(Received March 21, 1934.)

Transcription

1 I78.4 THE PRODUCTION OF CARDIAC IRREGULARITIES BY EXCITATION OF THE HYPOTHALMIC CENTRES. BY B. B. DIKSHIT. (From the Department of Pharmacology, University of Edinburgh.) (Received March 21, 1934.) LEVY [1912] showed that certain forms of cardiac irregularities could be readily produced in cats under light chloroform aneesthesia by injecting small quantities of adrenaline. He concluded that chloroform rendered the heart "irritable " and that stimulation of the sympathetic produced irregularities in such a heart. Adrenaline, nicotine, barium chloride and other drugs all produced this effect. Brow, Long and Be attie [1930] showed that in cats decerebration at the Sherrington level abolished the extrasystoles that were induced by light chloroform anesthesia. They concluded that there was some mechanism above the Sherrington level of decerebration which controlled the cardiac arrhythmias. As early as 1872 Knoll noted that extrasystolic arrhythmias occurred in experimental animals when the blood-pressure was raised, and it is now generally recognized that cardiac irregularities can be produced in animals either by pressor drugs or by mechanical compression of the aorta. The fact that disturbances in cardiac rhythm occur as an effect of vagal stimulation has been observed clinically as well as experimentally. Lennox, Graves and Levine [1922] took electrocardiographic records during anaesthesia in man and found that cardiac disturbances were more common in operations on the head and neck than in other operations. The abnormalities were transient, did not cause circulatory disturbance and were of physiological rather than of clinical importance. They concluded that vagal stimulation was in some way responsible for the irregularities. Rehn [1926] concluded that cardiac disturbances during an operation

2 CARDIAC IRREGULARITIES FROM HYPOTHALAMUS. 383 were due to nervous impulses from the seat of operation and that the strength of the stimulus to the vegetative nervous system determined the type of irregularity produced. Hill [1932] investigated the influence of the vagus on extrasystolic irregularities during chloroform ansnsthesia in man. Stimulation of the vagus by carotovagal pressure in the neck produced coupled rhythm due to ventricular extrasystoles, and pinching of the exposed nerve produced the same action. These effects were obtained with patients in the third stage of chloroform anesthesia, who had 1/100 gr. of atropine and in whom no form of vagal stimulation produced slowing of the heart. Hill concluded that increased vagal tone tended to favour the production of extrasystoles under chloroform ansesthesia. Brow, Long and Beattie [1930] found that stimulation of the central end of the vagus produced cardiac irregularities in cats under light chloroform ana3sthesia. They found the same effect after sciatic stimulation and concluded that vagus afferent fibres behaved like other afferent nerves and caused a reflex secretion of adrenaline which was responsible for the irregularity. It is interesting to note in this connection that extirpation of both adrenals did not prevent production of such irregularities. The author [19341 has shown that both the stimulation of the central end of the vagus and the injection of acetylcholine into the lateral ventricles of cats sometimes caused irregularities in a heart that previously had been perfectly regular in its action. These observations have been repeated and confirmed. The experiments described below suggest that both these procedures produce the cardiac irregularities by acting on certain nerve centres in the mid-brain. These results support Beattie, Brow and Long's view that certain centres in the hypothalamus control the rhythm of the heart. EXPERIMENTAL METHODS. Cats were used for all experiments. The animals were anesthetized with chloralose (0-08 g. per kg.). Blood-pressure was recorded by a cannula in the right carotid artery and a tracheal cannula was inserted in the trachea for artificial respiration. Both the vagi were dissected and cut in the middle of the neck. A trephine opening was made in the skull at the junction of the coronal and sagittal sutures and intraventricular injections of drugs were made through this hole by inserting a fine needle in the direction of the lateral ventricle. Electrocardiograms (lead II) and kymographic records were taken simultaneously. An injection of 1 mg.

3 384 B. B. DIKSHIT. per kg. atropine was given hypodermically about 20 mi. before the intraventricular injections were made. Vagal stimulation was effected by stimulating both vagi simultaneously with platinum electrodes. EFFECT OF VAGAL STIMULATION AND OF INTRAVENTRICULAR INJECTIONS OF ACETYLCHOLINE. It is well known that stimulation of the central end of the vagus can produce either a fall or a rise in blood-pressure. Irregularities of the heart occur more commonly after central vagal stimulation when there is a rise in blood-pressure than when there is a fall. The irregularities may occur during or after cessation of the stimulus. They persist for a short time only and after this the heart becomes regular again. Injections of small quantities of acetylcholine into the lateral or third ventricle of cats also precipitate irregularities in a rhythmically beating heart. Such injections can produce either a rise or a fall in blood-pressure, and in this case also the irregularities occur more frequently when there is a rise in blood-pressure than when there is a fall, but they may also occur when the blood-pressure is not much affected by the injection. These irregularities also are transient and the heart regaing its regular rhythm in a short time. Fig. 1 shows firstly the effect of stimulation of the central ends of the cut vagi. This caused a temporary arrest of respiration and a rise of blood-pressure which was followed by cardiac irregularities. An injection of 0 4y of acetylcholine did not produce any effect on respiration but caused cardiac irregularity. A second injection of 08y of acetylcholine caused respiratory arrest and more pronounced cardiac irregularity. The figure shows the striking similarity between the effects of central vagal stimulation and intraventricular injections of acetylcholine. Moreover it shows that cardiac irregularities can be produced without changes in either respiration or blood-pressure. The author [1934] has advanced the provisional hypothesis that stimulation of the afferent fibres of the vagus causes liberation of acetylcholine in the central nervous system, and that this may be the reason for the similarity in effects seen in Fig. 1. Brow, Long and Beattie [1930] concluded that the brain centre causing cardiac irregularities was situated above the Sherrington level, and the author's results support this conclusion, for he found that after decerebration below the Sherrington level application of acetylcholine to the brain even in as high concentrations as 1 in 100,000 did not produce any action on the rhythm of the heart.

4 CARDIAC IRREGULARITIES FROM HYPOTHALAMUS. 385 Irregularities of the heart can also be produced by various other means. Injections of caffeine citrate ( c.c. of 5 p.c. solution) in the lateral ventricle of cats produced a marked rise in blood-pressure and a marked cardiac arrhythmia which persisted for a fairly long time, and small doses of nicotine also had the same action. The arrhythmias can also be produced by clamping the common carotid arteries in the neck or by injecting air into the carotid artery. Fig. 1. In this and subsequent tracings R = respiration, B.P. = blood-pressure. The scale on the left measures B.P. in mm. Hg. Cat (wt. 2-3 kg.) ansesthetized with urethane. A, stimulation of the central end of both vagi. B, injection of 04y of acetylcholine in the right lateral ventricle. C, injection of 0-8y of acetylcholine in the right lateral ventricle. Time = 10 sec. INFLUENCE OF CHANGES IN BLOOD-PRESSURE ON CARDIAC IRREGULARITIES. All the procedures mentioned above, namely intraventricular injections of acetylcholine, caffeine or nicotine and clamping of the carotids, usually caused a marked rise in blood-pressure, and the question arises whether this may not be the cause of the cardiac irregularities. Levy [1913] pointed out that there was a close relation between the blood-pressure level and occurrence of ectopic beats. In all forms of stimuli used by Levy there was a rise in blood-pressure. Hering [1900]

5 386 B. B. DIKSHIT. showed that marked resistance to the action of the heart brought about by compression of the aorta near its arch gave rise to extrasystolic arrhythmia. Beattie, Brow and Long [1930] pointed out that the stimulation of the sympathetic system brought about during the operative procedure of clamping the aorta and the asphyxiation of the central nervous system which such an operation necessarily involved, were possible causes of these effects. Karplus and Kreidl [1911, 1927] showed that there was a well-localized region in the hypothalamus, stimulation of which led to a well-marked rise in blood-pressure. Since any pressor action can bring about extrasystolic arrhythmia it becomes doubtful whether all the procedures discussed above have an action on a special centre in the brain governing the heart or are the result of the rise in blood-pressure produced by their action on the centre of Ka rplus and Kreidl. It has indeed been shown that intraventricular injections of acetylcholine can produce cardiac arrhythmias when there is no appreciable change in the blood-pressure level (cf. Fig. 1), but intraventricular injections of caffeine and clamping of the carotids always cause a rise of blood-pressure and hence the mechanism by which they produce cardiac irregularities is doubtful. Further evidence on this point was obtained by studying the effects produced by hypnotics of the barbituric acid series which are believed to exert a selective depressant action on the mid-brain. Intraventricular injections of caffeine and cjamping of the carotids were selected as the best agents for provoking cardiac irregularities, because their effects are more marked and more persistent than the other agents with a similar action. EFFECT OF SODIUM BARBITONE ON CARDIAC IRREGULARITIES. The action of sodium barbitone in inhibiting the cardiac irregularities produced by agents mentioned above was studied. The sodium barbitone was either applied locally to the hypothalamus or else was injected intravenously. Fig. 2 shows the irregularity of the heart produced in a decerebrate animal with chloroform and adrenaline. The level of decerebration was well above the Sherrington level in this experiment. The level of blood-pressure was not high and a control injection of 0 05 mg. of adrenaline before administration of chloroform produced a good rise in blood-pressure but no cardiac irregularity. Chloroform by inhalation and 0*05 mg. adrenaline by intravenous injection produced the typical arrhythmia shown at the commencement of Fig. 2. A 5 p.c. solution of sodium barbitone (0.3 c.c.) was then applied directly to the hypothalamic nuclei. The effect is seen in the figure. There was an immediate action on

6 CARDIAC IRREGULARITIES FROM HYPOTHALAMUS. 387 Fig. 2. Decerebrate cat (wt. 341 kg.), blood-pressure showing irregularity of the heart provoked by previous administration of chloroform and adrenaline. At the signal 03 c.c. of 5 p.c. solution of sodium barbitone applied to the hypothalamus. Time 2 sec. Fig. 3. Cat (wt. 1X5 kg.), anesthetized chloralose. Blood-pressure. A, intraventricular injection of 15 mg. of caffeine citrate at the signal. B, tracing 5 min. after A. C, intraventricular injection of 15 mg. of caffeine citrate at the signal after an intraventricular injection of 0025 g. sodium barbitone. D, tracing 5 min. after C. Time 2 sec.

7 388 B. B. DIKSHIT. the rhythm of the heart although there was no marked change in the level of blood-pressure. It is interesting to note in this connection that the effect of sodium barbitone lasted for a short time only (about 20 min.), and after this interval administration of chloroform and adrenaline again produced an irregular heart, and this irregularity was abolished by a second application of sodium barbitone. Fig. 3 A shows the irregularity of the heart after an intraventricular injection of caffeine citrate (5 p.c. solution, 0 3 c.c.) in a chloralosed, atropinized cat. The injection was given through a small hole trephined Fig. 4. Electrocardiograms taken during experiment shown in Fig. 3. A., taken during period B (Fig& 3).- B, taken during period D (Fig. 3). Time 1/5 sec. at the junction of the coronal and sagittal sutures. There was a rise in blood-pressure and some irregularities of the heart immediately after the injection. The irregularities became most marked about 5 min. after the injection (Fig. 3 B) and the heart remained irregular for about 20 min. The electrocardiogram taken after 5 min. shows the character of the irregularities (Fig. 4A). An intraventricular injection of sodium barbitone (0.25 c.c. of a 10 p.c. solution) was given when the heart was showing a few irregularities. This injection produced a slight, rise in blood-pressure and slightly increased the irregular action of the heart for a short time. The heart however regained its regular rhythm immediately afterwards and remained so for about 15 min. A second injection of caffeine (0.3 c.c. of a 5 p.c. solution) was then given in the same way as the first one. This

8 CARDIAC IRREGULARITIES FROM H YPOTHALAMUS. 389 produced a rise in blood-pressure, almost about the same as the first one but very few irregularities of the heart (Fig. 3 C). The tracing to the right (Fig. 3D) shows the kymographic record taken 5 min. after the injection and it will be seen that the heart is quite regular. An electrocardiogram taken simultaneously also shows the regularity of the heart (Fig. 4B). The difference between the action of caffeine given intraventricularly before and after intraventricular injections of sodium barbitone is well seen both from the kymographic and electrocardiographic records. As Fig. 5. Cat (wt. 3-2 kg.), ansesthetized chloralose. Drum turned back to get superimposed tracings. Lower tracing taken before and upper tracing after intravenous administration of0-2 g. sodium barbitone. Carotid arteries clamped at the arrows. Time 2 sec. the rise in blood-pressure produced by the two injections of caffeine was about the same, it appears that the pressor effect is not the cause of the irregularities. Clamping of the carotids is the simplest method of producing a rise in blood-pressure without introduction of a drug. The rise is usually accompanied with irregular action of the heart. The lower tracing of Fig. 5 shows that a rise of blood-pressure produced in this way was accompanied by extrasystoles. After this tracing had been obtained the cat was given 0-2 g. of sodium barbitone intravenously, and after this clamping of the carotids produced a rise of blood-pressure without any extra-

9 390 B. B. DIKSHIT. systoles (upper curve, Fig. 5). As clamping of the carotids after sodium barbitone produced about the same rise in blood-pressure, it is evident that the rise itself is not responsible for the irregularity. This experiment further indicates that the reflex initiated by a fall in the carotid sinus pressure passes through two mechanisms-vaso-pressor and cardiac regulator and that sodium barbitone depresses the latter but not the former. INFLUENCE OF SODIUM BARBITONE ON ECTOPIC BEATS IN MAN. The effect of sodium barbitone on the incidence of ectopic beats was studied in a normal, healthy, young subject showing ectopic beats X g 1 ' _ 12 h -2~~~~~~~~~~ o ~~~~~~~~30~ 0 Z 2 - ~~~~~~~~~~~~~~~10 III10 hr Fig. 6. Effect of 1 g. sodium barbitone (taken by mouth at arrow) on incidence of ectopic beats per 2 min. (continuous line). Dotted line (pulse rate). Irregularities were counted by feeling the pulse at the wrist and electrocardiograms were taken every half hour. Sodium barbitone (1.0 g.) was given orally. It was found that the number of ectopic beats increased slightly within the first 10 mi. of administration of the drug and dropped to less than half within the next 30 mi. This effect was maintained for about 2 hours and the irregularities returned within 21 hours. Fig. 6 shows the effect of 1.0 g. of sodium barbitone on the pulse rate and incidence of ectopic beats. The rate of pulse slowed to a slight extent but there was a marked effect on the number of ectopic beats. The action however passed off within 2i hours, rather abruptly. Larger doses of sodium barbitone have a more prolonged action. The

10 CARDIAC IRREGULARITIES FROM H YPOTHALAM US. 391 effects of large doses (2.0 g.) of the drug were studied in the same subject. The number of extrasystoles was counted by feeling the pulse at the wrist. The normal variation in the incidence of ectopic beats was observed for a week, and it was found that the number of extrasystoles gradually increased during the evening and was maximum at about 11 o'clock at night. This increase in the incidence of ectopic beats persisted for about 2 hours. Sodium barbitone was therefore given at 10 o'clock at night, and it was found that the number of ectopic beats was markedly reduced by the drug and the effect lasted for more than 3 hours. The results are shown in Fig z~~~~~~~~~~~ o, a.m.p. 12 a.m. 10 Fig. 7. Effect of 2 g. sodium barbitone (taken by mouth at arrow) on incidence of ectopic beats per minute (continuous line) in subject B.B.D. Dotted line, highest and lowest figures obtained during 7 days' control observations. DIscussIoN. There are two theories advanced to explain the occurrence of ectopic beats. The theory of re-entry is based on the experimental observations of Mines [1913] that certain muscle fibres are in a refractory phase and do not respond to the stimulus but become responsive as the impulse travels along the other fibres and comes back to the point of stimulus. The theory of parasystole explains ectopic beats by assuming the existence of a focus in the heart which is capable of sending out but not of receiving impulses. Both these theories are myogenic, and this theory is supported by the fact that digitalis in large doses regularly produces extrasystoles and this drug almost certainly acts directly on the myo-

11 392 B. B. DIKSHIT. cardium. Hence the action of caffeine in producing extrasystoles has generally been ascribed to the direct action of the drug on the myocardium. In fact the neurogenic view has found little favour with physiologists and clinicians alike. The experiments of Brow, Long and Beattie have proved the existence of a centre in the hypothalamus, stimulation of which can cause cardiac extrasystoles. Experiments described in this paper support their view. The fact that all experimental procedures which produced irregularities were effective after bilateral vagal section and atropinization of the animal proves that the efferent impulses which provoke cardiac irregularities do not pass through the vagus but probably through the sympathetic. It is further evident from experiments with intraventricular injections of drugs that the centre responsible for the cardiac irregularities can be stimulated byvarious drugs such as acetylcholine, caffeine and nicotine. The ectopic beats met with clinically are produced by a wide variety of causes such as drugs, bacterial toxins, reflexes produced by disordered function of the digestive tract, and finally they may be produced by emotional disturbances without the presence of any definite lesion or disorder. Ectopic beats are very frequently seen in persons of advanced age, and these are believed to be due to sclerotic changes in the coronary vessels. Ectopic beats are therefore produced by so many different factors that it is unlikely that their production can be explained by one single mechanism. The experiments on man recorded in this paper show the effect of sodium barbitone on the incidence of ectopic beats. The cause of ectopic beats was unknown in this case, but a central nervous depressant like sodium barbitone markedly lessened the number of ectopic beats. Extrasystoles produced experimentally in cats by central drug action were also abolished by administration of sodium barbitone. Therefore probably the extrasystoles in the case referred to above were of central origin. Beattie, Brow and Long [1930] produced extrasystoles in cats by injecting caffeine intravenously in an amount equal to mg. per kg. of body weight. They observed that caffeine produced extrasystoles in a decerebrate animal, after this had been without an anaesthetic for 5 hours, and that section of all nerve connections to the heart and removal of the suprarenal glands had no effect whatever on the irregularities of the heart produced by intravenous injections of caffeine. They therefore concluded that the site of action of caffeine was either on the myocardium or the sympathetic nerve endings in the heart.

12 CARDIAC IRREGULARITIES FROM HYPOTHALAMUS. 393 I injected caffeine intravenously in cats and found that the dose required to produce extrasystolic arrhythmia was about 50 mg. per kg. of body weight. Intraventricular injections of caffeine in an amount equal to mg. per kg. were however sufficient to produce the cardiac irregularity. The fact that the minimum effective intraventricular dose of caffeine was one-fifth of corresponding intravenous dose is strong evidence against the drug acting on the heart and indeed against its acting on any tissue outside the central nervous system. The power of caffeine to produce extrasystoles in animals is of clinical interest because caffeine poisoning is a known cause of extrasystoles in man. The dose of caffeine given intravenously in the animal experiments is equivalent to a dose of 3 0 g. in a human being, whereas the daily consumption of caffeine by a heavy tea drinker is likely to be about 1 g. Sollmann [1932] states that doses about 1 g. of caffeine may produce alarming symptoms. In comparing the effects on animals to human beings it must be remembered that the animals were ansesthetized and that immoderate tea drinking only produces cardiac irregularity in a certain proportion of susceptible cases. The difference in animal and human dosage is therefore not so great as to preclude the possibility of a similar mode of action in the two cases. It has already been shown that in animals the production of extrasystoles by caffeine is probably due to some actions on the central nervous system. It is therefore possible that caffeine can produce extrasystoles in man in a similar way. SUMMARY. 1. Central vagal stimulation and injection of small quantities (0.4-1 y) of acetylcholine into the ventricles of the brain produce cardiac irregularities in cats. 2. Similar irregularities can be produced by intraventricular injections of caffeine and nicotine or by clamping both the carotid arteries', 3. Sodium barbitone given intracerebrally or intravenously lessens or abolishes cardiac irregularities provoked by caffeine or by clamping of the carotid arteries. 4. Large doses of sodium barbitone lessen the incidence of ectopic beats in man. 5. The evidence indicates that caffeine can produce cardiac irregularities by some action on the hypothalamic centres. My thanks are due to Prof. A. J. Clark for his suggestions and help. The expenses of this research were defrayed by a grant from the Moray Fund of Edinburgh University.

13 394 B. B. DIKSHII. REFERENCES. Beattie, J., Brow, G. R. and Long, C. N. H. (1930). The Vegetative Nervou8 Sy8tem, p Baltimore: Williams and Wilkins. Brow, G. R., Long, C. N. H. and Beattie, J. (1930). J. Amer. med. A88.95,715. Dikshit, B. B. (1934). J. Physiol. 80, 409. Hering, H. E. (1900). Pflhiger8 Arch. 82, 1. Hill, I. G. W. (1932). Edin. med. J. 39, 533. Karplus, J. P. and Kreidl, A. (1911). Pflfiger8 Arch. 143, 109. Karplus, J. P. and Kreidl, A. (1927). Ibid. 215, 667. Knoll (1872). S.-B. Akad. Wi88. Wien, 66, Abt. 3, 195. Lennox, W. G., Graves, R. C. and Levine, S. A. (1922). Arch. intern. Med. 30, 57. Levy, A. G. (1912). Heart, 4, 319. Levy, A. G. (1913). Ibid. 5, 299. Mines, G. R. (1913). J. Phy8iol. 46, 349. Rehn, E. (1926). Klin. W8chr. 5 (2), Sollmann, T. (1932). Manual of Pharmacology, p W. B. Saunders Company.