body is influenced in addition by a great number of changes in the

Transcription

1 THE CENTRAL AND REFLEX REGULATION OF THE HEART RATE. BY G. V. ANREP AND H. N. SEGALL. (From the Department of Physiology and Biochemistry, University College, London.) THE adaptation of the heart beat to changes in circulatory conditions is attained by two separate mechanisms: (a) by the adaptation of those parts of the central nervous system which regulate the rate and the strength of the cardiac contraction, and (b) by the adaptation of the heart muscle itself. While the rate of a denervated heart remains unaffected by changes in the circulatory conditions and is mainly determined by the temperature of the blood, the rate of the heart in the whole body is influenced in addition by a great number of changes in the mechanical conditions of the circulation. This difference to a large extent is explained by the presence of the extra-cardiac mechanism of adaptation which is lacking in the heart-lung preparation. The use of the whole animal for the study of this mech,nism is not entirely suitable, because it is difficult to control independently the cerebral and the systemic circulation and to decide whether changes in cardiac activity are of central, reflex, or peripheral origin. The different methods of interarterial and arteriovenous crossed circulation which have been introduced to overcome these difficulties do not materially improve the control over the circulation. The newer methods of crossed circulation as used by Anrep and Daly(i), Anrep and Starling(2) and Heymans(3), though they place the cerebral circulation under a better control yet leave the systemic circulation still uncontrolled. The experiments to be described were performed with a new technique which allows an independent control over the circulation in the brain and in the heart. Briefly this technique consists in establishing an innervated heart-lung preparation in contrast to the denervated preparations of Martin(4), Hering() and Starling(6). The innervated heart-lung preparation. Two dogs are used for each experiment. From one dog blood is collected, whilst the second dog is injected with morphia, anasthetised with chloralose (0.075 grm. per kilo), and bled from the femoral artery about one-quarter of its total blood volume. Artificial respiration with room air is started, and the PH. LXI. 15

2 216 G. V. ANREP AND H. N. SEGALL. chest is widely opened after a mid-sternal incision. The internal mammary blood vessels on both sides are now cut between ligatures; the left subelavian artery close to its origin from the aorta and the right sub-,clavian artery just beyond the origin of the right vertebrate are tied off. The azygos vein is ligatured in two places, close to its entry into the superior vena cava and about 2 or 3 cm. below this point so as to separate entirely the upper intercostal veins from the lower portion of the azygos 'vein. It is advisable also to ligature the right subclavian vein at its,entry into the superior vena cava. The following blood vessels are then prepared for the insertion of cannule: the aorta just beyond the origin of the left subclavian artery, the inferior and superior vene cavae, the brachiocephalic artery. One ligature for the brachiocephalic artery is placed intra-pericardially and the other just extra-pericardially. The apparatus consists of Starling's heart-lung apparatus, together with two small rubber pumps which are rhythmically compressed by adjustable eccentrics and which are provided with valves permitting the flow of blood only in one direction. The aorta and the inferior vena cava are connected to the heart-lung apparatus, while the head is perfused through the brachiocephalic artery by means of one of the pumps. The blood issuing from the superior vena cava is returned through the second pump into the reservoir of the heart-lung apparatus. As can be seen from Fig. 1 the head circulation is maintained in this preparation altogether independently of that in the heart and lungs. Thus there results a heart-lung preparation which retains all its nervous connections intact. The two independent circulations are supplied with blood from a common reservoir and therefore do not differ with regard to the composition of the inflowing blood. The separation of the thoracic circulation from the cerebral makes it possible to vary the mechanical conditions in each independently. On its way to the brain the blood passes through a separate warming spiral so that the temperature can be varied independently. The circulation in the head in our experiments is not supplied with an artificial compensator and it is therefore possible to observe vasomotor changes in the perfused head. In the absence of the compensator the bloodpressure in the cerebral circulation has to be adjusted by altering the str6ke of the perfusion pump. The sequence and mode of introduction of the four cannuiae are as follows: 1. The inferior vena cava is clamped and the heart is allowed partially to empty itself. The lower ligature on the aorta is then tied and the aortic cannula introduced: a side

3 REGULATION OF HEART RATE. 217 branch of this cannula is opened and immediately afterwards the vena cava is released. The blood which now flows from the cannula is collected and defibrinated, care being taken not 2. Fig. 1. Diagram of the innervated heart-lung preparation. The heart-lung apparatus contains the warming spirals and the artificial resistance. The heart-lung circuit consists of the venous reservoir A from which the blood flows through cannula B into the inferior vena cava; the blood leaves the heart from the aorta through cannula C. The cerebral circulation is maintained by pump 1, which drives the blood into the brachiocephalic artery D; the blood flowing from the head through the superior vena cava E is collected into a beaker and then returned by pump 2 into the venous reservoir. The beaker is kept at the level of the head. to bleed too much, but to leave enough blood to supply the heart and brain. The side branch of the cannula is then closed and the abdomen compressed so as to press the remainder of the animal's own blood into the heart, when the lower ligature on the inferior vena cava is tied. 15-2

4 218 G. V. ANREP AND H. N. SEGALL. 2. Meanwhile the venous reservoir of the heart-lung apparatus is filled with defibrinated blood to which is added about 0X02 grm. of heparin, in order to prevent the clotting of the blood which remains in the animal. After introduction of the cannula into the inferior vena cava the heart, lungs and brain are perfused. The artificial resistance in the heart-lung apparatus is kept high from the very beginning in order to ensure a good perfusion of the brain and of the coronary arteries in this stage of the experiment. 3. The third cannula to be introduced is that into the superior vena cava draining the brain. The tube connected to the cannula (which is clamped during the introduction) dips into a beaker from which the blood is sucked back into the venous reservoir by one of the two rubber pumps. 4. The last cannula to be introduced is the one into the brachiocephalic artery. All the system of tubes connecting this cannulawith the apparatus are filled with blood. Thecannula is quickly introduced into the artery, the clip on the superior vena cava is removed, and the circulation through the brain is started, the circulation through the heart and lungs being now separated from that of the brain. The only occasion when the brain is not supplied with blood is during the introduction of the arterial cannula, and this stage is passed through as quickly as possible. In cases when this operation was unduly prolonged the brain was found to be in a state of diminished activity for a considerable period of time. The conjunctival reflex as a rule disappears even with a rapid introduction of the cannulae, but it quickly returns and remains active as long as cerebral circulation is maintained. The reflexes of deglutition and salivary secretion, and the respiratory efforts continue as before. The artificial respiration is now changed to a mixture containing 4-0 to 4-8 p.c. CO2 and not less than 60 p.c. of oxygen. This percentage of CO2 ensures that the high pulmonary ventilation does not render the tissues acapnic, and the high tension of oxygen serves to minimise the effect of the blood issuing from the vena cava superior, reducing the oxygen saturation of the mixed blood in the common reservoir. The inverse relation between arterial blood-pressure and heart rate which was first demonstrated by Marey(7) has received different explanations. Bernstein(s), Fran9ois-Frank(s), Biedl and Reiner(lo) and Gerhardt(ii) believe it to be of a purely central vagal origin. Kochmann( 2) regards it as a reflex through the vagus centre, but finds that the centre itself is insensitive to changes in blood-pressure. Filehne and Biberfield(l3) state that the slowing of the heart rate depends entirely on the rise of intracranial pressure. Amongst recent authors Hedon(14) and Foam(1) subscribe to the theory of purely central origin of bradycardia, while Eyster and Hooker(16), as well as Tournade, Chabrol and March and(17), believe it to be based on a dual mechanism involving a central and a reflex stimulation of the vagus. Anrep and Starling state that "there is at present not sufficient experimental evidence in favour of any reflex mechanism being involved." Heymans, however, finds that the bradycardia and the vagus tone alike are purely reflex. It must be added that MacLeod(ls) and Stewart and Pike(19) regard the vagus tone as being reflex, while Tiegerstedt(20) ascribes it to a central stimulation. In view of all these contradictory statements

5 REGULATION OF HEART RATE. with regard to Marey's Law our first problem was to pursue the enquiry by means of our new technique. The central mechanism. Our experiments show, contrary to Heymans' observations and in confirmation of the results of Anrep and Starling, that with the vagi and sympathetic nerves intact a rise of the blood-pressure in the head is followed by slowing of the heart rate. The central mechanism thus becomes obvious as a factor of the Marey's Law, since the conditions in the heart itself with regard to output, arterial pressure and temperature remain constant throughout the experiment. Moreover, the slowing of the heart rate on raising the cerebral blood-pressure and the acceleration when the pressure in the head is diminished does not depend on the rate at which the change in pressure is produced. A quick rise of the cerebral pressure has the same ultimate effect as a rise produced slowly. Once the heart rate has been changed, either by a rise or by a fall in the cerebral pressure, it continues to beat at its new rhythm so long as the cerebral pressure remains unaltered. The effect of a fall of the cerebral pressure cannot be explained on the basis of an inadequate blood supply of asphyxia since changes in pressure of not more than mm. of mercury have often a considerable effect on the heart rate, while they have only a small effect on the blood flow through the head. In experiments in which the brain remains in a good condition the effect of changes in the cerebral pressure upon the heart rate can be observed at any stage of the experiment. The sensitivity of the brain to changes in bloodpressure varies from experiment to experiment. In most cases, however, we found that changes below a pressure of mm. of Hg had little or no effect on the heart rate. Changes produced in the higher ranges of pressure progressively increase in their effect. For instance, in many experiments, a rise of the cerebral blood-pressure from 60 to 100 mm. retarded the heart rate by only 10 to 20 p.c. while a rise of pressure from 140 to 170 mm. caused nearly a complete arrest of the heart lasting for a considerable time. Fig. 3 B and Exp. 1 illustrate the effect of changes in the cerebral pressure upon the heart rate. Exp. 1. Output of the heart 468 c.c. per min. The systemic blood-pressure is maintained between 90 and 105 mm. of mercury. Cerebral blood-pressure Heart rate per min The systemic blood-pressure dropped below 60 mm. when the cerebral pressure reached 200 mm. of mercury. 219

6 220 G. V. ANREP AND H. N. SEGALL. The reciprocal nature ofthe central regulation ofthe heart rate. C o o p e r (21) found that a temporary occlusion of both carotid arteries caused an acceleration of the heart beat. Fran9ois-Frank ascribed this effect to a stimulation of the sympathetic fibres; Hunt (22) and later S cilia no (23) explained the acceleration by a diminution of the vagus tone, while Schiff and Navalichin(24) found the acceleration to persist even after injection of atropine or after section of both vagi. Hunt and Sciliano, as well as Kish and Sakai(25), ascribe the effect to a diminution of the vagus tone and a simultaneous increase of the sympathetic tone. The acceleration of the heart rate is generally considered to be due to asphyxia of the brain or to the fall of cerebral blood-pressure. The opposite effect of a rise in the arterial blood-pressure was -ascribed by those authors who believed in the central origin of the effect either to the diminution of the vagus tone or to increase in the sympathetic tone. In our experiments we found that the effect is chiefly due to a stimulation of the vagus centre but to a small extent also to a diminution of the tone of the accelerator centre. The part played by the latter can be noticed after section of both vagi or injection of atropine, when a rise in the cerebral pressure still causes a slight retardation of the heart beat (Exp. 2). Exp. 2. Output of the heart 404 c.c. Systemic blood-pressure 100 mm. Both vagi cut. Cerebral blood-pressure Heart rate per min After extirpation of the stellate ganglia as well as section of both vagi the retardation disappears completely. Extirpation of the stellate ganglia alone does not change the effect to any appreciable extent. Since the changes in the cerebral circulation were never such as to cause any anaemia of the brain, it must be concluded that a rise in the bloodpressure in the brain besides stimulating the vagus centre also inhibits the centre of the accelerator nerves, and conversely a fall in the cerebral pressure stimulates the sympathetic centre and inhibits the vagal centre. The central mechanism of regulation of the heart rate is therefore of a reciprocal nature. A rise in the cerebral pressure produced by an injection of a small dose of adrenaline caused in our experiments an extreme slowing of the heart beat (Fig. 2). The blood flow through the brain was in most cases affected only slightly or not at all, so that asphyxia could not occur. Similarly to the slowing of the heart produced by the mechanical rise in the cerebral blood-pressure, the slowing produced by adrenaline is mainly due to an increase of the vagus tone but also to a diminution of the sympathetic

7 REGULATION OF HEART RATE. 221 tone. After section of both sets of nerves adrenaline injected into the cerebral circulation has no effect upon the heart rate. The effect of adrenaline upon the central nervous system can be observed at any stage of an experiment, provided the brain is in good condition. The slowing of the heart is not completely abolished by artificially maintaining the cerebral pressure at a constant level. However, this does not imply a specific action of adrenaline upon the vagus centre, since as shown by Anrep and Starling the pressure in the brachiocephalic artery does not necessarily run parallel with the changes in pressure in the circle of Willis. Fig. 2. Output of the heart 560 c.c.; blood flow through the head 180 c.c. per min. At A, injection of 0*2 c.c. of 1: 100,000 adrenaline into the cerebral circulation. At B the cerebral blood-pressure is reduced artificially so as to bring about a return of the heart beat to its previous rate. At C the cerebral pressure is returned to normal; the,heart rate, however, remains slow for a long time and returns only gradually. The tone of the accelerator nerves. The fact that the sympathetic fibres play a part in the central regulation of the heart rate makes it necessary to assume an existence of a definite tone of accelerator nerves. The presence of such a tone was obvious in most of our experiments and this could be shown in two ways, as follows: 1. An extirpation of both stellate ganglia led in almost every experiment to a retardation of the heart rate after a preliminary quickening. This retardation was most marked when the removal of the sympathetic ga-nglia was performed after the section of both vagi.

8 222 G. V. ANREP AND H. N. SEGALL. 2. After section of both vagi the heart assumes a rate which is quicker than that generally observed in a denervated heart-lung preparation. If after section of the vagi the circulation in the head is stopped and the whole preparation thus transformed into a denervated one, the heart after a considerable acceleration assumes a rate which is far below the one before cessation of the cerebral circulation (Exp. 3). The temperature of the blood in the heart and the mechanical conditions of the cardiac circulation remain in these experiments unchanged. It must be noted that the experiments with the removal of the stellate ganglia were performed under good circulatory conditions with a good oxygen supply to the brain. In one of the experiments in which the sympathetic tone was very obvious the blood in the cerebral circulation was 98 p.c. saturated with oxygen and contained 47 vol. p.c. of C02. Exp. 3. Both vagi cut. Output 456 c.c. Systemic pressure 92 mm. The heart rate keeps steady at 198 beats per min. After arrest of the circulation in the brain the heart rate per min. was (readings taken every 30 sec.) 210, 222, 234, 240, 252, 252, interval 3 min., 220, 204, 204, 198, interval 3 min., 186, 180, 180, 174, interval 3 min., 152, 152, 152. The effect of anoxcemia upon the vagus centre. Experiments upon the vagus centre under different tensions of oxygen and C02 will form the subject of a further communication. In the present paper we shall describe only the effects of inadequate blood supply or insufficient oxygenation of the blood. In our experiments anoxsemia was produced either by a temporary arrest of the cerebral circulation or by an insufficient oxygenation of the blood. In the latter case the artificial respiration was changed from 60 p.c. oxygen to air containing in both cases about 4 p.c. of C02. The observations upon the effect of a sudden cerebral anaemia did not present any new points. The first and immediate effect is always an acceleration of the heart which is best explained by the sudden fall of the cerebral blood-pressure. After about 1 minute the vagus centre is re-excited, the heart slows considerably and if the anaemia is prolonged may stop; soon, however, the vagus centre becomes paralysed and the heart now under the influence of the accelerator nerve beats at a much faster rate than before the cerebral aneemia. If the anaemia is produced after section of both vagi only an accelerator effect is observed. This shows that in the first case both centres are being simultaneously stimulated by the aneemia, the effect of the inhibitory centre predominating over that of the accelerator. Thus the two centres lose under these conditions their reciprocal relation. Readmission of blood quickly removes the effect of ansemia causing

9 REGULATION OF HEART RATE. an acceleration of the heart rate when the vagi are still active, and a retardation after their section or their paralysis. In both cases readmission of blood removes the excess of tone of the centres. Exp. 4 gives an example in which the blood on readmission was at a much higher pressure than before the anaemia. It can be seen that the excessive tone of the vagus centre was removed as soon as the period of aneemia was terminated: the heart accelerated its beat much beyond its rate before the period of anaemia. Soon, however, the vagus centre again entered into a hypertonic state, responding to the mechanical influence of the high pressure so that the heart rate came back again practically to the same extent as during the period of anaemia. This hypertonic state was now removed by dropping the cerebral pressure to its original level (Exp. 4). Exp Output of the heart 768 c.c.; systemic blood-pressure 100 mm. Readings every 30 seconds. Cerebral blood-pressure Heart rate per min We believe that experiments of this kind explain some of the contradictory statements made with regard to the central effect of bloodpressure. They show that the vagus centre can be in at least three different states: (1) when it is excited by high blood-pressure, the accelerator centre losing some of its tone and both centres causing a retardation of the heart; (2) when the vagus centre is excited by cerebral anwemia, the sympathetic centre being excited simultaneously; and (3) during the transition stage from stimulation by anaemia to the stimulation by high pressure, when the centre has lost its excessive tone created by the anwmia but is not yet responsive to the effect of high bloodpressure. In those experiments in which anoxeemia of the brain was produced by insufficient oxygenation of the blood without changing the C02 tension in the respiratory air or the blood supply to the brain, it was found that these three different states of the vagus centre were more pronounced and succeeded each other in gradual stages. The first effect of anoxaemia on the vagus centre is found in the alteration of its response to mechanical changes in the blood-pressure. Increases in the perfusion pressure are found to have a progressively smaller effect until, finally, they cease to have any effect at all. Often the heart is at this stage accelerated, and we are unable to state whether this acceleration is due to a diminution in the vagus tone or to increase in the sympathetic tone. On prolongation of the period of

10 224 G. V. ANREP AND H. N. SEGALL. anoxeemia the vagus centre is re-stimulated, the heart rate slows and now every rise in the blood-pressure causes an acceleration of the heart beat by removing the excessive inhibitory tone. Section of both vagi performed at this stage causes an extreme acceleration of the heart which is now subjected to the unrestrained influence of the excited accelerator centre. Increases in the cerebral pressure performed now retard again the heart beat by removing some of the excessive tone of the accelerators (Exp. 5). Exp. 5. Output of the heart 540 c.c. Systemic pressure 92 mm. Respiration with 60 p.c. 02 and 2 42 p.c. CO2 10 mins. after changing to air 15 mins. 20 mins. After section Cerebral and 4-1 p.c. CO2 after after of both vagi blood- Heart - - pressure rate C.B.-P. H.R. C.B.-P. H.R. C.B.-P. H.R. C.B.-P. H.R Group 1 represents the normal response of the vagus centres to an increase in the cerebral pressure. Group 2 shows the first effect of anoxsmia in that the effect of a rise of the cerebral blood-pressure is diminished. In Group 3, which is recorded 5 minutes later, the effect of raising the blood-pressure is absent. Group 4 shows the slowing of the heart which is due to the stimulation of the vagus centre by anoxsemia; a rise in the cerebral blood-pressure relieves the state of anoxaemia and instead of slowing the heart further now produces an acceleration. Group 5 is recorded immediately after section of both vagi but with continuation of anoxaemia; a rise in the cerebral blood-pressure removes the excessive tone of the sympathetic nerves and again reduces the heart rate. As stated above we have not studied the effect of oxygen lack and of CO2 separately, and we are not in the position to state at present even the approximate oxygen saturation which is necessary for the maintenance of the vagus centre in a normal condition. After complete denervation of the heart cerebral anaemia has no effect on the heart rate. The evidence presented thus far leads us to the conclusion that an increased cerebral blood-pressure has under physiological conditions an antagonistic effect upon the vagus centre and the sympathetic cardiac centre, increasing the tone of the first and diminishing the tone of the second. A mild degree of cerebral anoxaemia gradually renders the vagus centre insensitive to changes in the arterial blood-pressure.

11 REGULATION OF HEART RATE. Prolongation of the anoxammia or greater degrees of anoxaemia stimulate both centres so that they tend now to antagonize each other. We do not find any explanation for the negative results of Heymans except only in the damage which was produced in his case by section of the spinal cord, and which abolished the sympathetic innervation of the heart. With an inadequate blood supply to the brain, the blood flow of which he could not determine, the vagus tone might have been due to an anoxsemia which prevented the rise in blood-pressure from causing a retardation of the heart beat. Heymans mentions that in the early period of some of his experiments he obtained an indication of the central effect, a fact which he considers to be of no importance since it disappeared very soon. 225 In our experiments, the rise in pressure in the brain produced this effect normally, so long as the experiment lasted. The reflex mechanism. (a) The effect of changes in the aortic pressure. The innervated heartlung preparation allows us to change the blood-pressure in the aorta and in the heart without simultaneously affecting the pressure in the brain. Our experiments complete the observations of Anrep and Starling in showing that Marey's Law is based not only on the central mechanism but also on a reflex mechanism. In confirmation of the observations of Heymans we find that a rise in the aortic pressure, without any corresponding change in the cerebral pressure, produces a slowing of the heart beat (Fig. 3 A and C). This slowing of the heart is of a reflex origin and entirely disappears after section of the vagi. After destruction of the sympathetic nerve supply the reflex remains unchanged, but after injection of atropine we still find in several experiments a small diminution of the heart rate following an increase in the aortic pressure. These experiments suggest that the reflex mechanism of the regulation of the heart rate like the central mechanism is most probably based on a dual innervation, the vagus and the sympathetic nerves working in a reciprocal manner. Since the reflex disappears after section of the vagi the afferent path most probably runs in these nerves. We did not perform any experiments with the object of determining the seat of the peripheral receptor organs. The existence of separate central and reflex mechanisms, which both play a part in Marey's Law, shows a striking similarity between the mode of innervation of the cardiac inhibitory centre and the vaso-motor centre, both centres being under central and reflex control. The reason why the results of the experiments by An rep and Starling

12 226 G. V. ANREP AND H. N. SEGALL. were negative with regard to the reflex mechanism is not quiite clear. But it is certain that the central nervous system in our experiments was Fig. 3. Showing the reflex retardation of the heart rate at A and C, and the central retardation at B. The two parts of the figures were taken from two different experiments. in a considerably better condition. Moreover, in our experiments not only was the brain but also the heart supplied with blood containing approximately a normal amount of CO2. There are also some definite conditions under which either the reflex or the central effect can be observed with greater facility. In cases when the vagus tone is reduced because of a low cardiac pressure we find it more difficult to produce a slowing of the heart by a rise of pressure in the brain (this was the case in most of the experiments by Heymans who worked on the spinal animal). If, on the other hand, the vagus tone is diminished on account of a low cerebral pressure it is more difficult to decrease the heart rate by the reflex effect of high aortic pressure. (b) The effect of changes in the output on the heart rate-the " Bainbridge reflex." It has been well established on the denervated heart-lung preparation that neither arterial pressure (and therefore the magnitude of the coronary flow), nor the changes in the output of the heart have any influence upon the heart rate. In the whole animal Bainbridge(26)

13 REGULATION OF HEART RATE. 227 showed that the heart rate is affected by changes in its minute output, an increase in the output being followed by a considerable acceleration of the heart. This acceleration Bainbridge found to be based on a reflex which is initiated from the venous side of the heart due to increase in venous pressure. The afferent path was traced along the vagi, and the efferent mainly along the vagi, but also to some extent along the sympathetic nerves, The cardiac acceleration was thus the result of a reciprocal action of the two sets of nerves. Bainbridge obtained the increase in the output of the heart by means of injections of saline or defibrinated blood into the circulation of the whole animal. His experiments are open to criticism on account of the alteration of the composition of the blood, introducing changes with respect to its oxygen and C02 saturation, its H-ion concentration and its viscosity. Moreover, the changes in the output of the heart and in the venous pressure affected not only the venous side of the heart but also the circulation in the centres and in the lungs. Sassa and Miyasaki(27) confirmed the observation of Bainbridge, using rubber balloons to raise the pressure in the big veins and auricles. This eliminated the introduction of foreign fluids but introduced a number of other complicating factors. Since the Bainbridge reflex may be open to criticism on these grounds, we decided to perform a series of experiments upon this question. All our results showed definitely that the Bainbridge reflex does exist and plays a very important part in the adaptation of the heart to changes in the circulatory conditions. Since we used the heart and lungs as a heart-lung preparation, it is obvious that any increase in the venous inflow into the heart within certain limits had no effect upon the arterial blood-pressure. Any rise in the arterial pressure accompanying very large increases in the inflow could be corrected practically instantaneously by adjusting the artificial resistance. The factor of temperature had also to be considered. According to Mansfeld(2s) a sharp rise in the venous temperature of even less than one degree sets in operation an accelerating reflex. Kish and Sakai(29) deny that the acceleration is of a reflex origin and find no differences in the reaction of the heart to changes in temperature before and after denervation. Nevertheless, we thought it advisable to maintain the temperature of the circulatory fluid both in the heart and in the brain rigidly constant. With large flows this was not found to be difficult, and though in many experiments we observed changes of something less than ± 0.30 C. in others there was no change in temperature whatsoever. The Bainbridge reflex was observed in all these experiments. The

14 228 G. V. ANREP AND H. N. SEGALL. heart began to accelerate a few seconds after the output was increased, reached its maximum rate within 60 to 90 seconds and remained accelerated so long as the increased output was maintained. When the output was again reduced to its original volume the heart slowed down and reached its original rate within a couple of minutes. The acceleration was never such as to keep the output of blood per beat constant, but this was generally reduced by one-third or one-half of what it would have been without the operation of the Bainbridge reflex (Figs. 4 and 5). After.4 R_ ~~~~~~~~~_ Fig. 4 (bottom tracing). On increasing the minute output of the heart from 300 to 630 c.c. per min. the heart rate accelerates from 93 beats to 132 beats. The output per beat which was 3-3 c.c. (figures in brackets) increased on account of this acceleration instead of to 6-8 c.c. only to 4-8 c.c. On reducing the minute output the heart rate returns to normal. The blood-pressure in the head was kept at 110 mm. Hg. Fig. 5 (top tracing). Same as Fig. 4, but the cerebral pressure is slightly lower and the heart beats faster to start with. A large augmentation of the minute output increased the heart rate from 114 to 174 beats per min. and this output per beat instead of increasing from 2-4 to 9-8 c.c. increased only to 6-4 c.c. The blood-pressure in the head was kept at 125 mm. Hg. section of both vagi the reflex disappears entirely, but it is still present after extirpation of the stellate ganglia. In experiments in which the efferent fibres of the vagus were paralysed by atropine the reflex was found to be greatly diminished, and after extirpation of the stellate ganglia absent. We thus confirm the conclusions of Bainbridge that the reflex' is of a reciprocal nature, involving the inhibitory and the accelerator nerves. The afferent path appears to lie exclusively in the vagus nerve.

15 REGULATION OF HEART RATE. 229 As regards the location of the receptor part of the reflex our experiments are of a negative character. Bainbridge regarded the rise in the venous pressure as being the stimulus which sets the reflex in operation. He did not consider, however, several other factors which are involved in every case of increased output, namely, (1) increase in the diastolic volume of the heart, affecting the muscle and the visceral and parietal layers of the pericardium, (2) increase in the pulmonary pressure. To describe briefly the results of our experiments, we can say that the reflex is unaltered after section of the pulmonary branches of the vagi and after removal of the parietal layers of the pericardium. On many occasions we observed a definite Bainbridge reflex with a minimum rise of the venous pressure, and in several cases the venous pressure did not rise at all or rose only for a short time. We therefore think that the question of the location of the receptor part of the reflex arc should be still left open and that it is premature to regard the venous pressure as being responsible for the reflex. APPENDIX. The depressor and the pressor reflexes. Some vascular reactions were observed in the course of the preceding experiments, which though not subjected to special study speak in favour of the existence of a distinct depressor and pressor reflex as advanced by Pavlov(30) and by MacDowell(31). Anrep and Starling showed that a sharp fall in the aortic pressure is accompanied by a rise in pressure in the perfused upper part of the body. This effect could be explained either by a diminution of the depressor tone or by a separate pressor reflex. In several of our experiments we obtained the same effect but could not decide with certainty between the two possible explanations. However, we have recorded up to the present three different experiments in which it was possible to determine the threshold bloodpressure in the aorta at which the depressor reflex is set into operation. In this way the depressor mechanism could be separated from the pressor reflex. Changes in the blood-pressure above 120 mm. caused in one of these experiments a definite depressor action; variation in p;essure between 80 and 120 had no depressor effect. We can conclude, therefore, that the threshold aortic pressor of the depressor reflex was in this experiment about 120 mm. Hg. In the same experiment a fall of pressure below 80 mm. Hg was accompanied by an evident rise of the pressure in the head. Since the depressor mechanism was not involved

16 230 G. V. ANREP AND H. N. SEGALL. we believe that this increase in pressure speaks in favour of the existence of a separate pressor mechanism and thus supports the conclusion reached by Pavlov and Mac Do well. Both reflexes disappeared after section of the vagi. Experiments of this kind do not bear out the suggestion that the natural thresholds of the reflexes are usually separated by a kind of gap in which neither one nor the other are stimulated. CONCLUSIONS. 1. The experiments described in this communication were carried out on the innervated heart-lung which is described in the text. 2. In confirmation of the experiments of Anrep and Starling and contrary to those of Hey mans, the heart rate was found to be influenced directly by the blood-pressure in the brain. A rise in the cerebral pressure caused a slowing of the heart rate, an effect determined by a reciprocal action of the vagus and the sympathetic nerve I. 3. Anoxsemia of the brain diminishes and finally reverses the central effect of blood-pressure upon the heart rate. 4. In confirmation of the experiments of Heymans and contrary to those of Anrep and Starling, the heart rate was found to be influenced also by reflexes arising from changes in the aortic blood-pressure. A rise in pressure caused a retardation of the heart. 5. The observation of Bainbridge that an increased output of the heart gives rise to a reflex acceleration of the heart beat finds confirmation in our experiments with the innervated heart-lung preparation. We wish to express our thanks to Mr R. A. Nash for the very valuable assistance he rendered us during this work. The expenses of this research were defrayed by a grant from the Medical Research Council held by one of us (G. V. A.). 1 During the preparation of this paper a preliminary communication by Hering came to our notice in which he claims to have shown that the central effect of bloodpressure upon the heart rate is based upon a reflex originating within the sinus caroticus, the afferent path being in the glossopharyngeal nerve. After destruction or denervation of the sinus changes in blood-pressure had no effect upon the heart rate. In conjunction with R. A. Nash one of us (G. V. A.) found that after destruction of the sinus caroticus changes in the cerebral blood-pressure continue, in the innervated heart lung preparation, to exercise the effect upon the heart rate as described in this paper.

17 REGULATION OF HEART RATE. 231 REFERENCES. 1. Anrep and de Burgh Dalv. Proc. Roy. Soc. 97. p Anrep and Starling. Ibid. 97. p Heymans. Arch. Internat. de Pharmac. et Therapie, 30. p Martin. Philos. Trans. p Hering. Pfliiger's Arch. 72. p Starling and Knowlton. This Journ. 44. p Marey. Mem. Soc. Biol. p Bernstein. Zeits. f. d. med. Wissensch. p Francois-Frank. Trav. du Labor. de Marey, 4. p Biedl and Reiner. Pfluiger's Arch. 73. p Gerhardt. Arch. f. exp. Path. u. Pharm. 49. p Kochmann. Zeits. f. Physiol. 20. p ; Arch. intern. de Pharmacodyn. 16. p Filehne and Biberfield. Pfluiger's Arch p Hedon. Arch. intern. Physiol. 10. p Eoa. Ibid. 18. p Eyster and Hooker. Zeits. f. Physiol. 21. p ; Amer. Journ. Physiol. 21. p Tournade, Chabrol and Marchand. C. R. Soc. Biol. 1. p MacLeod. Physiol. and Biochem. 3rd ed. p Stewart and Pike. Amer. Journ. Physiol. 19. p Tiegerstedt. Physiol. d. Kreislaufes, 2nd ed. 2. p Cooper. Guy's Hospital Reports, 1. p Hunt. Amer. Journ. Physiol. 2. p Sciliano. Arch. Ital. di Biol. 33. p Schiff and Navalichin. Quoted after Sciliano. 25. Kish and Sakai. Pfliiger's Arch p Bainbridge. This Journ. 50. p Sassa and Miyasaki. Ibid. 54. p Mansfeld. Pfluiger's Arch p Kish and Sakai. Ibid p Pavlov. Ibid. 20. p Mac Dowell. This Journ. 59. p PH. LXI. / Q