0.8)
32.4 & 1.1 32.3 f 1.1 6.9 f 0.3 7.2 f 0.4 32.2 + 1.3 32.6 f 1.5 6.8 f 0.3 7.4 + 0.3 4 (p = 0.9)
4 (p = 0.9)
*Where + = not significant at level of p = 0.05 B refers to before and A after adding lignocaine at the indicated added either as a eingle bolus or infused at a constant rate as indicated. When given as an infusion the infusion 10 minutes before the ventricular function curve was established. tVentrlcnlar efficiency index calculated: L.V. work/minute (gmM./min.) L.V.02 consumption (ml./min.)
4 (p = 0.9)
4 (p = 0.7)
dose. Ligccaine was maintained
wa@ for
344
Nnyler
et (11.
failed to cause any significant change in the myocardial stores of either ATP (p > 0.9) or CP (p = 0.7) in these preparations. Discussion
These results show that lignocaine has a direct negative inotropic effect on dog and human heart muscle. This effect is accompanied by a decline in the rate at which tension is produced during individual contractions, so that during each contraction a longer period of time is required for the development of peak tension. This negative inotropic effect of lignocaine, which was significant only when the dose used exceeded 1 kg per milliliter, cannot be accounted for in terms of a negative “staircase effect” since, although lignocaine did cause the heart rate to slow in intact animals, the isolated papillary muscles were stimulated to contract at a constant rate. In this respect, then, lignocaine resembles propranolol. lo The negative inotropic effect of lignocaine on human heart muscle was not significantly (p > 0.8) different from that on dog heart muscle. Even when large doses of lignocaine were used, its effect on the left ventricular function was only apparent at the upper end of the curve under conditions of high load. Previous experiments have shown that propranolol depressesthese left ventricular function curves even at the bottom of the function curve and hence under conditions of low load. In contrast to the resultslo obtained when propranolol was used, the present results indicate that in the presence of lignocaine coronary blood flow was either maintained or slightly increased throughout the whole range of the minutework curve. These results show that, within the dose range used, lignocaine failed to have any significant effect on the rate at which oxygen is extracted from the coronary circulation, a finding which again contrasts with results already described for propranolol.1° These showed that propranolol depresses or has a “sparing” effect on the rate at which oxygen is extracted from the coronary circulation even though it impairs coronary blood flow throughout the entire range of the ventricular function curve. The rate at which oxygen was extracted from the coronary circulation in the present
experiments is in approximate agreement with the control human data recently published by Dodge and Baxley.i4 Like propranolol, lignocaine failed to cause any significant change in the concentration of high energy phosphates present in the myocardium, so that like propranolol, its negative inotropic effect cannot be explained in terms of a decrease in the availability of energy to support the process of contraction. In general, these results are in agreement with those already described for lignocaine by Asokan and associates,i5 Schumacher and associates,r6 and Constantino and co-workers,” and may provide the basis for its relatively safe use1,i8for the treatment of cardiac arrhythmias, in contrast to the well-documented dangers associated with the use of propranolol.1g~20 Summary
The effect of lignocaine on the tension produced during isometric contraction by isolated dog and human papillary muscle, on ventricular function, on myocardial oxygen utilization and high energy phosphate stores, and on coronary blood flow was determined and compared with the effects already described for propranolol. Doses of lignocaine of or in excess of 1.7 pg per milliliter decreased the tension produced during isometric contraction by isolated papillary muscle preparations and increased the time needed to reach “peak” tension during each contraction. Doses of lignocaine below 4 mg. per kilogram or infusions of 0.5 to 1.0 mg. of lignocaine per kilogram per minute did not cause any significant change in left ventricular function as determined by left ventricular work-function studies. After 5 mg. per kilogram of lignocaine was given as a single bolus, the work-function curve was flattened at high but not significantly changed at low rates of work. Bigh energy phosphate stores and myocardial oxygen consumption were not significantly modified when doses of lignocaine up to 5 mg. per kilogram or infusions of lignocaine at a rate of 0.5 to 1.0 mg. per kilogram per minute were used. Lignocaine caused the heart rate to slow and reduced the resistance to blood flow in the coronary circulation. The efficiency
with which the left ventricle pumped blood into the circulation was not modified when lignocaine was given as a single injection or infused. Mrs.
\%‘e gratefully acknowledge the technical B. Skym and Miss Kathleen Clarkson.
help
11.
of
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F.R.A.C.P.
R
ecently Jewitt, Kishon, and Thomas’ investigated the value of intravenous lignocaine (2-diethylamino-2’,6’-aceto-xylidide) (Xylocaine)* as an antiarrhythmic agent and concluded that it is “the antiarrhythmic drug of choice in the management of ventricular arrhythmias after acute myocardial infarction.” The effectiveness of lignocaine as an antiarrhythmic agent in the treatment of ventricular arrhythmias and atria1 ectopic beats which may occur after cardiac surgery, and in the treatment of digitalis-induced arrhythmias is well established.2-6 Other investihave advocated that gators, however, propranolol, an adrenergic P-receptor blocking drug, should be used for this purpose6-s but this view should perhaps be modified by subsequent investigationss-10 which have shown that propranolol impairs the ability of the left ventricle to perform mechanical work over a wide range of left atria1 filling pressures, and hence over a wide range of left ventricular end-diastolic fiber lengths. From the Baker Medical These investigations were Received for publication *American generic name.
338
Research Institute. Commercial supported by a Grant-in-Aid Dec. 6. 1968. lidocaine.
American Heart Journal
In addition, propranolol has been shown to cause vasoconstriction in the ‘coronary circulation.1° As it had not been established that lignocaine is free from these undesirable effects the following experiments were carried out to determine the effect of lignocaine on myocardial function, high energy phosphate stores, oxygen consumption, and coronary blood flow. Methods
Efect of lignocaine on myocardial contractions. The direct effect of lignocaine on cardiac contractions was determined using either small papillary muscles excised from exsanguinated dogs or discarded from patients undergoing open-heart surgery, usually for mitral valve replacement. The muscle preparations used were approximately 1.5 mm. in diameter and were suspended isometrically in aerated (95 per cent 02 and 5 per cent CO4 modified Tyrode’s solution10 maintained at 37 f Rd., Prahran. from the National
Victoria Heart
3181, Australia. Foundation of Australia.
September, 1969
Vol. 78, No. 3, pp. 338-345
Comparison
0.5” C. Stimulation was effected with suprathreshold rectangular pulses of 10 milliseconds’ duration delivered from a Tektronix square wave stimulator assembly at a rate of 38 pulses per minute. Preliminary experiments have shown that under the present experimental conditions high energy phosphate stores in strips of human and dog heart muscle are not significantly (p > 0.5) changed after 4 hours’ stimulation at this rate. Diastolic tension was adjusted until maximum tension developed during regular contractions. The contractions were detected with microsensor semiconductor strain gauges (type MS 132-120) arranged to form a wheatstone bridge, the output from which was displayed on an ultraviolet light optical recorder (S. E. Laboratories, type 200s). Preparations were equilibrated in Tyrode’s solution for 60 minutes before any drugs were added and the diastolic tension applied at the end of the equilibration period was maintained throughout the remainder of the experiment. The tension developed during contraction was recorded continuously for 30 minutes before and for at least 60 minutes after lignocaine had been added to provide the required concentration. These apparently long periods of recording were used to ensure that any delayed action of the drug would not be missed. The Tyrode’s solution was prepared in all-glass distilled water using Merck analytical reagent grade chemicals. Effect of lignocaine on left ventricular function. In previous studieslOnll dogs on right-sided cardiac bypass, in which inflow to the left ventricle and hence cardiac output is controlled, have been used to determine the effect of various drugs, including dl-propranolol, on ventricular function, high energy phosphate stores, coronary blood flow, and myocardial oxygen consumption. In the present experiments this same technique has been used to determine the effect of lignocaine on ventricular function and to establish whether the effect of this drug on the heart is accompanied by a change in coronary blood flow, myocardial oxygen consumption, or in the level of high energy phosphate stores in the myocardium. Healthy mongrel dogs (12 to 16 Kg.)
of lignocaine and propmnolol
339
were premeditated with 30 mg. morphine sulfate given intramuscularly 1 hour before anesthesia was induced with 20 mg. per kilogram sodium thiopental given intravenously. An intermittent positive pressure respirator delivered oxygen to the dog through a cuffed endotracheal tube. Arterial blood pressure in the left femoral artery was detected by a Statham strain gauge transducer (P23Db). Left ventricular function curves were established and left ventricular “work per minute” (IV) at a particular flow was calculated in gram-meters per minute, as previously described,‘@ as the product of total flow (Q, milliliters per minute) multiplied by the pressure difference between the systemic arterial (PAN, in centimeters of HzO) and left atria1 pressures (PLA, in centimeters of HzO): W= Q X (PAN - PLA). Although the term “work” is commonly used for this product, it is a measure of pow-er, i.e., work per unit time. In the control, as in the experimental series, the output from the pump (and hence left atria1 pressure) was increased in increments of approximately LO ml. per kilogram per minute. As soon as stable conditions were established after each increment in flow mean atria1 and arterial pressures were noted. The calculated left ventricular work per minute was plotted against left atria1 pressure. After a ventricular function curve had been established for each preparation and a ventricular biopsy taken (see below) to provide control observations, lignocaine was added intravenously either as a single bolus to provide a concentration within the range 0.2 to 5 mg. per kilogram, or as an infusion at a rate of 0.5 to 1.0 mg. per kilogram per minute. After lignocaine had been added as an infusion for 10 minutes, or 10 to 20 minutes after it had been added as a single bolus, both a left ventricular function curve and a ventricular biopsy were repeated. These biopsy samples were analyzed for adenosine triphosphate (ATP) and creatine phosphate (CP). Throughout these experiments samples of arterial and coronary sinus blood were taken when required and their percentage oxyhemoglobin saturation estimated spectrophotometrically as previously described.lOsl” Biopsy technique and assay procedure for
340
.4m. Hcavt J. .sc~~tcvnhrl~, 1Y 6Y
Nnyler et al.
high energy phosphates. A description of the method used to ensure that the biopsy tissue was rapidly frozen has been described in detail elsewhere.” Briefly, a small piece of muscle was drawn into a stainless steel tube, which had been precooled with liquid nitrogen, placed in close contact with the tissue. Liquid nitrogen was then poured into the tube and the frozen biopsy tissue snipped off with a tonsil snare and immediately dropped into liquid nitrogen in which it was stored until analyzed, usually on the same day. Successive biopsies were taken from closely adjacent areas. Preliminary studies showed that the levels of ATP, CP, and IP in any one biopsy sample were not significantly (p < 0.001) different from the levels found in biopsies taken from closely adjacent areas. ATP in a trichloracetic acid (TCA) extract of the biopsy was determined chromatographically as previously described,12CP was determined by the method of Furchgott and de Gubareff.13 Statistical analysis. The significance of results was determined by the Student t test, taking p = 0.05 as the limit of significance. Drugs. Dilutions were prepared in 0.9 per cent saline. Lignocaine was used as Xylocaine. Results
Efect of lignocaine on cardiac contractions. The mean results of experiments designed to study the effect of lignocaine on the tension developed by isolated isometrically suspended strips of human and dog papillary muscle are summarized in Fig. 1, where each point represents the mean f S.E.M. of six separate experiments. Cumulative doses of lignocaine were not used and the dose range studied was chosen to include the therapeutic range. In these experiments the negative inotropic effect of lignocaine was evident 2 or 3 minutes after it had been added to the Tyrode’s solution in the organ bath, and was fully developed within approximately 20 minutes. The data shown in Fig. 1 relate to the fully developed response and show that the effect of lignocaine on the tension developed during contraction in dog muscle is not significantly different from that
which occurs when human heart muscle is used. Since these muscle preparations were stimulated to contract at a constant rate, the depressant effect of lignocaine on cardiac contractions is not due to a change in the duration of the time interval separating successivecontractions. If after the negative inotropic effect of lignocaine was fully developed the Tyrode solution in the organ bath was replaced with lignocaine-free solution, then the tension developed during subsequent contractions increased gradually until control conditions were re-established. Recovery was usually complete within 20 minutes. The negative inotropic effect of lignocaine on these electrically stimulated muscle strips was accompanied by a decline in the rate at which tension developed during individual contractions. For example, when the negative inotropic effect caused by adding 3 pg per milliliter of lignocaine was fully developed, an additional 82 f 12 msec.* (6 experiments) was required after the onset of contraction before the maximum or “peak” tension was developed for that contraction. This difference was significant (p < 0.001). The negative inotropic effect of lignocaine on human and dog heart muscle is dosedependent, as is shown by the data in Fig. 1, and although the negative inotropic responsecaused by adding 1 I*g per milliliter of lignocaine lacked significance (p > O.S), the negative inotropic effect of doses of lignocaine of, or in excess of, 1.75 pg per milliliter was significant (p = 0.01). Effect of lignocaine on left ventricular function, high energy phosphate stores, coronnry bloodjkw, myocnrdial oxygen consumption, and ventricular ejkiency. Previous studies have established that in control left ventricular work function studies increasing the output from the pump to provide small increments in left atria1 filling pressure, and hence in left ventricular end-diastolic fiber length, results in comparatively large increments in left ventricular power so that when left atria1 pressure is plotted against left ventricular work per minute the resultant curve has a steep slope.1° In addition, these preliminary studies showed that successive *Results
presented
as mean
f S.E.M.
Comparison
Stin rate
38 beatslmin human paplllary dog
o-a
1
x--x
muscle
n:6
3 oz+I 6 -lO& 6 9 ?
-2o-
5 .E -3oY 5 J -4o%
diastolic fiber lengths, uT;asnot signiticantl~ different from that recorded from the same preparation before lignocaine \vas added. Left ventricular function curves recorded from a typical preparation before and 10 minutes after the addition of 1.0 and 5.0 mg. per kilogram lignocaine, as a single bolus, are shown in Fig. 2. Left ventricular \vork per minute performed Iq- six other preparations at indicated left atria1 pressures before and after adding lignocaine, either as a bolus or as an infusion as indicated, are listed in Table 1. The data in Table I relating to f)reparations SOS. 9 and 10 show that a dose of 5.0 mg.
PO001 I
p(0001
I
I
I
1
to
20
30
40
,ug/ml
p(Ooo1 I
5-O
LIGNKAINE
1. Dose-response curve for the effect of 1.0 to 5.0 pg per milliliter of lignocaine on the tension produced by dog and human papillary muscle during isometric contraction. Per cent change in tension B-A 100 calculated ~ X -, where B refers to tension Fig.
B
1
produced before and A after the addition of lignocaine. Each point represents mean + S.E.M. from 6 experiments. 4 = not significant at level of p = 0.05.
curves established during 90 minute control perfusion do not differ significantly (p > 0.5) from one another and that the addition of 0.1 to 0.3 mg. per kilogram dl-propranolol to the perfusion system results in the curve being significantly flattened and displaced to the right. This effect of dl-propranolol on ventricular function was found to be accompanied by coronary vasoconstriction, bradycardia, and a diminution in the rate at which oxygen is extracted from the coronary circulation.1° lIespite these changes in ventricular function the concentration of high energy phosphates stores in the myocardium remained unchanged.12 When, in the present experiments, lignoCaine was added either as a single bolus to provide a final concentration of from 0.2 to 4.0 mg. per kilogram or infused at a rate of 0.5 to 1.0 mg. per kilogram per minute, left ventricular function over a range of left atria1 filling pressures, and hence over a range of left ventricular end-
34 1
0J’ 1ignocciin.c~rind ~roprt~nolol
per
kilogram
lignocaine
given
as
a single bolus did depress ventricular work per minute at the indicated left atria1 filling pressure (4 cm. of H20) ,md the left ventricular function curve displayed in Fig. 2 ~110~s that in contrast to tlie result otjtained \I-hen tile smaller dose tbf lignoCaine M-as used, a dose of 5.0 nlg. per kilo-
gram of lignocaine flattened the luft ventricular b\:ork function curve, partic.ularl!. at higher left atria1 filling pressures (6.5 to 10.5 cm. of HrO), and displaced ii to the right.
Five
other
preparations
wielded
similar results. Other data listed iu ‘i’able 1 show that the infusion of 0.2 to 1.0 rng. per kilogram per minute of lignocaine or the injection of 0.1 to 5.0 mg. per kilogranl of lignocaine as a single I)olus caused the heart rate to slo~v from a mean value (8 experiments) of 119 & 9.6 to 1OX.T + 10.6 I)eats
per
nlinute.
Althougll
lignocaine
reduced the heart rate, coronar\’ I)lood How \vas maintained. Thus, in tllv x experiments listed in Tattle I the coronary l)lood flow tjefore lignocaine was added was 16.25 i
After kilOgriln1
1.1 nil.
per kilogram
per niinute.
adding either 2.0 to 5.0 jug. per of
lignocaine
as
;I single
I~olus
or
a ten minute infusion of 0.2 to 1.O mg. per kilogrant per nlinute of lignocaine, tllc. coronary I)lood flow in these same l)rcparations \las 16.73 f 1.6 nil. per kikqranl per minute. This difference \vas not signitic;tnt. The conclusion that 0.2 to 3.0 mg. per kilogranl of lignoraine does not c;~ust! any significant
fall
in
coromr\~
11lood
tlow
iii
these studies is supported 1:)~. t ho dat.;l slio\vn in PYg. 2, IS, \vhich iudicirtes th;lt coronary blood flow \\.‘lS mailttaitied throughout
the
whole
range
0i Irit vcri-
342
Nayler
Am. Heart I. September. 1969
et al.
l a
x -x o l -•
5E
o
Ccfbtrd I.0 mg/Kg 5.0 mq/Kg
Lignccahe Lignocaine
x0*
700
Y 5
600 t
%
400-
l20-
500-
Xo@
B i
100
l -
l
ElO-
l
300-X0@
2 9
200-
6
‘T
8 d >
X0.
A
1 LEFT
:,
A
A
ATRIAL
to
40-
24
’
’
’
IO
12
14
PRESSURE
60-
0
0 X
l
0
l X
X
,
uB
01
’
LEFT
(cmH201
’
’
200
VENTRICULAR
’
400 WORK
’
’
600
’
’
800
/ min cgm M/ minute)
Fig. 2. Effect of lignocaine on left ventricular work/minute and coronary blood flow. A, Left ventricular function curve recorded from a typical preparation before and after 1.0 and 5.0 mg. per kilogram of lignocaine was added, as indicated (preparation no. 15). B, Relationship between left ventricular work per minute and coronary blood flow in a typical preparation (no. 15) before and after adding either 1.0 and 5.0 mg. per kilogram of lignocaine, as indicated.
Table I. Efect of lignocaine on ventricular function, coronary bloodJEow,and heart rate*
Dog NO. 1 2 4 5 7 8 9 10
Lignocaine 0.2 mg./Kg./min. (infusion) 2.0 mg./Kg. (single bolus) 1.0 mg./Kg./min. (infusion) 2.0 mg./Kg. (single bolus) 3.0 mg./Kg. (single bolus) 4.0 (single bolus) fiigle 5.0 bolus)
(single bolus) Mean * S.E.M.
B A B A B A B A B A B A B i BA A
Left atrial pressure (cm. HeO)
Left venkicle work/m&. (gmM./min.)
2 2 2 2 2 2 4 4 2
740 750 790 800 860 750 860 840 820 815 1,210 1,162 92.5 660 1,006 790 901.4 * 53.1 820.9 * 52.3
Et 122 114 119.1 * 9.6 108.5 f 10.6
17 1.5 21 27 16 15 16 15 20 19 17 13 14 15 13 15 16.3 * 1.1 16.8 * 1.6
4
4
4
z 5 4 4 4 4
Coronary blood Heart rate (beats/n&.) 126 108 156 1.56 152 140 x 125 110 96 88
sow
(ml./Kg./min.)
*Where + = not significant at level of D - 0.05, B refers to before and A after adding lignocaine at the indicated dose as either a single bolus or an infusion. When given as an infusion. the infusion was maintained for 10 minutes before the ventricular function curve was m-established.
Comparison
tricular function after either 1.0 or 5.0 mg. per kilogram lignocaine had been added as a single bolus to the circulation. Myocardial oxygen consumption was determined for eight preparations before and after adding lignocaine and the results obtained, summarized in Table II, show that in these experiments the addition of this drug failed to cause any significant change in myocardial oxygen consumption. Before lignocaine was added the mean rate of myocardial oxygen consumption was 10.21 f 1.59 compared with a rate of 11.20 f 1.23 ml. per kilogram per minute (8 experiments) after adding lignocaine. This difference was not significant (p= 0.6).
Table II. Effect of lignocaine high energy phosphate stores* Dog Dog no.
weight (IQ.)
on myocardial
Left atrial ptez.srure (cm. I&O)
Lignocaine
343
of lignocaine and propran.
When the ventricular was calculated for these dividing left ventricular ute (in gram-meters per ventricular
oxygen
efficiencv index preparations, by “work” per minminute) by left
consumption
(milli-
liters
per minute), the results indicated that, within the dose range studied, lignoCaine failed to cause any significant change (p > 0.01) in the efficiency with which left ventricular work was performed. In these eight preparations the efficiency index
before
lignocaine
was
added
was
32.4 f 1.1 compared with an efficiency of 32.2 f 1.3 after the drug had been added. Analysis of the muscle biopsies for ATI’ and CP showed (Table II) that lignoraine
oxygen consumption,
Left ventricle work/min. (gmM./min.)
MyocardialO2 (ml./min./lOO Gm. heart wt.)
ventricular
e&dewy,
and
Left ventricle 02 (mI./min.)
Ve&riudar eigidcncv ins
ATP bmW Gm.)
CP bd4 Gm.)
1
16.0
0.2 mg./Kg./min. (infusion)
B A
6 6
1,280 1,300
15.5 15.4
47.7 47.4
26.8 27.4
7.3 7.2
7.6 7.0
2
15.5
2.0 mg./Kg. (single bolus)
B A
4 4
1,002 1,116
10.3 11.3
31.7 34.8
31.6 32.0
6.7 5.9
5.6 6.2
3
10.5
1 .O mg./Kg./min. (infusion)
B A
2 2
790 825
8.2 6.6
25.3 26.9
31.2 30.6
6.6 5.0
9.6 8.2
4
15.0
1.0 mg./Kg./min. (infusion)
B A
4 4
1,206 1,080
11.9 10.0
36.7 30.7
32.8 35.1
7.4 7.6
5.8 6.4
5
12.0
2.0 mg./Kg. (single bolus)
B A
5 5
940 1,180
9.3 11.3
28.7 34.7
32.8 34.0
8.8 7.8
6.8 7.2
6
17.5
1.0 mg./Kg./miu. (mfuaion)
B A
6 6
1,788 2,002
14.9 17.7
49.0 58.1
36.4 34.5
5.4 7.5
7.3 7.8
7
15.0
1 .O mg./Kg. (single bolus)
B A
1,000 1,002
8.7 8.3
27.2 25.5
36.7 39.4
6.3 6.8
7.4 8.6
10
15.5
5.0 mg./Kg. (single bolus)
B A
1,006 790
10.9 9.4
32.8 28.1
30.7 28.1
6.5 6.9
7.6 7.9
B A
1,126.5 f 109.1 lJ61.9 f 58.2
Mean
Sig.
* S.E.M.
4 (p = 0.8)
32.4 & 1.1 32.3 f 1.1 6.9 f 0.3 7.2 f 0.4 32.2 + 1.3 32.6 f 1.5 6.8 f 0.3 7.4 + 0.3 4 (p = 0.9)
4 (p = 0.9)
*Where + = not significant at level of p = 0.05 B refers to before and A after adding lignocaine at the indicated added either as a eingle bolus or infused at a constant rate as indicated. When given as an infusion the infusion 10 minutes before the ventricular function curve was established. tVentrlcnlar efficiency index calculated: L.V. work/minute (gmM./min.) L.V.02 consumption (ml./min.)
4 (p = 0.9)
4 (p = 0.7)
dose. Ligccaine was maintained
wa@ for
344
Nnyler
et (11.
failed to cause any significant change in the myocardial stores of either ATP (p > 0.9) or CP (p = 0.7) in these preparations. Discussion
These results show that lignocaine has a direct negative inotropic effect on dog and human heart muscle. This effect is accompanied by a decline in the rate at which tension is produced during individual contractions, so that during each contraction a longer period of time is required for the development of peak tension. This negative inotropic effect of lignocaine, which was significant only when the dose used exceeded 1 kg per milliliter, cannot be accounted for in terms of a negative “staircase effect” since, although lignocaine did cause the heart rate to slow in intact animals, the isolated papillary muscles were stimulated to contract at a constant rate. In this respect, then, lignocaine resembles propranolol. lo The negative inotropic effect of lignocaine on human heart muscle was not significantly (p > 0.8) different from that on dog heart muscle. Even when large doses of lignocaine were used, its effect on the left ventricular function was only apparent at the upper end of the curve under conditions of high load. Previous experiments have shown that propranolol depressesthese left ventricular function curves even at the bottom of the function curve and hence under conditions of low load. In contrast to the resultslo obtained when propranolol was used, the present results indicate that in the presence of lignocaine coronary blood flow was either maintained or slightly increased throughout the whole range of the minutework curve. These results show that, within the dose range used, lignocaine failed to have any significant effect on the rate at which oxygen is extracted from the coronary circulation, a finding which again contrasts with results already described for propranolol.1° These showed that propranolol depresses or has a “sparing” effect on the rate at which oxygen is extracted from the coronary circulation even though it impairs coronary blood flow throughout the entire range of the ventricular function curve. The rate at which oxygen was extracted from the coronary circulation in the present
experiments is in approximate agreement with the control human data recently published by Dodge and Baxley.i4 Like propranolol, lignocaine failed to cause any significant change in the concentration of high energy phosphates present in the myocardium, so that like propranolol, its negative inotropic effect cannot be explained in terms of a decrease in the availability of energy to support the process of contraction. In general, these results are in agreement with those already described for lignocaine by Asokan and associates,i5 Schumacher and associates,r6 and Constantino and co-workers,” and may provide the basis for its relatively safe use1,i8for the treatment of cardiac arrhythmias, in contrast to the well-documented dangers associated with the use of propranolol.1g~20 Summary
The effect of lignocaine on the tension produced during isometric contraction by isolated dog and human papillary muscle, on ventricular function, on myocardial oxygen utilization and high energy phosphate stores, and on coronary blood flow was determined and compared with the effects already described for propranolol. Doses of lignocaine of or in excess of 1.7 pg per milliliter decreased the tension produced during isometric contraction by isolated papillary muscle preparations and increased the time needed to reach “peak” tension during each contraction. Doses of lignocaine below 4 mg. per kilogram or infusions of 0.5 to 1.0 mg. of lignocaine per kilogram per minute did not cause any significant change in left ventricular function as determined by left ventricular work-function studies. After 5 mg. per kilogram of lignocaine was given as a single bolus, the work-function curve was flattened at high but not significantly changed at low rates of work. Bigh energy phosphate stores and myocardial oxygen consumption were not significantly modified when doses of lignocaine up to 5 mg. per kilogram or infusions of lignocaine at a rate of 0.5 to 1.0 mg. per kilogram per minute were used. Lignocaine caused the heart rate to slow and reduced the resistance to blood flow in the coronary circulation. The efficiency
with which the left ventricle pumped blood into the circulation was not modified when lignocaine was given as a single injection or infused. Mrs.
\%‘e gratefully acknowledge the technical B. Skym and Miss Kathleen Clarkson.
help
11.
of
REFERENCES 1. Jewitt, D. E., Kishon, Y., and Thomas, M.: Lignocaine in the management of arrhythmias after acute myocardial infarction, Lancet I :266, 1968. 2. Katz, M. J., and Zitnik, R. S.: Direct current shock and lignocaine in the treatment of digitalis-induced ventricular tachycardia, Am. J. Cardiol. 18:552, 1968. .3 . \\‘eiss. LV. A.: Intravenous use of lidocaine for ventricular arrhythmias, Anesth. Anal). (Cleveland) 39:369, 1960. 4. Carden, N. L., and Steinhaus, J. E.: Lidocaine in cardiac resuscitation from ventricular fibrillation, Circulation Res. 4:680, 1956. 5. I-own, B., Fakhro, A. M., Hood, W. B., Jr., and Thorn, G. W.: The coronary care unit, J. A. M. A. 199:156, 1967. 6. Stock, J. I’. Ii.: Beta-adrenergic blocking drugs in the clinical management of cardiac arrhythmias, Am. J. Cardiol. 18:444, 1966. 7. Turner, J. K. B.: Propranolol in the treatment of digitalis-induced and digitalis tachycardia, Am. J. Cardiol. 18:450, 1966. 8. Sloman, G., Kobinson, J, S., and McLean, K.: i ro p ranolol (Inderal) in persistent ventricular fibrillation, Brit. M. J. 1:895, 1965. 9. Epstein, S. E., and Braunwald, E.: Clinical and hemodynamic appraisal of beta-adrenergic blocking agents. ,4m. New York Acad. SC. 139:952; 1967. 10. Nayler, LV. G., McInnes, I., Swann, J. B., Race, I)., Carson, V., and Lowe, T. E.: Some effects of diphenylhydantoin and propranolol
12.
13.
14.
15.
16.
17.
18.
19
20.
on the cardiovascular system, ~13~. I tEAKT J. X:83, 1968. Nayler, Xv. G., Stone, j., Carson, \‘.tlerie, McTnnes, I., Mack, Valerie, and l.owe, ‘I’. I:.: The effect of /3-adrenergic antagonist5 OII cardiac contraction, myofibrillar ATf’ase activity, high energy phosphate stores and lipid-farilitated transport of calcium ions, J. I’h~umarol. & Exper. Therap. 165:225, 1969. Koos, A., and Rich, J. A.: Spectl-opt~~~tometric determination of oxyhaemoglobin s,rttrration and oxygen content of blood, J. I.al~ & Clin. Med. 4bT431, 1952. FurchPott. F. R.. and de Gubareff. T.: I)etermination of inorganic phosphate and crcatine phosphate in tissue extracts, J. Biol. f’hem. 223:377, 1965. Dodge, H. T., and Baxley, I\;. A.: Ileruody,namic aspects of heart faillrre, Xm. .I Cnrdiol. 22:24, 1968. Asokan, S. K., Frank, M. J,, and JZegan, I‘. J.: Assessment of myocardial depression with therapeutic doses of lidocaine ;rnd procaineamide. Am. I. Cardiol. 21:91. 1968. Schnmacher: R. K., Lieberson, .I. I)., Childress, 1~. H., and \villiams, J. E.: Hemod!m~mic effects of lidocaine in patients with heart disease, Circulation .38:965, 1968. Constantine, 1~. T., Crockett, S. E., and L’asko, J. S.: Cardiac and peripheral vascular effects of lidocaine, Am. J. Cardiol. 21:98, 1968. Frieden, J.: Antiarrhythmic drugs. l’art VI I. 1,idocaine as an antiarrhythmic agent. i\\f. HEART J. 70:713, 196.5. Conway, IX., Seymour, J., and Gelson, A.: Cardiac failure in patients with vabar heart disease after use -of propranolol 1-r) control atria1 fibrillation. Brit. M. I. 2:213. 1968. Sun, S. C., Burch, G. E., and De I’asquale, N.: Histochemiral and electron microscopic study of heart muscle after beta-adreuergic I)lorkade, Xx HEART J. 74:340, 1967.