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The effect of heparin on the heart in anaphylaxis
erimental laborator
e effect
of heparin
on t
ariy workers did not recognize the importance of the heart as one of the target organs of anaphylactic shock, because the guinea pig heart is seen to beat for quite sometime after all respiratoqlnovements have ceased. It was later demonstrated that, in the rabbit, the heart is one of the primary sites of anaphylactic shocl-i.r The electrocardiographic changes during anaphylaxis in this species are indicative of disturbances in conduction, partial heart block, smooth muscle spasm of the coronary blood vessels, and changes associated with axphyxia.2.4 The entire arterial system of the rabbit tindergoes vasoconstriction during anaphylactic sh0ck.j It has been suggested recent11 l-hat a fundamental process in severe ana:phylactic shock in the rabbit is the formarion of intravascular thrombus, particularly in the pulmonar>- blood vesselse; this can jje prevented by pretreatment of the anisiia! \l,ith heparin immediately before challenge.7 Similar changes may possibly occur in the heart, and in fatal cases, coronarylhrombosis may be added to coronary ~asospasm. It is possible that the thromijotic changes can be prevented by pre:reatinent n-ith heparin. The effect of pretreatment with heparin :\‘;tS, therefore, studied in anaphJ,lactic
shock in the raibjit. i’Slecrtol~,tn~..;,,rapil c changes n-ere recorded in the anirnais undergoing anaphylactic shock. ‘!‘he effect of the antigen on contractiliq~, how-t rate, ,ind coronary flow was studied i,-! the isolated perfused heart preparation. In both types of experiments the effectlood pressure during anaphylaxis in the ran may be c’!ue to cardiac depression.8 hlbino rats of either sex, wci&ing be~ween 100 and 150 grams, were oi>tained *ram the National Institute of (_‘o:nmuni<.able Diseases, New Delhi. ~lon~.rel rabl)its of either sex weighing l)etneen I and 2 Glograms v\-ere purchased frmr Irml dealeen reported previously.7 The rats were sensitized \a+th ii.5 ml. of ‘10~Se serum inject.ed intrapcrltr,:le~~~~,,~
400
Dhuv, Mukherjee, und Sunyul
and were used 14 to 16 days later for intravenous challenge with 0.25 ml. of horse serum. The rabbits were sensitized with 6 daily intraperitoneal injections of 1 ml. of 50 per cent egg white in saline; they were used 3 weeks later, either for intravenous challenge with 1 ml. of the antigen solution or, after being killed, for study of the anaphylactic reaction of the isolated heart. The electrocardiographic changes were recorded in the classic limb leads by means of a Galileo electrocardiograph. The recordings were taken immediately before challenge, and continuously during the injection of the challenging dose, as well for the next 1.5 minutes. In animals which survived beyond this period, intermittent records were made for the next 6 hours. The isolated heart was perfused through the coronary arteries (Langendorff preparation) with Ringer-Locke solution.g The
contractions were recorded on the smoked drum. The coronary flow was measured and the heart rate counted for 5 minutes, before and after each injection of antigen. Similar readings were then taken every fifth minute, for 1 hour, or until normalcy was restored. Results
Studies in the rabbit. In normal control animals, the intravenous injection of the antigen was innocuous; furthermore, there was no change in the electrocardiographic record. Anaphylactic shock was produced by the intravenous injection of a challenging dose in 18 sensitized rabbits. The shock produced was mild in 3 animals and severe in the rest. The results are shown in Table I, and Figs. 1 and 2. The electrocardiographic changes in ani-
Fig. 1. ECG tracings in mild anaphylactic shock in the rabbit (Lead II). 111 the control tracing, the P wave buried in the T wave, rate 274 per minute, normal QRS, T upright. At 3 minutes, rate 278 per minute, depression of S-T segment, upright intrinsic deflection of S wave leading to widening of QRS. At 5 minutes, rate 268 per minute, depression of S-T segment. At 10 minutes, rate 320 per minute, marked sinus tachycardia, S-T segment isoelectric, P wave buried in T. At 6 hours, normal ECG, rate 230 per minute.
mdAs undergoing mild shock were transient, and normalcy was restored within 6 hours :
Thus heparin
;t was seen 7ha.r :~~.;cc;:j3~isEli afforded considerable prelection against anaphylactic shock and prevented myocardial damage (p > 0.001:. When the isolated hearts obtained irom nonsensitized animals were perfused with Ringer-Locke solution, the addition ol 0.5 ml. of egg-white solution did not produce any change in tone or contractility. There was a reduction of approximately 10 per cent in coronary flow! lasting for 4 to 5 minutes after the addition of a,ntigen solution (Table II). It is possible that this transient reduction was due to viscosity of the r.mtigen solu.tion. In one experiment -the perfusion fluid contained heparin in a concentration of 50 1.C. per miililiter. The effect oi the
L ig. 1. ECC; ,hanges in ia~al anaphylactlc shock in lite rabbii. .IL 4 lo 5 :tlmutes after I& ::M. iel,:. ,iih iiu=e in Lead I the mean deflections are inverted, with sharply inverted T wave. The reverse is seen in i,ead il!. The heart rate is 250 per minute, in contrast to 300 per minute before challenge. A4~ 9 to 10 minutes, changes xe essentially similar, but, in addition, there is heart block changitlg from 2 :l to 3:1. The heart r;te varies Crcm 70 to 100 per minute. At 14 to 15 minutes, the S-T segment is depressed in Lead 1 and elevated i,: iead [I -!-he heart b!ock is persistent, with occasional premature beats, the heart rate being 88 per tnirixtc,.
492
Dhur,
Mukhevjee,
Sensitized only (18 animals)
Sensitized and pretreated with heparin before challenge (12 animals)
Am. Heart J. October, 1967
und Sunyal
Hurried respiration, progressive weakness, occasional convulsion, recovery in 2 to 3 hours; completely recovered within 24 hours
Mild
16.7
Immediate reduction in heart rate, followed by sinus tachycardia. At the height of sinus tachycardia, widening of QRS complex. Changes in S-T segment indicative of exhaustion of bundle or transient spasm of arteries
Hurried respiration, repeated convulsions, passage of stool and urine, cessation respiration earlier than stoppage of heart, death within 20 minutes to 2 hours
Severe
83.3
Progressive reduction in heart rate, changing pacemaker, atria1 fibrillation, in some animals; atrioventricular block, ventricular extrasystoles, changes in S-T segment suggestive of cardiac ischemia
100
Bradycardia followed by tachycardia, widening of QRS complex, transient sagging of S-T segment. Normal records within 6 hours
Respiration weakness. IJltimate 24 hours
of
hurried. Marked No convulsions. recovery in
addition of egg-white solution was similar to that noted above (Table II). When similar experiments were performed with heart obtained from sensitized animals, the addition of 0.5 ml. of 50 per cent egg-white solution led to marked alterations in contractility, reduction in heart rate, a,nd marked reduction in coronary flow (Table II). The reduction in coronary flow lasted for 15 to 20 minutes. When heparin (50 I.U. per milliliter) was present in the perfusion fluid in similar experiments performed with heart from sensitized animals, the addition of antigen to the perfusion fluid produced similar effects (Table II). Studies in the rat. In a group of 14 sensitized animals, 2 animals died in anaphylactic shock within 2 hours of challenge. Another group of 13 sensitized animals received heparin intravenously in a dose of 5,000 I.U. per kilogram of body weight. On challenge, 7 animals died within 2 hours. The electrocardiographic changes were similar in both groups and consisted of initial bradycardia followed by persistent
Mild
tachycardia. Thus it was seen that, in contrast to the results obtained in the rabbit, pretreatment with heparin aggravated anaphylactic shock. When the isolated heart was perfused through the coronary arteries, the addition of antigen (0.25 ml. of horse serum) to the perfusing fluid led to a slight reduction in coronary flow. The reduction in coronary flow and heart rate was marked when antigen was added to the fluid used to perfuse the hearts obtained from sensitized animals. With heparin (50 I.U. per milliin the perfusion fluid, liter) present similar but less intense effects were produced (Table III). Discussion It has been suggested before that there is a generalized spasm of arteries of the rabbit during anaphylactic shock.” A spasm of the coronary artery has now been demonstrated in both in vivo and in vitro experiments. The spasm in in vitro experiments with the isolated heart subsided within 20
1 Before
j After
PeY cent change
~ Per cent Before
.ljter
(appinx.) Control Contra!
-icnsitized
Ringer-Locke Ringer-Locke and heparin Ringer-Locke and heparin Ringer-Locke
184 164
180 160
100
96
-4
108
80
-26
15 0
3 0
- 80
+risitized
Ringer-Locke
118
IO
-92
40
10
- 73
Sensitized
Rkger-Locke
160
120
-25
20.0
10 0
-50
S::nsitized
Ringer-Locke
164
139
-15
21 0
13 0
-38
Glwitized
Ringer-Locke
112
79
-29
70
I.0
-86
+mitized
Ringer-Locke
120
84
-30
11.5
6.0
-48
Zicn~itized
Ringer-Locke and heparin
160
-1X
8.2
!O !I
-44
~SXltrOl
-?
-2
19 0 50 60
17.0 40
1 change (appY0.x.)
41
-10
ITo effec:
-20
X0 etiec:
-32
No
effect
Xxplitiide incrr.~5ctl. Diastoiic tmie dec~reasei; Mild sys?t~lic ari-c~~ bitholii reco~zi:‘> Rise in diasto!ic- torte and amplitiide Rise in cliast;)lii- tone anti ampiiti;de Transieni mid-syslolic ai-t-eSt
132
w 30 minutes, and there was no permanent damage. Since the perfusion fluid was Ringer-Locke’s, there was no possibility of thrombus formation. In the in vivo experinlents, there was transient spasm without permanent cardiac damage in animals undergoing mild anaphylactic shock. In severe cases, it seems to be probable that L-hrombus fortnation perpetuated cardiac &hernia. Heparin, because of its wellknown anticoagulant properties, might have prevented this change. This may be one of the factors responsible for the protective action of heparin in anaphylaxis ln this species, although it is possible that heparin may have an antianaphylactic .:ction of its own. As expected, there was no action of heparin in the isolated heart. In rats, heparin aggravated the intensity of anaphylactic shock but did not modify the ECG changes. It is known that hemorrhage is a characteristic feature of anaphy-
Every foi1rx.h be;!r rnking. Xtriai contrac:ioil riot !ollo:ved ity i cnwictilais,ontrxt ion Silght rise in ciia5tcriic tuile
In the isolated heart, the adtlition of antigen caused bradycardia and a reduction coronary flow. In the prexerrce of Oi heparin, these changes were cor&stentl? iess marked. It seems to be possible that inore than one mechanism of action of heparin is involved. It may aggravate anaphylactic shock in the ra: becw;yse of its anticoagulant action, and n~ay also possess direct antianaphylactic action. In the guinea Dig, asphyxia accounts for ~:a1 anaphylac& shock, but recently ithas been reportedLo that, x\-hen the spasni of ljronchial muscles is prevented i)> antihistaminic drugs, there is heart failure due I.0 anapliylactic constriction of pulnionary 1Aood vessels, as is charac:eristicalIy seei: in the rabbit. It is interesting to note l-hat :he EC{;
Am. Heavt J. October. 1967
Dhar, Mlckherjee, md Sanyal
494
Table III. Effecl oj‘ antigen (horse serum) on rate and coronary $0~ in isolated rut hea.rt (cmfro1 or sensitized) perfused by Langendorf method”
Perfusion
(temp.
TyPe
fluid 37°C.)
Heart (per ~-
~-
Before
After
Control Control Control Control Control Control
Ringer-Locke Ringer-Locke Ringer-Locke Ringer-Locke Ringer-Locke Ringer-Locke and heparin
92 60 100 105 120 52
99 52 98 108 12.5 48
Sensitized Sensitized Sensitized Sensitized Sensitized
Ringer-Locke Ringer-Locke Ringer-Locke Ringer-Locke Ringer-Locke
140 110 116 10.5 109
Sensitized
Ringer-Locke and heparin Ringer-Locke and heparin Ringer-Locke and heparin Ringer-Locke and heparin Ringer-Locke and heparin
Sensitized Sensitized Sensitized Sensitized
*See text
for method
rate
Coronary $0~ (ml./min.) ____--
min.)
__-Per cent change (aPProx.)
+7
Before
After
Effect on contractility
Per cent change (approx.)
3 5 2.8 3.5 3 .5 7.5 1.0
-12 -34 -12 -12 -6 +0
No
+8
4.0 3.5 4.0 4.0 80 1.0
75 60 90 55 65
-46 -45 -22 -48 -37
4.6 3.0 3.5 3.0 3.5
0.3 0.3 0.5 0.5 1.5
-93 -90 -86 -83 -57
Amplitude reduced
of contraction
74
42
-43
1.9
1.2
-37
Amplitude reduced
of contraction
78
34
-56
2.0
1.0
-50
142
95
-33
3.4
1.8
-47
90
95
+6
6.0
5.0
-17
100
95
+5
5.0
4.0
-20
-13 -2 +3 +4
change
in contractility
of sensitization
changes in man during anaphylactic shock, as in severe cases in rabbits, consist of cardiac arrhythmia, heart block, bundle branch block, and patterns of acute myocardial ischemia.“J2
rabbit has been emphasized, and the findings have been discussed in the light of current knowledge. and
The technical assistance of Mr. D. N. Sharma Mr. S. L. Kapoor is gratefully acknowledged.
Summary
The electrocardiographic changes in the rabbit heart during severe anaphylactic shock are indicative of disturbances in function and coronary infarction. Pretreatment with heparin reduces the intensity of anaphylactic shock and also modifies the electrocardiographic changes, which then resemble patterns seen in mild, nonfatal shock. In the rat, heparin increases the severity of anaphylactic shock. The importance of coronary thrombus formation in determining fatal outcome in anaphylaxis in the
REFERENCES 1. 2.
3.
4.
5.
Auer, J.: Lethal cardiac anaphylaxis in the rabbit, J. Exper. Med. 140:476, 1911. Auer, J., and Robinson, G. C.: An electrocardiographic study of the anaphylactic rabbit, J. Exper. Med. 18:450, 1913. Criep, L. H.: Electrocardiographic studies of effect of anaphylaxis on cardiac mechanism, Arch. Int. Med. 48:1098, 1931. Mikulicich, G.: Electrocardiographic changes in experimental anaphylactic reactions, J. Allergy 22:249, 1951. Abell, R. G., and Schenck, H. P.: Microscopic observations on behaviour of living blood vessels of rabbit during reaction of anaphylaxis, J. Immunol. 34:195, 1938.
b.
i.
ii.
Sanyal, ii. k., and N’est, G. IS.: ‘The relationshlp uf histamine and 5-hydroxytryptamine to anaphylactic shock in different species, J. Physiol. 144:525, 1958. Char, H. L., and Sazyal, R. K.: Anticoagulants and anaphylaxis, Int, Arch. Allergy 21:172, 1962. Sanyal, R. K.: The mechanism of anaphylactic shock in the rat, Indian. J. Med. Res. 47:413, 19.59.
0.
i.
2.
Giertz, H., Berilaeur, M’., Hahi:, Cd’., arid Schmutzler, W.: Histamine independen: mechanism in shock in guinea pigs, Int. .!!rci:. Ri?erg); 28:46, 1965. Mcmanus, J. F., and Lawlor, J. J.: Myocardial infarction foilowing administration or tetanus antitoxin, New England 1. Med. 242:j 7. 1950. -Bernreitek, M. : Ele&oca;diogram of patient in anaphylactic shock, J.A.M.A. I’iC?rlGZS, 1959.
e effect
of heparin
on t
ariy workers did not recognize the importance of the heart as one of the target organs of anaphylactic shock, because the guinea pig heart is seen to beat for quite sometime after all respiratoqlnovements have ceased. It was later demonstrated that, in the rabbit, the heart is one of the primary sites of anaphylactic shocl-i.r The electrocardiographic changes during anaphylaxis in this species are indicative of disturbances in conduction, partial heart block, smooth muscle spasm of the coronary blood vessels, and changes associated with axphyxia.2.4 The entire arterial system of the rabbit tindergoes vasoconstriction during anaphylactic sh0ck.j It has been suggested recent11 l-hat a fundamental process in severe ana:phylactic shock in the rabbit is the formarion of intravascular thrombus, particularly in the pulmonar>- blood vesselse; this can jje prevented by pretreatment of the anisiia! \l,ith heparin immediately before challenge.7 Similar changes may possibly occur in the heart, and in fatal cases, coronarylhrombosis may be added to coronary ~asospasm. It is possible that the thromijotic changes can be prevented by pre:reatinent n-ith heparin. The effect of pretreatment with heparin :\‘;tS, therefore, studied in anaphJ,lactic
shock in the raibjit. i’Slecrtol~,tn~..;,,rapil c changes n-ere recorded in the anirnais undergoing anaphylactic shock. ‘!‘he effect of the antigen on contractiliq~, how-t rate, ,ind coronary flow was studied i,-! the isolated perfused heart preparation. In both types of experiments the effect
400
Dhuv, Mukherjee, und Sunyul
and were used 14 to 16 days later for intravenous challenge with 0.25 ml. of horse serum. The rabbits were sensitized with 6 daily intraperitoneal injections of 1 ml. of 50 per cent egg white in saline; they were used 3 weeks later, either for intravenous challenge with 1 ml. of the antigen solution or, after being killed, for study of the anaphylactic reaction of the isolated heart. The electrocardiographic changes were recorded in the classic limb leads by means of a Galileo electrocardiograph. The recordings were taken immediately before challenge, and continuously during the injection of the challenging dose, as well for the next 1.5 minutes. In animals which survived beyond this period, intermittent records were made for the next 6 hours. The isolated heart was perfused through the coronary arteries (Langendorff preparation) with Ringer-Locke solution.g The
contractions were recorded on the smoked drum. The coronary flow was measured and the heart rate counted for 5 minutes, before and after each injection of antigen. Similar readings were then taken every fifth minute, for 1 hour, or until normalcy was restored. Results
Studies in the rabbit. In normal control animals, the intravenous injection of the antigen was innocuous; furthermore, there was no change in the electrocardiographic record. Anaphylactic shock was produced by the intravenous injection of a challenging dose in 18 sensitized rabbits. The shock produced was mild in 3 animals and severe in the rest. The results are shown in Table I, and Figs. 1 and 2. The electrocardiographic changes in ani-
Fig. 1. ECG tracings in mild anaphylactic shock in the rabbit (Lead II). 111 the control tracing, the P wave buried in the T wave, rate 274 per minute, normal QRS, T upright. At 3 minutes, rate 278 per minute, depression of S-T segment, upright intrinsic deflection of S wave leading to widening of QRS. At 5 minutes, rate 268 per minute, depression of S-T segment. At 10 minutes, rate 320 per minute, marked sinus tachycardia, S-T segment isoelectric, P wave buried in T. At 6 hours, normal ECG, rate 230 per minute.
mdAs undergoing mild shock were transient, and normalcy was restored within 6 hours :
Thus heparin
;t was seen 7ha.r :~~.;cc;:j3~isEli afforded considerable prelection against anaphylactic shock and prevented myocardial damage (p > 0.001:. When the isolated hearts obtained irom nonsensitized animals were perfused with Ringer-Locke solution, the addition ol 0.5 ml. of egg-white solution did not produce any change in tone or contractility. There was a reduction of approximately 10 per cent in coronary flow! lasting for 4 to 5 minutes after the addition of a,ntigen solution (Table II). It is possible that this transient reduction was due to viscosity of the r.mtigen solu.tion. In one experiment -the perfusion fluid contained heparin in a concentration of 50 1.C. per miililiter. The effect oi the
L ig. 1. ECC; ,hanges in ia~al anaphylactlc shock in lite rabbii. .IL 4 lo 5 :tlmutes after I& ::M. iel,:. ,iih iiu=e in Lead I the mean deflections are inverted, with sharply inverted T wave. The reverse is seen in i,ead il!. The heart rate is 250 per minute, in contrast to 300 per minute before challenge. A4~ 9 to 10 minutes, changes xe essentially similar, but, in addition, there is heart block changitlg from 2 :l to 3:1. The heart r;te varies Crcm 70 to 100 per minute. At 14 to 15 minutes, the S-T segment is depressed in Lead 1 and elevated i,: iead [I -!-he heart b!ock is persistent, with occasional premature beats, the heart rate being 88 per tnirixtc,.
492
Dhur,
Mukhevjee,
Sensitized only (18 animals)
Sensitized and pretreated with heparin before challenge (12 animals)
Am. Heart J. October, 1967
und Sunyal
Hurried respiration, progressive weakness, occasional convulsion, recovery in 2 to 3 hours; completely recovered within 24 hours
Mild
16.7
Immediate reduction in heart rate, followed by sinus tachycardia. At the height of sinus tachycardia, widening of QRS complex. Changes in S-T segment indicative of exhaustion of bundle or transient spasm of arteries
Hurried respiration, repeated convulsions, passage of stool and urine, cessation respiration earlier than stoppage of heart, death within 20 minutes to 2 hours
Severe
83.3
Progressive reduction in heart rate, changing pacemaker, atria1 fibrillation, in some animals; atrioventricular block, ventricular extrasystoles, changes in S-T segment suggestive of cardiac ischemia
100
Bradycardia followed by tachycardia, widening of QRS complex, transient sagging of S-T segment. Normal records within 6 hours
Respiration weakness. IJltimate 24 hours
of
hurried. Marked No convulsions. recovery in
addition of egg-white solution was similar to that noted above (Table II). When similar experiments were performed with heart obtained from sensitized animals, the addition of 0.5 ml. of 50 per cent egg-white solution led to marked alterations in contractility, reduction in heart rate, a,nd marked reduction in coronary flow (Table II). The reduction in coronary flow lasted for 15 to 20 minutes. When heparin (50 I.U. per milliliter) was present in the perfusion fluid in similar experiments performed with heart from sensitized animals, the addition of antigen to the perfusion fluid produced similar effects (Table II). Studies in the rat. In a group of 14 sensitized animals, 2 animals died in anaphylactic shock within 2 hours of challenge. Another group of 13 sensitized animals received heparin intravenously in a dose of 5,000 I.U. per kilogram of body weight. On challenge, 7 animals died within 2 hours. The electrocardiographic changes were similar in both groups and consisted of initial bradycardia followed by persistent
Mild
tachycardia. Thus it was seen that, in contrast to the results obtained in the rabbit, pretreatment with heparin aggravated anaphylactic shock. When the isolated heart was perfused through the coronary arteries, the addition of antigen (0.25 ml. of horse serum) to the perfusing fluid led to a slight reduction in coronary flow. The reduction in coronary flow and heart rate was marked when antigen was added to the fluid used to perfuse the hearts obtained from sensitized animals. With heparin (50 I.U. per milliin the perfusion fluid, liter) present similar but less intense effects were produced (Table III). Discussion It has been suggested before that there is a generalized spasm of arteries of the rabbit during anaphylactic shock.” A spasm of the coronary artery has now been demonstrated in both in vivo and in vitro experiments. The spasm in in vitro experiments with the isolated heart subsided within 20
1 Before
j After
PeY cent change
~ Per cent Before
.ljter
(appinx.) Control Contra!
-icnsitized
Ringer-Locke Ringer-Locke and heparin Ringer-Locke and heparin Ringer-Locke
184 164
180 160
100
96
-4
108
80
-26
15 0
3 0
- 80
+risitized
Ringer-Locke
118
IO
-92
40
10
- 73
Sensitized
Rkger-Locke
160
120
-25
20.0
10 0
-50
S::nsitized
Ringer-Locke
164
139
-15
21 0
13 0
-38
Glwitized
Ringer-Locke
112
79
-29
70
I.0
-86
+mitized
Ringer-Locke
120
84
-30
11.5
6.0
-48
Zicn~itized
Ringer-Locke and heparin
160
-1X
8.2
!O !I
-44
~SXltrOl
-?
-2
19 0 50 60
17.0 40
1 change (appY0.x.)
41
-10
ITo effec:
-20
X0 etiec:
-32
No
effect
Xxplitiide incrr.~5ctl. Diastoiic tmie dec~reasei; Mild sys?t~lic ari-c~~ bitholii reco~zi:‘> Rise in diasto!ic- torte and amplitiide Rise in cliast;)lii- tone anti ampiiti;de Transieni mid-syslolic ai-t-eSt
132
w 30 minutes, and there was no permanent damage. Since the perfusion fluid was Ringer-Locke’s, there was no possibility of thrombus formation. In the in vivo experinlents, there was transient spasm without permanent cardiac damage in animals undergoing mild anaphylactic shock. In severe cases, it seems to be probable that L-hrombus fortnation perpetuated cardiac &hernia. Heparin, because of its wellknown anticoagulant properties, might have prevented this change. This may be one of the factors responsible for the protective action of heparin in anaphylaxis ln this species, although it is possible that heparin may have an antianaphylactic .:ction of its own. As expected, there was no action of heparin in the isolated heart. In rats, heparin aggravated the intensity of anaphylactic shock but did not modify the ECG changes. It is known that hemorrhage is a characteristic feature of anaphy-
Every foi1rx.h be;!r rnking. Xtriai contrac:ioil riot !ollo:ved ity i cnwictilais,ontrxt ion Silght rise in ciia5tcriic tuile
In the isolated heart, the adtlition of antigen caused bradycardia and a reduction coronary flow. In the prexerrce of Oi heparin, these changes were cor&stentl? iess marked. It seems to be possible that inore than one mechanism of action of heparin is involved. It may aggravate anaphylactic shock in the ra: becw;yse of its anticoagulant action, and n~ay also possess direct antianaphylactic action. In the guinea Dig, asphyxia accounts for ~:a1 anaphylac& shock, but recently ithas been reportedLo that, x\-hen the spasni of ljronchial muscles is prevented i)> antihistaminic drugs, there is heart failure due I.0 anapliylactic constriction of pulnionary 1Aood vessels, as is charac:eristicalIy seei: in the rabbit. It is interesting to note l-hat :he EC{;
Am. Heavt J. October. 1967
Dhar, Mlckherjee, md Sanyal
494
Table III. Effecl oj‘ antigen (horse serum) on rate and coronary $0~ in isolated rut hea.rt (cmfro1 or sensitized) perfused by Langendorf method”
Perfusion
(temp.
TyPe
fluid 37°C.)
Heart (per ~-
~-
Before
After
Control Control Control Control Control Control
Ringer-Locke Ringer-Locke Ringer-Locke Ringer-Locke Ringer-Locke Ringer-Locke and heparin
92 60 100 105 120 52
99 52 98 108 12.5 48
Sensitized Sensitized Sensitized Sensitized Sensitized
Ringer-Locke Ringer-Locke Ringer-Locke Ringer-Locke Ringer-Locke
140 110 116 10.5 109
Sensitized
Ringer-Locke and heparin Ringer-Locke and heparin Ringer-Locke and heparin Ringer-Locke and heparin Ringer-Locke and heparin
Sensitized Sensitized Sensitized Sensitized
*See text
for method
rate
Coronary $0~ (ml./min.) ____--
min.)
__-Per cent change (aPProx.)
+7
Before
After
Effect on contractility
Per cent change (approx.)
3 5 2.8 3.5 3 .5 7.5 1.0
-12 -34 -12 -12 -6 +0
No
+8
4.0 3.5 4.0 4.0 80 1.0
75 60 90 55 65
-46 -45 -22 -48 -37
4.6 3.0 3.5 3.0 3.5
0.3 0.3 0.5 0.5 1.5
-93 -90 -86 -83 -57
Amplitude reduced
of contraction
74
42
-43
1.9
1.2
-37
Amplitude reduced
of contraction
78
34
-56
2.0
1.0
-50
142
95
-33
3.4
1.8
-47
90
95
+6
6.0
5.0
-17
100
95
+5
5.0
4.0
-20
-13 -2 +3 +4
change
in contractility
of sensitization
changes in man during anaphylactic shock, as in severe cases in rabbits, consist of cardiac arrhythmia, heart block, bundle branch block, and patterns of acute myocardial ischemia.“J2
rabbit has been emphasized, and the findings have been discussed in the light of current knowledge. and
The technical assistance of Mr. D. N. Sharma Mr. S. L. Kapoor is gratefully acknowledged.
Summary
The electrocardiographic changes in the rabbit heart during severe anaphylactic shock are indicative of disturbances in function and coronary infarction. Pretreatment with heparin reduces the intensity of anaphylactic shock and also modifies the electrocardiographic changes, which then resemble patterns seen in mild, nonfatal shock. In the rat, heparin increases the severity of anaphylactic shock. The importance of coronary thrombus formation in determining fatal outcome in anaphylaxis in the
REFERENCES 1. 2.
3.
4.
5.
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