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The influence of vagal activity on heart block
THE
lI\‘FI,TJEN(‘E
ADDISON
OF \‘AG\l,
.\~“l‘IVI’I’Y
OK
HEART
I,. &IESSEK, M.D., ~HAKlzES K. hNEC;AN, .\KD ELIWARDS. ORWIN, M.D. DC'KH.lM,
s.
BI,O(‘K
h/l.D.,
(‘.
T
HE reports of Bruenn,’ Keith,” and Robinson” have shown clearly that large doses of atropine will shorten the P-R interval in a majority of the cases of partial heart block associated with acute rheumatic fever, as well as in certain vagotonic individuals. The findings of Logue and Hanson4j” indicated that this effect is not specific for acute rheumatic fever. The last named authors studied thirty-eight indivitlt.als with prolonged P-R intervals associated with various diagnoses and found that twenty-five (65 per cent) showed a return of the P-R interval to normal after administration of 0.96 mg-. of atropine sulfate intravenously. There was no correlation between the clinical diagnosis and the effectiveness of atropine; however, it is of interest that in this group seven patients with rheumatic fever showed a return of the P-R interval to normal while six did not. The reduction of the P-K interval in a control group was found by Bruenn’ and Keith2 to be less than that in rheumatic subjects with prolonged P-R intervals. This is due very probably to the fact that in normal individuals the P-R interval is closer to the minimum possible conduction time; hence, less shortening is possible. Bruennl has interpreted these results to indicate that an increased vagal tone exists in acute rheumatic fever and has suggested that the site of the lesion may be in the central nervous system, probably in the medulla. Robinson” concurred in the opinion that an increased vagal tone exists in acute rheumatic fever with partial heart block. However, Logue and Hanson4 felt that the effect of atropine did not preclude a pathologic change either in the heart muscle or in the conduction system and that the change in vagal tone might be due to altered physiology at the myoneural junction. Dameshek, Loman, and Myerson li found that the P-R interval increased in almost every instance in normal individuals following the administration of Mecholyl. The maximum effect occurred within two to four minutes and the average percentage increase was 46 per cent. This was abolished within thirty to sixty seconds after t.he intravenous injection of atropine. That heart block of all gracles, including complete heart- block, may bc produced by asphyxia and succeeded by recovery, independent of vagus a(.Persistent hear 1 tivity, was shown experimentally by Lewis and Mathison.’ block of a high grade is generally considered to be due to intrinsic heart disease Prom the DeparLmnnt Durham, N. C.
of
Medicine,
Duke
University 732
Rtzhool
of
Medicine
and
Duke
Hospital,
MESSEK
ET
AL.:
VAGAL
ACTIVITY
AND
HEART
733
BLOCK
and temporary or transient block to be of vagal origin.‘,” When heart block responds to atropine, the question arises as to whether the reduction in conduction time is due to the abolition of an increased primary central neurogenic effect or to a normal neurogenic effect upon a heart rendered more susceptible to vagal influence by some metabolic alteration in the conduction system, at the myoneural junction, or in the myocardium. The present study was undertaken to investigate the effect of vagal activity on unselected cases of heart block. In addition to the effect of atropine, the effects of breathing 100 per cent oxygen and of the subcutaneous injection of acetyl-beta-methylcholine chloride (Mecholyl) on patients with heart block were studied. METHOD
OF STUDY
The subjects used in this study were fifty-one unselected patients from the wards and outpatient clinics of Duke Hospital whose electrocardiograms revealed a P-R interval of 0.21 second or over manifested in all leads, or higher degrees of heart block. No attempt was made to select the patients with regard to age, general condition, or diagnosis. The distribution of the patients according to age is shown in Table I, and the associated diagnoses are listed in Table II. Mecholyl was not administered to patients with a history of asthma or pulmonary disease. .rAtlLE __..-
/ AGE (YEBRS)
o--
PATIENTS ATROPINE
9
) 1 ~ ! 1 1 I
Total
‘rABl& ;.
T\iPI’
OF HIiART
II.
r\GE ~~IS1‘RIBUTION OF PATIEXTS .~ ~__--.~__ - -I
I
1
IO-19 ‘O-29 30--39 40-49 50-59 60-69 70-79 80-89
1.
RECEIVING ALONE
Nonedemonstrable Hypertensive Arteriosclerotic Rheumatic,active Rheumatic,inactive Congenital Undiagnosed -‘Total
,
TOTAL NUMBER OF PATIEXTS IN SERII’S
1
n
1 5
:
4 6
:: 5 7 2 2
ii
29
22
C.4RDIOvASCULAR __..-
UISEASE
PATIENTS RECBIVIKG OXYGEN, ATROPINE, AND MECHoLyI.
PATIENTS ATROPINE
9 6 8 8 10 2 2
i 3 3 I
L)IAG~~SI’.S
RECEIVING ALONE
OF PATIEKTS
5I COMPOSING
GROUPS
1 AND
2
i PATIENTS RECEIVING OXYGEN, ATROPINE, AND MECHOLYI,
. -__-__.
29
I
I 5 ! 1 I
22
.-___----
t1 1x 7 7 0 I 1 51
.__..._
734
AMEHIC;\N
HEART
JOURNAL
The patients were divided into two groups. In Group 1 there were twenty-one patients with partial heart block without dropped beats, four patients with partial heart block and dropped beats, and four patients with complete heart block. In Group 2 there were sixteen patients with partial heart block without dropped beats, four with partial heart block with dropped beats, and two with complete heart block. There were eight patients in each group who were receiving digitalis at the time of this stud>- and of these only one was considered to be definitely intoxicated with the drug. Those patients with partial heart block with dropped beats and those with complete heart block are referred to in Tables 1V and V. In Group 1 a control electrocardiogram was taken and 2.0 to 3.0 11~~:.of sterile atropine sulfate solution were injected intravenously. (One child, 6 years of age, was given 0.8 milligram.) Electrocardiograms were repeated at various intervals. However, since the maximum effect occurred generally at twenty minutes, records taken at this interval were selected for comparison with the control. In Group 2 a control electrocardiogram was taken, and the patient was allowed to breathe pure oxygen through a standard Benedict-Roth basal metabolism machine for five minutes. The electrocardiogram was repeated while the patient was still breathing pure oxygen. The oxygen was discontinued, and the needle of a syringe containing 2.0 mg. of sterile atropine sulfate solution was inserted into an arm vein and fixed in place by adhesive tape. The patient then was given a subcutaneous injection of 20 to 2.5 mg. of Mecholyl, and the electrocardiogram was repeated after an interval of three minutes. As soon as the electrocardiogram was completed, the atropine solution \vas iIljectec1 and the final record was taken twenty minutes later. When the P-R interval varied in any single record, the variation is shown The control in the table, and the mean is used for comparative purposes. record was used for comparison with those records taken after administration of the various drugs. Although it is realized that a P-R interval of 0.21 or even 0.22 second may be normal for some individuals, we have included these instances in this study under the diagnosis of no demonstrable heart disease when such delay was the onl!- manifest abnormalit>. present.
The results in the patients of Group 1 who showed partial heart block without dropped beats are summarized in Table III. Following the injection of atropine, the mean shortening of the P-R interval was 0.044 second, with a range 0.00 to 0.11 second. The mean increase in the cardiac rate was 28.1 There was no beats per minute, with a range of -4 to +82 beats per minute. strict correlation between the increase in rate and the shortening of the P-R interval. In one of the patients in this group blocked premature auricularbeats Among t hestb patients with partial appeared as the auricular rate increased. heart block without dropped beats, 52.4 per cent showed a return of the P-R interval to normal; 38.1 per cent showed a reduction of the P-R interval; and 9.5 per cent showed no change.
17 18 19 20 21 ___
2
1-l
12 13
::
9
l3
ii
::
1 2
CAST: SO.
111.
‘1‘HE
lung
DISEASE DIAGXOSIS
Rheumatic, inactive Rheumatic, inactive Rheumatic, inactive Arteriosclerotic Hypertensive Dystrophia myotonica Dystrophia myotonica Rheumati?, active Hypertenstve and cystic Hypertensive None demonstrable Hypertensive Hypertensive Peptic ulcer Arthritis Arteriosclerotic Arteriosclerotic Hypertensive Bronchiectasis Rheumatic, active Arteriosclerotic
TYPE OF HEART ASSOCIATED
~1‘ABLI’.
disease
OR
~WIKT
1 1
1 0.21 0.32 0.24 0.24 0.28 0.22 0.26 0.23 0.2-l 0.27 0.26.-0.28 y~-o."
0.28 0.28
P-R ISTERVAL BEFORE ;\TROPI?;E (SEC.)
OF .jTROPISI:. PARTIAL
OS HURT
1
I
i I
67 72
:::
63 70
72
62
z 2 58
63 70 80 12 83 68 62 76
I
0.2i 0.16 0.19 0.14-0.28
0.16
0.20 0.28 0.24 0.20 0.20 0.21 0.23 0.22 0.18 0.24 0.22 0.20 0.22 0.18 0.20 0.18
P-R ISTERVAL AFTER ATROPINE (SEC.)
KATE ASI) ~LXA’I’IOS \~FITHO~-T DROPPED
VESTRICI’LAR RATE BEFORE ATROPIKE
BLOCK
HEAKT ISTER\-AL
90*
115
72 111
80
9s 92 80 103 79 58 93 78 84 138 102 100 90 58 72
145
I.AR RATE AFTER ATROPISb
UP P-I< BEATS
I’A’I’IEXTS
0.015 0.07
0.11
0.02 0.02 0.00 0.02 0.06 0.08 0.02 0.04 0.06 0.04 0.06 0.0s 0.08 0.03
0.08 0.00 0.04 0.04
SHORTESING OF P-R ISTERVAI. (SEC.)
IS
’
-2 +37 +48 f18
+10
+9
+17 +1-l $22 +76 +24 t25 +18
+11 -4
0
+a2 +25 i-12 +38 +21
CHANGE IN VENTRICULAR RATE
\\~r’m
-
I>IGITALII
F .i. x x
‘fhe effects of atropine on foul patients not included in the figures just cited are summarized in Table I\,?. Two of these four had partial heart block with dropped beats; after atropine, one patient with a 2:l A-V ratio showed an increase in the cardiac rate without a change in the P-R interval and tht other showed a decrease in the P-R interval and the number of dropped beats, In one patient with frequent areas of sinoauricular block and nodal escape, as well as partial heart block, the sinoauricular block was abolished by atropine without an effect on the P-R interval. In one patient with partial heart block and a shifting pacemaker, nodal rhythm was produced by atropine. Atropine had no effect on the A-L: conduction time in four cases of complete heart block in this group. The effect on the auricular and ventricular rates is shown in Table 1,‘. The results in the patients comprising Group 2 who exhibited partial heart block without dropped beats are summarized in Table VI. The average change in the cardiac rate after oxygen was breathed for five minutes was less than one beat per minute, and there was no change in the P-R interval. Therefore, these results are omitted from the table. The mean change in the P-R interval after the injection of 20 to 2.5 mg. of Mecholyl subcutaneously was a decrease of 0.032 second with a range of +0.03 second to -0.14 second. The mean increase in the auricular rate was 25.7 beats per minute with a range of -1 to +SO beats per minute, and the mean increase in the ventricular rate was 20.3 beats per minute with a range of -42 to f50 beats per minute. In two patients with active rheumatic fever, A-\’ dissociation was produced in one and a 2:l heart block in the other. The P-R interval was slightly increased in a third patient with no demonstrable heart disease. In this group the P-R interval returned to normal after Mecholyl in 37.5 per cent of the patients; decreased, but not to normal, in 31.3 per cent: increased in 25.0 per cent; and was unchanged in 6.2 per cent. The mean change in the P-R interval in the patients comprising Group 2 after the injection of 2.0 mg. of atropine sulfate, which was given intravenousl\ shortly after Mecholyl had been administered, was a decrease of 0.061 second with a range of 0.00 to -0.13 second. The mean increase in cardiac rate was 25.3 beats per minute with a range of -2 to +.52 beats per minute. In two patients in whom A-V dissociation and 2:l block had occurred following the injection of Mecholyl, 1:l rhythm was restored after atropine, and the P-R interval either returned to the previous control level or was shortened. Following the injection of atropine, the P-K interval returned to normal in 62.5 per cent of the patients; decreased, but not to normal, in 25 per cent: and was unchanged in 12.5 per cent. Four patients with partial heart block and dropped beats were given Mecholyl, and atropine, in that order. The results are given in Table oxygen, VII. In no instance did Mecholyl abolish dropped beats. However, in two patients the dropped beats were abolished by atropine, and the P-R interval shortened to normal or just beyond normal limits.
-~..
-
___--
Arleriosclerotic Hypertensive Arteriosclerotic
Hypertensive
---~--
-..
TYPE OF HEART DISEXSI:
__
EwbzCI
/i
1
0.24 0.2ot
i
* .Z6
I.I.AK
ii 36
40 --
rsc:ape.
by atropine.
!
abolished
0.24 ~(I<-P) 0.14
0.19 0.23
(
sinoaurirular
::,
IO-I 78
block.
52 75 82 60
VI<& TRICULAR RATE
Ii.4~17 AND DURATION OF TIIE I’-I< RLOCK WITH I~ROPPRD REATS
Atropine
HEART HURT
‘TRICULAR
0s PARTIAL
nodal
01; .1TRoImli
0.19 o.15-o.36
ISTBK\-AL
‘I‘HII
*This patient showed simauricular block \tith tShifting pacemaker changed to nodal rhythm
i 3 4
CASE so.
‘l‘.AHI.t< 11..
0.00 -0.025 l 0.00
I
I
, CIIhSGE i IN P-R ~ INTERVAL (SEC.) ~
I-‘aTItrxTs
+I2 +20 +47 +24
CHANGE IN VENTRICULAR j RATE
Is
ISTEKVAL
\YITH
No Yes
K 4
”
c %
16
15
:"7 14
11
demonstrable
I
appeared after
Hypertensive Rheumatic, inactiv-c with subacute bacterial endocarditis
1
~
i
/
Mecholyl: atropiw
0.23
0.23 0.29 0.26. 0.32 0.21
Rheumatic, active None demonstrable Hypertensive
0.23 0.24 0.210.24 0.33
0.2% 0.32 0.22 0.28
demonstrable
active
I Cardiac enlargement : undiagnosed
Sone
Hypertensive Rheumatic, i\rteriosclerotic
-!
follo\rilig rmtowd
110
60
112 92 72
y”;
88
66
90 100 71
76 64
110
74
LBR RATE
: ;
\-AL (SEC.)
YES-
/ TRICI:-
i
IXTER-
P-R
.1I 0.220.20 ~ 0.24 0.36 0.24
after Mwholyl’
OF HEART DISE.4SE OR ASSOCIATED DIAGNOSIS
Rheumatic, active Rheumatic, active None demonstrable
None
TYPE
*A-V dissociation t2:l block appeared
10
9
C.\SE s-0.
COSTROL
P-K
0.20. 0.19 * 0.22 0.26. 0.28 0.22 0.20
\'AL (SEC.)
;
0.28. 0.32 0.24 0.24
1
1 I
136
86
140 100
140
1;:
loo
112
112 70
140
113 94 92
120
AURICULAR RATE
atropine, sinus sinus rhythm.
0 20
0.18
: 0.26 ~ 0.20 0.20
I
0.21 0.24
I I 0.20- !
I ~
!
~ INTER-
/
rhythm
~
~
!
:
~
/
,
DROPPED
was
136
86
100
70 140
90 108
100
112
140 56 70
97 94 92
120
TRICULAR RATE
VEX-
restored
-0.03
-0.03
+0.03 -0.09 -0.09
+0.02 -0.04
-0.09
-0.01 -0.04 -0.02
0
-0.14 +o 03
-0.015
P-R INTERVAL (SEC.)
i CHANGE t IN
MF:CHOLPL
WITHOUT
AFTER
PAKTIAL HEART BLOCK
+26
f26
-42t +48 +28
i-22 +16
+12
+46
-1
+50 f12
-13* f18 +28
+jO
CHANGE IN VEP\TTRICULAR RATE
BEATS ___.
; i
0.170.19
0.12
0.22 0.19 0.16
0.18
0.200.22 0.22. 0.24 0.18 0.16.
0.20 0.16 0.20
0.200.19 0.24 0.24 0.24
P-R INTRRVAL (SEC.)
-
i
122
84
110 128 94
100 i43
118
95
112 74
142
120 115 90’
102
LAR R;ZTE
AFTER
-0.12
-0
-0.09
-0.01 -0.10 -0.13
-0.04 -0.11
/ -0.07
I -0.12
!1 r”,::;!
~ -0.03
;
5
:
I
05 !
0
0
/ -O.OlS(
(SEC.) :
CHANGE IN P-R / INTERj VAL
ATROPINE
f12
i-24
- 2 +37 +22
+32 +51
+30
+29
+52 +12 +3
+10 +39 +26
+28
CHANGE IN VEXTRICL LAR RATE
b-0
Ye5
NO NO NO
Yes
No
No
NO
NO
Yes Yes
No
DIGITALIS
‘-
5 i 7
c
i %
z ;;:
> z c7
X
C.4SE NO.
CASE SO.
TABLE
I
TYPE OF HEART DISEASE
TABLE
Iypertensive
Iyptensive
Iypertensive
/ P-R ~ INTERVAL (SEC.)
EFFECT
1 0.20i 0.32 0.200.24 0.180.26 0.20
76
80
90
AURICi ULAR ) RATE I
)
CONTROL
0.160.30 0.20
P-R INTERVAL (SEC.)
P-R ~ INTERj VAL i (SEC.) /
I
1 1 AURICULAR
AND DURATIOX
2HANGE IN P-R INTERVAL (SEC.)
~
1 ,
3
’
52
AURICULAR RATE
15
i TRICU] LAR I RATE
CHAXGE
I
0.19
1 VAL / (SEC.)
/
~ 106
86
(
140
ULAR RATE
Iu I’ATIESTS
0.20
!
i;
I ~
I-
HEART
70
1 LAR i RATE
AFTER
0.01
: INTER1 v.4L i (SEC.)
CHANGE
ATROPIXE
I j
IrEART
0 i
BLOCK
30
6
34
25
4x
72
DROPPED
15
46
)
30
25
IN VENTRICULAR R.4TE
‘( !HAh%E
’
--28
46
CHANGE IN VENTRICULAR RATE
~~~~~___-
\%??a
AURICULAR RATE
BLOCK
0.0%’
I -0.02
! -0.0651
COMPLETE
.53
86
62
90
.4FTER ATROPIhE
PARTIAL
WITH
WITH
I 90 ’ ~ 124
IN P.4TIESTS
0.200.21 -19 1, 0.20 I 38jO.20’
15
CHANGE IN VENTRICULAR RATE
Ix~~Rv.41,
OF P-R INTERVAL ~-~~~~-~
-14
0)
~18
35
CHANGE IN AURICULAR RATE
OF P-B
AND DURATION ~~~~~
-4.02
a.03
CHANGE IN P-R INTERVAL (SEC.)
AFTER MECHOLYL
BATE
70
60
; VEX~ TRICU~ LAR R.4TE
~
1
I
VENTRICU) LAR / RATE
AFTER MECHOLYL
BATE
ON HEART ~~__.._~
72
100
AURICULAR RATE
ON HEART
AND ATROPINE
38
40
VENTRICULAR RATE
YEN; TRICU1 LAR ; RATE
OF RIECHOLTL
1
1
65
AURICULAR RATE
COSTRGL
OF ~fl~EC!HOLYI, ASD ATROPISE
P-R INTERVAL (SEC.)
EFFECT
VIII.
TYPE OF HEART DISEASE
THE
iypertensive
VII.
!
:
;
/
I
se
SQ
Ia,:T.il.i-
5,,
‘I-*,
ss.
1-c.
DIGITALI-
BEAT:
740
\\IP:KI(‘.\N
III~:.\I:‘I‘
JOtlKN;\I
()sq~ge~l, lUec~liol~~1. .tnti ,ltropine. administered in that sequence. had no eft’ect on one l)atient with completr heart block other than an increase in both auricular and ventricular rates after atropine. In a second patient with A-\’ dissociation, 2:l block occurred after the administration of oxygen and rcmained after the administration of both NTecholyl and atropine. These results ;lt-e shown in Table VII 1. There was no predictable relationship between the reaction to atropine or Mecholyl and the presence or absence of digitalis in either group. One patient in Group 2 who was thought to be intoxicated with digitalis (Case 3, Table VII) showed slight prolongation of the P-R interval with a decrease in the number of dropped beats after YTecholyl, and a 1:l response with a normal P-R interval after atropine. The blood pressure was recorded in about one-half of the patients in Group 2, and in general there was a drop after the injection of Mecholyl with an immediate rise after atropine followed by a gradual fall to the previous control level at the end of fifteen minutes. No serious reactions were observed to follow the administration of any oi these drugs under the conditions of these experiments. One patient complained of discomfort because of tachycardia following the injection of atropine and several noted dizziness or slight drowsiness. The majority of the patients who received Mecholyl noted temporary discomfort consisting of sweating, increased salivation, tightness in the chest, and dyspnea. In no case did the chest symptoms suggest coronary insufficiency, and in no case did the electrocardiogram show depression of the RS-T segment consistent with coronary insufficiency. In each instance the unpleasant- symptoms from Mecholyl were abolished within sixty seconds by the intravenous injection of atropine. The effects of atropinc generalI>, were dissipated at the end of two hours. I)ISCUSSION
In this study the mean shortening of the P-R interval after the administration of atropine to unselected patients with partial heart block was found to be of similar magnitude to that reported by Keith” and by Robinson,R who studied patients with rheumatic fever, but not so great as that reported b,Bruenn.’ Our results in general confirm the findings of Logue and Hanson’ that atropine will shorten to normal, or significantly reduce the P-R interval in a majority of unselected cases of partial heart block, regardless of the etiolog) or the associated disease. .Yn atropine test, therefore, is of little value in differentiating between heart block of neurogenic origin and that due to myocardial disease. The effects of Mecholyl and atropine, when given in this sequence, upon t-he cardiac rate and the blood pressure were fmnd to agree in general with those observed by Dameshek, I,oman, and Myerson.” Following the administration of Mecholyl, if atropine is given intravenously at the time of the fall in blood pressure, there is a prompt, sharp, and sudden rise in blood pressure above the previous normal level. This suggests that when the action of
XIt’SstIK
1.x
.\I..:
\~.\(;.\I. .\(“l-I\‘lTY
.\NI) II I<.\KT til.O(‘t;
7‘41
Mecholyl is abolished bq. atropillc thrrtb is it r&s twsso~- responw froI1k atI itIfall in blood pressure. c’rease in circulating adrenalin as ;I resiilt of t tw irlitial In favor of this view is the fact that when atropine leas given prior to Mecholyl to four normal subjects there was no sign&cant fall in blood pressure initiall>The pressor response, therefore, is and no secondaryrise in blood pressure. probabl>. of the same nature as that occurring during the histamine test folpheochromocytoma suggested b\. Roth and k-vale” l)ut differs veq. greatly in magnitude. We found the change in the P-R interval which followed the injection of Mecholyl to be unpredictable, in contradistinction to the findings of Dameshek, I.oman, and Myerson.” These authors, using normal individuals, noted an increase in A-V conduction time in almost every instance, while it was observed by us that in patients with partial heart block without dropped beats, \vell over one-half showed a decrease, and onI>. one-fourth showed a definite increase in the P-R interval. Acetylcholine in large dosage has been shown b,. Hoffmann and associates’” and b,- McDowall” to produce a stimulating effect on the atropinized heart but not on the unatropinized heart in isolated perfusion experiments. 12:hile the results of heart-lung experiments cannot be applied directl?. to human pharmacology, they do suggest the complex nature of the problem. The paradoxical effects of Mecholyl on cardiac rate and -4-V conduction time in the human subject indicate that the magnitude of the various side effects of the drug, unrelated to its direct action on the m\roneural junction, often ma)’ be as great as the vagomimetic effect. The unpredictable effect of Mechol\.l on A-V conduction time in patients with partial heart block suggests that this drug is of no value in evaluating the part played by vagal activity in unselected cases of heart bloc-k. It is apparent from our observations that heart block, per se, does not contraindicate thr use of Mecholyl. These results clo not preclude the possibilit), that the action of these drugs on A-Y conduction time is related to changes in coronary blood flow. Although we produced no significant change b>. having the patients breathe pure ox>.gen, this does not eliminate the possibilit)that changes in the caliber of the vessels supplying the conducting tissues ma)- be of importance. \\‘edd,‘? Essex and associates,‘” and Katz and Lindner ‘I have shown that Mecholvl increases the coronary blood flow. The effects of atropine on coronar!’ bltrntl flow are some\vhat conflicting. Essex and co-workers’:’ found atropine to increase coronar!. blood flow, while Katz and I,indner’-’ observed a weak vasoconstrictor effect on the coronary arteries. HalseyI; noted that partial heart block assocGted with digitalis intoxication in the dog could b(. reduced signiticantl>. 1~1, amyl nitrite but believed this to be due to a lessened vagal effect as a result of a drop in blood pressure. It should be pointed out, however, that large doses of digitalis in the dog cause constriction oi the c-oronar). vessels. The results of our observations on the response 0i human subjects to atrol)ine. Mecholyl, and oxygen do not serve to delineate the physiologic mechanisms illvolved in the production of heart block. These drugs do not determine whether
l;ift>--one cases of heart block associated with various etiological factors were studied electrocardiographicall]. for changes in the P-K interval after the administration of atropine. In twenty-two of these cases the effects of oxygen and Mecholyl were analyzed and the results comparecl. Both atropine and MecholJ4 were found to decrease the P-K interval in a majority of these cases, but atropine proved the more effective drug. It is concluded that atropine, Mecholyl, and osygen are of no value in determining either the etiology of heart block or the underlying physiologic mechanisms in human subjects. KEFEKENCES 1.
Bruenn,
2.
Keith,
H. G.: The Mechanism of Impaired Auriculoventricular RheumaticFever, AM. HEART J.13:413, 1937. J.: Over-stimulation of the Vagus Serve in Rheumafic 7139
3. 1. 5. 6.
7. 8. 9.
Conduction Fever,
in
Quart,
J.
-\ct~tc Med.
1938
Robinson, R. W.: Effect of Atropine Upon the Prolongation of the P-R Interval Found in Acute Rheumatic Fever and Certain L’aeotonic Persons. AM. HEART 1. 29:378. 1945. Logue, R. B., and Hanson, J. F.: Heart Block: A Study of 100 Cases \I;ith Prolonged P-R Interval, Am. J. M. Sc. 207:765, 1944. Logue, R. B., and Hanson, J. F.: Complete Heart Block in German Measles, AM. HEART J.30:205, 1945. Dameshek, W., Loman, J., and Myerson, X.: Human Xlltonomic Pharmacology. VII. The Effect on the Yormal Cardiovascular System of Acetyl-Beta-Methylcholine Chloride, Atropine, Prostigmin, Benzedrine-With Especial Reference to the Electrocardiogram! Am. J. M. SC. 195:88, 1938. Lewis. T.. and Mathlson. G. C.: f\uriculo-Ventricular Heart-Block as a Result of Asphyxia. - ~ ‘Heart 2:47, 1910. Lewis, T., Drury, A. r\;., and Iliescu, C. C.: Some Observations Upon Atropine and Strophanthin, Heart 9:21, 1921. Roth, G. M., and Kvale, W. F.: A Tentative Test for Pheochromocytoma, Xm. J. M. SC.
210:653, 1945. 10. 11.
Hoffmann, F., Hoffmann, E. J., Middleton, S., and Talesnik, J.: The Stimulating Effect of Acetylcholine on the Mammalian Heart and the Liberation of an Epinephrine-like Substance by the Isolated Heart, Am. J. Physiol. 144:189, 1945. McDowall. R. J. S.: The Stimulating Action of Acetylcholine on the Heart, J. Physiol.
12.
LI’edd,
104:392, 1946. 13. 11. 15.
A. M.: The Action of Certain Choline Derivatives on macol. & Exper. Therap. 57:179,, 1936. Essex, H. E., W&gria, R. G. E., Herrlck, J. F., and Mann, F. DruPs on the Coronarv Blood Flow of the Trained Dog. Katz, L. NY., and Lindner, I?.: The Reaction of the Coronarv Substances, J. A. M. A. 113:2116, 1939. Halsey, J. T.: The Digitalized Dog’s Heart as Affected by Studied Electrocardiographically, J. Exper. Med. 25:729,
the Coronary
Flow,
J. Phar-
C.: The Effect of Certain ,qM. HEART I. 19654, 1940. Vessels to ljrugs and Other Amy1 1917.
Nitrite
or r\tropinc,
lI\‘FI,TJEN(‘E
ADDISON
OF \‘AG\l,
.\~“l‘IVI’I’Y
OK
HEART
I,. &IESSEK, M.D., ~HAKlzES K. hNEC;AN, .\KD ELIWARDS. ORWIN, M.D. DC'KH.lM,
s.
BI,O(‘K
h/l.D.,
(‘.
T
HE reports of Bruenn,’ Keith,” and Robinson” have shown clearly that large doses of atropine will shorten the P-R interval in a majority of the cases of partial heart block associated with acute rheumatic fever, as well as in certain vagotonic individuals. The findings of Logue and Hanson4j” indicated that this effect is not specific for acute rheumatic fever. The last named authors studied thirty-eight indivitlt.als with prolonged P-R intervals associated with various diagnoses and found that twenty-five (65 per cent) showed a return of the P-R interval to normal after administration of 0.96 mg-. of atropine sulfate intravenously. There was no correlation between the clinical diagnosis and the effectiveness of atropine; however, it is of interest that in this group seven patients with rheumatic fever showed a return of the P-R interval to normal while six did not. The reduction of the P-K interval in a control group was found by Bruenn’ and Keith2 to be less than that in rheumatic subjects with prolonged P-R intervals. This is due very probably to the fact that in normal individuals the P-R interval is closer to the minimum possible conduction time; hence, less shortening is possible. Bruennl has interpreted these results to indicate that an increased vagal tone exists in acute rheumatic fever and has suggested that the site of the lesion may be in the central nervous system, probably in the medulla. Robinson” concurred in the opinion that an increased vagal tone exists in acute rheumatic fever with partial heart block. However, Logue and Hanson4 felt that the effect of atropine did not preclude a pathologic change either in the heart muscle or in the conduction system and that the change in vagal tone might be due to altered physiology at the myoneural junction. Dameshek, Loman, and Myerson li found that the P-R interval increased in almost every instance in normal individuals following the administration of Mecholyl. The maximum effect occurred within two to four minutes and the average percentage increase was 46 per cent. This was abolished within thirty to sixty seconds after t.he intravenous injection of atropine. That heart block of all gracles, including complete heart- block, may bc produced by asphyxia and succeeded by recovery, independent of vagus a(.Persistent hear 1 tivity, was shown experimentally by Lewis and Mathison.’ block of a high grade is generally considered to be due to intrinsic heart disease Prom the DeparLmnnt Durham, N. C.
of
Medicine,
Duke
University 732
Rtzhool
of
Medicine
and
Duke
Hospital,
MESSEK
ET
AL.:
VAGAL
ACTIVITY
AND
HEART
733
BLOCK
and temporary or transient block to be of vagal origin.‘,” When heart block responds to atropine, the question arises as to whether the reduction in conduction time is due to the abolition of an increased primary central neurogenic effect or to a normal neurogenic effect upon a heart rendered more susceptible to vagal influence by some metabolic alteration in the conduction system, at the myoneural junction, or in the myocardium. The present study was undertaken to investigate the effect of vagal activity on unselected cases of heart block. In addition to the effect of atropine, the effects of breathing 100 per cent oxygen and of the subcutaneous injection of acetyl-beta-methylcholine chloride (Mecholyl) on patients with heart block were studied. METHOD
OF STUDY
The subjects used in this study were fifty-one unselected patients from the wards and outpatient clinics of Duke Hospital whose electrocardiograms revealed a P-R interval of 0.21 second or over manifested in all leads, or higher degrees of heart block. No attempt was made to select the patients with regard to age, general condition, or diagnosis. The distribution of the patients according to age is shown in Table I, and the associated diagnoses are listed in Table II. Mecholyl was not administered to patients with a history of asthma or pulmonary disease. .rAtlLE __..-
/ AGE (YEBRS)
o--
PATIENTS ATROPINE
9
) 1 ~ ! 1 1 I
Total
‘rABl& ;.
T\iPI’
OF HIiART
II.
r\GE ~~IS1‘RIBUTION OF PATIEXTS .~ ~__--.~__ - -I
I
1
IO-19 ‘O-29 30--39 40-49 50-59 60-69 70-79 80-89
1.
RECEIVING ALONE
Nonedemonstrable Hypertensive Arteriosclerotic Rheumatic,active Rheumatic,inactive Congenital Undiagnosed -‘Total
,
TOTAL NUMBER OF PATIEXTS IN SERII’S
1
n
1 5
:
4 6
:: 5 7 2 2
ii
29
22
C.4RDIOvASCULAR __..-
UISEASE
PATIENTS RECBIVIKG OXYGEN, ATROPINE, AND MECHoLyI.
PATIENTS ATROPINE
9 6 8 8 10 2 2
i 3 3 I
L)IAG~~SI’.S
RECEIVING ALONE
OF PATIEKTS
5I COMPOSING
GROUPS
1 AND
2
i PATIENTS RECEIVING OXYGEN, ATROPINE, AND MECHOLYI,
. -__-__.
29
I
I 5 ! 1 I
22
.-___----
t1 1x 7 7 0 I 1 51
.__..._
734
AMEHIC;\N
HEART
JOURNAL
The patients were divided into two groups. In Group 1 there were twenty-one patients with partial heart block without dropped beats, four patients with partial heart block and dropped beats, and four patients with complete heart block. In Group 2 there were sixteen patients with partial heart block without dropped beats, four with partial heart block with dropped beats, and two with complete heart block. There were eight patients in each group who were receiving digitalis at the time of this stud>- and of these only one was considered to be definitely intoxicated with the drug. Those patients with partial heart block with dropped beats and those with complete heart block are referred to in Tables 1V and V. In Group 1 a control electrocardiogram was taken and 2.0 to 3.0 11~~:.of sterile atropine sulfate solution were injected intravenously. (One child, 6 years of age, was given 0.8 milligram.) Electrocardiograms were repeated at various intervals. However, since the maximum effect occurred generally at twenty minutes, records taken at this interval were selected for comparison with the control. In Group 2 a control electrocardiogram was taken, and the patient was allowed to breathe pure oxygen through a standard Benedict-Roth basal metabolism machine for five minutes. The electrocardiogram was repeated while the patient was still breathing pure oxygen. The oxygen was discontinued, and the needle of a syringe containing 2.0 mg. of sterile atropine sulfate solution was inserted into an arm vein and fixed in place by adhesive tape. The patient then was given a subcutaneous injection of 20 to 2.5 mg. of Mecholyl, and the electrocardiogram was repeated after an interval of three minutes. As soon as the electrocardiogram was completed, the atropine solution \vas iIljectec1 and the final record was taken twenty minutes later. When the P-R interval varied in any single record, the variation is shown The control in the table, and the mean is used for comparative purposes. record was used for comparison with those records taken after administration of the various drugs. Although it is realized that a P-R interval of 0.21 or even 0.22 second may be normal for some individuals, we have included these instances in this study under the diagnosis of no demonstrable heart disease when such delay was the onl!- manifest abnormalit>. present.
The results in the patients of Group 1 who showed partial heart block without dropped beats are summarized in Table III. Following the injection of atropine, the mean shortening of the P-R interval was 0.044 second, with a range 0.00 to 0.11 second. The mean increase in the cardiac rate was 28.1 There was no beats per minute, with a range of -4 to +82 beats per minute. strict correlation between the increase in rate and the shortening of the P-R interval. In one of the patients in this group blocked premature auricularbeats Among t hestb patients with partial appeared as the auricular rate increased. heart block without dropped beats, 52.4 per cent showed a return of the P-R interval to normal; 38.1 per cent showed a reduction of the P-R interval; and 9.5 per cent showed no change.
17 18 19 20 21 ___
2
1-l
12 13
::
9
l3
ii
::
1 2
CAST: SO.
111.
‘1‘HE
lung
DISEASE DIAGXOSIS
Rheumatic, inactive Rheumatic, inactive Rheumatic, inactive Arteriosclerotic Hypertensive Dystrophia myotonica Dystrophia myotonica Rheumati?, active Hypertenstve and cystic Hypertensive None demonstrable Hypertensive Hypertensive Peptic ulcer Arthritis Arteriosclerotic Arteriosclerotic Hypertensive Bronchiectasis Rheumatic, active Arteriosclerotic
TYPE OF HEART ASSOCIATED
~1‘ABLI’.
disease
OR
~WIKT
1 1
1 0.21 0.32 0.24 0.24 0.28 0.22 0.26 0.23 0.2-l 0.27 0.26.-0.28 y~-o."
0.28 0.28
P-R ISTERVAL BEFORE ;\TROPI?;E (SEC.)
OF .jTROPISI:. PARTIAL
OS HURT
1
I
i I
67 72
:::
63 70
72
62
z 2 58
63 70 80 12 83 68 62 76
I
0.2i 0.16 0.19 0.14-0.28
0.16
0.20 0.28 0.24 0.20 0.20 0.21 0.23 0.22 0.18 0.24 0.22 0.20 0.22 0.18 0.20 0.18
P-R ISTERVAL AFTER ATROPINE (SEC.)
KATE ASI) ~LXA’I’IOS \~FITHO~-T DROPPED
VESTRICI’LAR RATE BEFORE ATROPIKE
BLOCK
HEAKT ISTER\-AL
90*
115
72 111
80
9s 92 80 103 79 58 93 78 84 138 102 100 90 58 72
145
I.AR RATE AFTER ATROPISb
UP P-I< BEATS
I’A’I’IEXTS
0.015 0.07
0.11
0.02 0.02 0.00 0.02 0.06 0.08 0.02 0.04 0.06 0.04 0.06 0.0s 0.08 0.03
0.08 0.00 0.04 0.04
SHORTESING OF P-R ISTERVAI. (SEC.)
IS
’
-2 +37 +48 f18
+10
+9
+17 +1-l $22 +76 +24 t25 +18
+11 -4
0
+a2 +25 i-12 +38 +21
CHANGE IN VENTRICULAR RATE
\\~r’m
-
I>IGITALII
F .i. x x
‘fhe effects of atropine on foul patients not included in the figures just cited are summarized in Table I\,?. Two of these four had partial heart block with dropped beats; after atropine, one patient with a 2:l A-V ratio showed an increase in the cardiac rate without a change in the P-R interval and tht other showed a decrease in the P-R interval and the number of dropped beats, In one patient with frequent areas of sinoauricular block and nodal escape, as well as partial heart block, the sinoauricular block was abolished by atropine without an effect on the P-R interval. In one patient with partial heart block and a shifting pacemaker, nodal rhythm was produced by atropine. Atropine had no effect on the A-L: conduction time in four cases of complete heart block in this group. The effect on the auricular and ventricular rates is shown in Table 1,‘. The results in the patients comprising Group 2 who exhibited partial heart block without dropped beats are summarized in Table VI. The average change in the cardiac rate after oxygen was breathed for five minutes was less than one beat per minute, and there was no change in the P-R interval. Therefore, these results are omitted from the table. The mean change in the P-R interval after the injection of 20 to 2.5 mg. of Mecholyl subcutaneously was a decrease of 0.032 second with a range of +0.03 second to -0.14 second. The mean increase in the auricular rate was 25.7 beats per minute with a range of -1 to +SO beats per minute, and the mean increase in the ventricular rate was 20.3 beats per minute with a range of -42 to f50 beats per minute. In two patients with active rheumatic fever, A-\’ dissociation was produced in one and a 2:l heart block in the other. The P-R interval was slightly increased in a third patient with no demonstrable heart disease. In this group the P-R interval returned to normal after Mecholyl in 37.5 per cent of the patients; decreased, but not to normal, in 31.3 per cent: increased in 25.0 per cent; and was unchanged in 6.2 per cent. The mean change in the P-R interval in the patients comprising Group 2 after the injection of 2.0 mg. of atropine sulfate, which was given intravenousl\ shortly after Mecholyl had been administered, was a decrease of 0.061 second with a range of 0.00 to -0.13 second. The mean increase in cardiac rate was 25.3 beats per minute with a range of -2 to +.52 beats per minute. In two patients in whom A-V dissociation and 2:l block had occurred following the injection of Mecholyl, 1:l rhythm was restored after atropine, and the P-R interval either returned to the previous control level or was shortened. Following the injection of atropine, the P-K interval returned to normal in 62.5 per cent of the patients; decreased, but not to normal, in 25 per cent: and was unchanged in 12.5 per cent. Four patients with partial heart block and dropped beats were given Mecholyl, and atropine, in that order. The results are given in Table oxygen, VII. In no instance did Mecholyl abolish dropped beats. However, in two patients the dropped beats were abolished by atropine, and the P-R interval shortened to normal or just beyond normal limits.
-~..
-
___--
Arleriosclerotic Hypertensive Arteriosclerotic
Hypertensive
---~--
-..
TYPE OF HEART DISEXSI:
__
EwbzCI
/i
1
0.24 0.2ot
i
* .Z6
I.I.AK
ii 36
40 --
rsc:ape.
by atropine.
!
abolished
0.24 ~(I<-P) 0.14
0.19 0.23
(
sinoaurirular
::,
IO-I 78
block.
52 75 82 60
VI<& TRICULAR RATE
Ii.4~17 AND DURATION OF TIIE I’-I< RLOCK WITH I~ROPPRD REATS
Atropine
HEART HURT
‘TRICULAR
0s PARTIAL
nodal
01; .1TRoImli
0.19 o.15-o.36
ISTBK\-AL
‘I‘HII
*This patient showed simauricular block \tith tShifting pacemaker changed to nodal rhythm
i 3 4
CASE so.
‘l‘.AHI.t< 11..
0.00 -0.025 l 0.00
I
I
, CIIhSGE i IN P-R ~ INTERVAL (SEC.) ~
I-‘aTItrxTs
+I2 +20 +47 +24
CHANGE IN VENTRICULAR j RATE
Is
ISTEKVAL
\YITH
No Yes
K 4
”
c %
16
15
:"7 14
11
demonstrable
I
appeared after
Hypertensive Rheumatic, inactiv-c with subacute bacterial endocarditis
1
~
i
/
Mecholyl: atropiw
0.23
0.23 0.29 0.26. 0.32 0.21
Rheumatic, active None demonstrable Hypertensive
0.23 0.24 0.210.24 0.33
0.2% 0.32 0.22 0.28
demonstrable
active
I Cardiac enlargement : undiagnosed
Sone
Hypertensive Rheumatic, i\rteriosclerotic
-!
follo\rilig rmtowd
110
60
112 92 72
y”;
88
66
90 100 71
76 64
110
74
LBR RATE
: ;
\-AL (SEC.)
YES-
/ TRICI:-
i
IXTER-
P-R
.1I 0.220.20 ~ 0.24 0.36 0.24
after Mwholyl’
OF HEART DISE.4SE OR ASSOCIATED DIAGNOSIS
Rheumatic, active Rheumatic, active None demonstrable
None
TYPE
*A-V dissociation t2:l block appeared
10
9
C.\SE s-0.
COSTROL
P-K
0.20. 0.19 * 0.22 0.26. 0.28 0.22 0.20
\'AL (SEC.)
;
0.28. 0.32 0.24 0.24
1
1 I
136
86
140 100
140
1;:
loo
112
112 70
140
113 94 92
120
AURICULAR RATE
atropine, sinus sinus rhythm.
0 20
0.18
: 0.26 ~ 0.20 0.20
I
0.21 0.24
I I 0.20- !
I ~
!
~ INTER-
/
rhythm
~
~
!
:
~
/
,
DROPPED
was
136
86
100
70 140
90 108
100
112
140 56 70
97 94 92
120
TRICULAR RATE
VEX-
restored
-0.03
-0.03
+0.03 -0.09 -0.09
+0.02 -0.04
-0.09
-0.01 -0.04 -0.02
0
-0.14 +o 03
-0.015
P-R INTERVAL (SEC.)
i CHANGE t IN
MF:CHOLPL
WITHOUT
AFTER
PAKTIAL HEART BLOCK
+26
f26
-42t +48 +28
i-22 +16
+12
+46
-1
+50 f12
-13* f18 +28
+jO
CHANGE IN VEP\TTRICULAR RATE
BEATS ___.
; i
0.170.19
0.12
0.22 0.19 0.16
0.18
0.200.22 0.22. 0.24 0.18 0.16.
0.20 0.16 0.20
0.200.19 0.24 0.24 0.24
P-R INTRRVAL (SEC.)
-
i
122
84
110 128 94
100 i43
118
95
112 74
142
120 115 90’
102
LAR R;ZTE
AFTER
-0.12
-0
-0.09
-0.01 -0.10 -0.13
-0.04 -0.11
/ -0.07
I -0.12
!1 r”,::;!
~ -0.03
;
5
:
I
05 !
0
0
/ -O.OlS(
(SEC.) :
CHANGE IN P-R / INTERj VAL
ATROPINE
f12
i-24
- 2 +37 +22
+32 +51
+30
+29
+52 +12 +3
+10 +39 +26
+28
CHANGE IN VEXTRICL LAR RATE
b-0
Ye5
NO NO NO
Yes
No
No
NO
NO
Yes Yes
No
DIGITALIS
‘-
5 i 7
c
i %
z ;;:
> z c7
X
C.4SE NO.
CASE SO.
TABLE
I
TYPE OF HEART DISEASE
TABLE
Iypertensive
Iyptensive
Iypertensive
/ P-R ~ INTERVAL (SEC.)
EFFECT
1 0.20i 0.32 0.200.24 0.180.26 0.20
76
80
90
AURICi ULAR ) RATE I
)
CONTROL
0.160.30 0.20
P-R INTERVAL (SEC.)
P-R ~ INTERj VAL i (SEC.) /
I
1 1 AURICULAR
AND DURATIOX
2HANGE IN P-R INTERVAL (SEC.)
~
1 ,
3
’
52
AURICULAR RATE
15
i TRICU] LAR I RATE
CHAXGE
I
0.19
1 VAL / (SEC.)
/
~ 106
86
(
140
ULAR RATE
Iu I’ATIESTS
0.20
!
i;
I ~
I-
HEART
70
1 LAR i RATE
AFTER
0.01
: INTER1 v.4L i (SEC.)
CHANGE
ATROPIXE
I j
IrEART
0 i
BLOCK
30
6
34
25
4x
72
DROPPED
15
46
)
30
25
IN VENTRICULAR R.4TE
‘( !HAh%E
’
--28
46
CHANGE IN VENTRICULAR RATE
~~~~~___-
\%??a
AURICULAR RATE
BLOCK
0.0%’
I -0.02
! -0.0651
COMPLETE
.53
86
62
90
.4FTER ATROPIhE
PARTIAL
WITH
WITH
I 90 ’ ~ 124
IN P.4TIESTS
0.200.21 -19 1, 0.20 I 38jO.20’
15
CHANGE IN VENTRICULAR RATE
Ix~~Rv.41,
OF P-R INTERVAL ~-~~~~-~
-14
0)
~18
35
CHANGE IN AURICULAR RATE
OF P-B
AND DURATION ~~~~~
-4.02
a.03
CHANGE IN P-R INTERVAL (SEC.)
AFTER MECHOLYL
BATE
70
60
; VEX~ TRICU~ LAR R.4TE
~
1
I
VENTRICU) LAR / RATE
AFTER MECHOLYL
BATE
ON HEART ~~__.._~
72
100
AURICULAR RATE
ON HEART
AND ATROPINE
38
40
VENTRICULAR RATE
YEN; TRICU1 LAR ; RATE
OF RIECHOLTL
1
1
65
AURICULAR RATE
COSTRGL
OF ~fl~EC!HOLYI, ASD ATROPISE
P-R INTERVAL (SEC.)
EFFECT
VIII.
TYPE OF HEART DISEASE
THE
iypertensive
VII.
!
:
;
/
I
se
SQ
Ia,:T.il.i-
5,,
‘I-*,
ss.
1-c.
DIGITALI-
BEAT:
740
\\IP:KI(‘.\N
III~:.\I:‘I‘
JOtlKN;\I
()sq~ge~l, lUec~liol~~1. .tnti ,ltropine. administered in that sequence. had no eft’ect on one l)atient with completr heart block other than an increase in both auricular and ventricular rates after atropine. In a second patient with A-\’ dissociation, 2:l block occurred after the administration of oxygen and rcmained after the administration of both NTecholyl and atropine. These results ;lt-e shown in Table VII 1. There was no predictable relationship between the reaction to atropine or Mecholyl and the presence or absence of digitalis in either group. One patient in Group 2 who was thought to be intoxicated with digitalis (Case 3, Table VII) showed slight prolongation of the P-R interval with a decrease in the number of dropped beats after YTecholyl, and a 1:l response with a normal P-R interval after atropine. The blood pressure was recorded in about one-half of the patients in Group 2, and in general there was a drop after the injection of Mecholyl with an immediate rise after atropine followed by a gradual fall to the previous control level at the end of fifteen minutes. No serious reactions were observed to follow the administration of any oi these drugs under the conditions of these experiments. One patient complained of discomfort because of tachycardia following the injection of atropine and several noted dizziness or slight drowsiness. The majority of the patients who received Mecholyl noted temporary discomfort consisting of sweating, increased salivation, tightness in the chest, and dyspnea. In no case did the chest symptoms suggest coronary insufficiency, and in no case did the electrocardiogram show depression of the RS-T segment consistent with coronary insufficiency. In each instance the unpleasant- symptoms from Mecholyl were abolished within sixty seconds by the intravenous injection of atropine. The effects of atropinc generalI>, were dissipated at the end of two hours. I)ISCUSSION
In this study the mean shortening of the P-R interval after the administration of atropine to unselected patients with partial heart block was found to be of similar magnitude to that reported by Keith” and by Robinson,R who studied patients with rheumatic fever, but not so great as that reported b,Bruenn.’ Our results in general confirm the findings of Logue and Hanson’ that atropine will shorten to normal, or significantly reduce the P-R interval in a majority of unselected cases of partial heart block, regardless of the etiolog) or the associated disease. .Yn atropine test, therefore, is of little value in differentiating between heart block of neurogenic origin and that due to myocardial disease. The effects of Mecholyl and atropine, when given in this sequence, upon t-he cardiac rate and the blood pressure were fmnd to agree in general with those observed by Dameshek, I,oman, and Myerson.” Following the administration of Mecholyl, if atropine is given intravenously at the time of the fall in blood pressure, there is a prompt, sharp, and sudden rise in blood pressure above the previous normal level. This suggests that when the action of
XIt’SstIK
1.x
.\I..:
\~.\(;.\I. .\(“l-I\‘lTY
.\NI) II I<.\KT til.O(‘t;
7‘41
Mecholyl is abolished bq. atropillc thrrtb is it r&s twsso~- responw froI1k atI itIfall in blood pressure. c’rease in circulating adrenalin as ;I resiilt of t tw irlitial In favor of this view is the fact that when atropine leas given prior to Mecholyl to four normal subjects there was no sign&cant fall in blood pressure initiall>The pressor response, therefore, is and no secondaryrise in blood pressure. probabl>. of the same nature as that occurring during the histamine test folpheochromocytoma suggested b\. Roth and k-vale” l)ut differs veq. greatly in magnitude. We found the change in the P-R interval which followed the injection of Mecholyl to be unpredictable, in contradistinction to the findings of Dameshek, I.oman, and Myerson.” These authors, using normal individuals, noted an increase in A-V conduction time in almost every instance, while it was observed by us that in patients with partial heart block without dropped beats, \vell over one-half showed a decrease, and onI>. one-fourth showed a definite increase in the P-R interval. Acetylcholine in large dosage has been shown b,. Hoffmann and associates’” and b,- McDowall” to produce a stimulating effect on the atropinized heart but not on the unatropinized heart in isolated perfusion experiments. 12:hile the results of heart-lung experiments cannot be applied directl?. to human pharmacology, they do suggest the complex nature of the problem. The paradoxical effects of Mecholyl on cardiac rate and -4-V conduction time in the human subject indicate that the magnitude of the various side effects of the drug, unrelated to its direct action on the m\roneural junction, often ma)’ be as great as the vagomimetic effect. The unpredictable effect of Mechol\.l on A-V conduction time in patients with partial heart block suggests that this drug is of no value in evaluating the part played by vagal activity in unselected cases of heart bloc-k. It is apparent from our observations that heart block, per se, does not contraindicate thr use of Mecholyl. These results clo not preclude the possibilit), that the action of these drugs on A-Y conduction time is related to changes in coronary blood flow. Although we produced no significant change b>. having the patients breathe pure ox>.gen, this does not eliminate the possibilit)that changes in the caliber of the vessels supplying the conducting tissues ma)- be of importance. \\‘edd,‘? Essex and associates,‘” and Katz and Lindner ‘I have shown that Mecholvl increases the coronary blood flow. The effects of atropine on coronar!’ bltrntl flow are some\vhat conflicting. Essex and co-workers’:’ found atropine to increase coronar!. blood flow, while Katz and I,indner’-’ observed a weak vasoconstrictor effect on the coronary arteries. HalseyI; noted that partial heart block assocGted with digitalis intoxication in the dog could b(. reduced signiticantl>. 1~1, amyl nitrite but believed this to be due to a lessened vagal effect as a result of a drop in blood pressure. It should be pointed out, however, that large doses of digitalis in the dog cause constriction oi the c-oronar). vessels. The results of our observations on the response 0i human subjects to atrol)ine. Mecholyl, and oxygen do not serve to delineate the physiologic mechanisms illvolved in the production of heart block. These drugs do not determine whether
l;ift>--one cases of heart block associated with various etiological factors were studied electrocardiographicall]. for changes in the P-K interval after the administration of atropine. In twenty-two of these cases the effects of oxygen and Mecholyl were analyzed and the results comparecl. Both atropine and MecholJ4 were found to decrease the P-K interval in a majority of these cases, but atropine proved the more effective drug. It is concluded that atropine, Mecholyl, and osygen are of no value in determining either the etiology of heart block or the underlying physiologic mechanisms in human subjects. KEFEKENCES 1.
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