Principles of General Physiology

Rohde found that the effect of adding atropine, or adrenaline, or retarding oxidation by potassium cyanide, is to increase the consumption of glucose and (probably as a secondary effect) to diminish the relative amount of reserve material consumed. The sugar does not appear to be completely oxidised, since, especially under the action of cyanide, organic acids and aldehydes are formed. The effect of increase of carbon dioxide is interesting. Here there is no evidence of abnormal forms of oxidation of glucose, and yet the amount of pressure produced per unit of oxygen consumed is enormously depressed. The pressure produced, in fact, falls almost to zero, yet the oxygen consumed continues to be more than half that of the normal period. It seems that the chemical processes go on normally, but the change of chemical to mechanical energy is prevented by carbon dioxide.

The experiments of Mines (1913, 3) have shown the importance of H- ion concentration as regards the spontaneous beat of the heart. He finds that there is an optimal concentration. Excess may abolish the mechanical change while the electrical change may remain intact. The absence of Ca" ions has the same effect, as shown in Fig. 172 (page 539). Whatever may be the impulses that cause the heart to beat rhythmically in certain invertebrates, as in Limulus, where Carlson (1904) showed that they are given off by ganglion cells, there is no doubt that the heart muscle of the vertebrate is capable of rhythmic beats in the absence of nerves. This fact is shown most conclusively, perhaps, by the experiments of Burrows (1912), who showed that bits of heart muscle from embryo chicks continued to beat in blood plasma as long as thirty days, and that cells wandered off from the mass and continued to multiply. The newly formed cells then commenced to beat rhythmically. Similar facts are described by Margaret R. Lewis (1915) for skeletal muscle.

It was first definitely shown by Gaskell (1882) that all the phenomena observed in the hearts of the frog and tortoise are to be explained satisfactorily on the basis of a " rnyogenic " origin, that is, not only does the beat arise spontaneously in muscular cells, but also the conduction of the excitation from one part of the same heart cavity to another part of that cavity, and from one cavity to another, takes place by muscular tissues. A portrait of Gaskell will be found in Fig. 229. This view was taken up by Engelmann on the Continent, and powerfully supported by his work. Now, while there is no difficulty, as far as muscular continuity is concerned, in the case of the lower vertebrates, it was believed, -until the work of Stanley Kent (1893) and of His (1893), that there is no muscular continuity between the auricles and ventricles of the mammal. These observers showed that there is a bundle of a special kind of muscle fibres at a particular place, putting the muscular structures of auricle and ventricle into direct connection. The anatomy of the "bundle of

His," as it is called, was further worked out by Tawara (1906), and it is almost universally accepted now that the transmission of excitation in the mammalian heart takes place by means of this muscular bundle. Kent (1893 and 1914) describes another conducting path between the right auricle and the external wall of the right ventricle ; but it is doubtful whether this has any functional importance under normal conditions. The existence of nerve fibres in the heart muscle is sufficiently accounted for by the vagus and sympathetic supply. Whether there is any kind of transmission by a nerve network seems very questionable ; the heart beat is certainly not initiated by periodic discharges of ganglion cells, and if a nerve network plays any part in the transmission of excitation, it must be one of that kind whose existence has never been proved in the higher animals (see pages 472-473 above). It must be, in fact, able to conduct equally in all directions. Beats can be obtained by stimulation at any point of the heart muscle, and auricular beats can be brought about by backward transmission from the ventricle.

As was shown by Gaskell, the automatic rate of each chamber, when it is beating by itself, is slower than that of the chamber preceding it in the cardiac cycle. Thus, in the frog and tortoise, the rate of the sinus is the quickest, that of the bulbus slowest, the order being sinus, auricle, ventricle, bulbus. The sinus is therefore the "pace-maker." In the mammalian heart there is no separate sinus. Where is then the "pace-maker"? An excellent account of the history of the work on this question will be found in the paper by Thos. Lewis (1913, 3). The main facts only can be given here. Keith and Flack (1907) found traces of sinus tissue in certain parts of the auricle, especially at the junction of the superior vena cava with the right auricle. At this point there is a collection of peculiar muscular tissue in intimate relation with the nerves entering the heart. The clearest proof that the normal beat arises in this " Keith-Flack node " has been given by Thos. Lewis (1910). The principle of the method used is simple, depending merely on the fact that muscle in excitation is electrically negative to that at rest. By taking a series of photographs, with the string galvanometer, of the electrical effects from electrodes placed on various points of the auricle, it was shown that the normal beat actually commences in this sino-auricular node. This place was found to become electrically negative before any other place. From it the excitation spreads in all directions. Confirmatory evidence that the beat takes its origin here is afforded by the effect of warming and cooling the node, which is to affect greatly the rate of the whole heart, whereas similar results cannot be obtained from any other part. There is also other evidence, although less conclusive.

The work of Sansum (1912), on the shortened compensatory pause after extra-systoles, shows that the sino-auricular or Keith-Flack node behaves like the sinus of the frog. When the sino-auricular node is put out of action in any way, the beats are initiated by a point in the auriculoventricular bundle of His. They are transmitted from this point in both directions, so that simultaneous contraction of auricle and ventricle results. The rate of discharge of this node is, normally, slower than that of the Keith-Flack node, so that the latter sets the pace. Some observations by Cushny (1912) suggest that there is an additional cause for the subordination of the auriculoventricular node. If the bundle of His be cut across on the auricular side of its node, the ventricle is cut off from the impulses arriving from the auricle. But it does not at once develop its own rhythm, and Cushny brings evidence to show that the node is normally kept in a state of diminished excitability, owing to fatigue, by the impulses reaching it from the auricle. A similar state can, in fact, be induced by artificial stimulation of the auriculo-ventricular node, and is not due to inhibition.

We must suppose that these nodes discharge when they have stored up something to a sufficiently high degree, and that, after a discharge, they are incapable of further discharge until a fresh quantity has been formed. The experiments of Gaskell on the effects of clamping the auriculo-ventricular junction seem to show that the local effect of the clamp is to depress the rate at which the capacity of the tissue to contract is recovered. When the clamp is gradually closed, at

a certain stage it is found that the ventricle only responds to every second or third beat of the auricle. The cause must be at the part clamped, and due to the fact that a second impulse arrives before the tissue has recovered from the previous contraction. It is not easy to see how this could happen if the tissue were merely a conductor of excitation, since mere conduction would not leave the tissue in so pronounced a state of inexcitability. Lewis (1915, 1) gives the following summary of the course of the excitation wave in the dog's heart. Starting from the sino-auricular node, it spreads in the auricle in all directions, finally arriving at the auriculo-ventricular node, where it is delayed. It then passes along the bundle of Purkinje tissue and is distributed to all parts of the ventricular muscle by the branches of this tissue, which conducts much more rapidly than the muscle itself. The advantage is a more simultaneous contraction of the whole of the ventricle. The actual conducting tissue consists of striated muscle, containing large amounts of glycogen. The following are the rates of conduction in the three different tissues concerned : —

In the toad, Lewis (1915, 2) finds that the excitation spreads along the interior of the ventricle and passes out radially to the surface. The general direction of travel is thus from base to apex, but, at the surface, the extreme base is usually activated somewhat later than the apex. The electrical change in the heart muscle has been discussed in the preceding chapter, and it is sufficient to refer here to the value of the electro-cardiogram as a method of investigation. We have seen above how it was used to determine the site of the pace-maker, and it is of equal value in detecting irregularities of transmission from auricle to ventricle, especially as they occur in disease.

The hearts of the higher vertebrates have, as would be expected, effective means of supply of oxygen by arteries which arise from the commencement of the aorta. The factors which influence the flow through this " coronary " circulation have been investigated by Markwalder and Starling (1913), using the method of Morawitz of introducing a canula into the coronary sinus. They found that the heart is insufficiently supplied with oxygen if the aortic pressure is lower than about 90 mm. of mercury, an important fact to be remembered in experimental work. The most potent agents in increasing the rate of flow are non volatile metabolites produced by the heart muscle itself in its activity. These substances are present in considerable amount in asphyxia ; in fact, the maximum circulation through the coronary vessels is just when the heart fails. Adrenaline causes dilation, probably by its action in increasing the rate and strength of the beats. The amount of blood flowing through the coronary vessels is very considerable, much more than had been supposed by previous workers. We shall have occasion to return to the question of the action of metabolites on blood vessels later. Since their concentration becomes so much greater in asphyxia, it -seems that they are such products of activity as are normally removed in oxidation processes : lactic acid naturally occurs to the mind. The products of partial combustion of carbohydrates, as in Rohde's experiments (page 678 above), may also play a part. We have seen (page 611) that the anaerobic products of cell metabolism, however, are not necessarily the same as the intermediate products of normal oxidation.

In recording the movements of the heart cavities, each for itself, the myocardiograph of Cushny (1910, 1) is very useful. For determining the intraventricular or aortic pressure, Piper's modification of Frank's apparatus, already referred to, is the most accurate. The changes in volume of the heart are followed FIG. 230. EFFECT OF VAUUS STIMULATION UPON THE AURICULAR BEATS AND UPON Upper tracing1, ventricle of turtle, at rest owing to presence of clamp on auriculo-ventricular groove.

The effect of vagiis stimulation at B is to slow the auricular rhythm, and thus the conducting tissue is enabled to transmit the wave of excitation to the ventricle. At A, with weaker stimulation, where the rate is unaffected, but the strength diminished, the ventricle remains by some form of plethysmograph, such as the glass cardiometer of Jerusalem and FIG. 231. EFFECT OF VAGUS ON CONDUCTION. — The ventricle, owing to auriculo-ventricular clamp, follows only each alternate beat of the auricle. Stimulation of the vagus causes complete block, together with diminution in size of auricular beats, without change of rate.

§tarling (1910). The output of blood may be recorded by the method described by Ishikawa and Starling (1912). Inhibition. — The discovery by the brothers Weber of the fact that the heart can be stopped by stimulation of the peripheral ends of the vagus nerves was of such fundamental importance that a few words as to its history are required. It was at the meeting of Italian Scientific Investigators at Naples in 1845 that Ernst Heinrich Weber made the announcement that he, with his brother Eduard, had found this to take place. As Tigerstedt (1893) remarks, a new kind of nervous action was brought to light, of which previously there had been scarcely any idea, an action which could never have been discovered by anatomical observations alone. A nerve, which supplied a muscle, was stimulated, and instead of strengthening or accelerating the movements of the muscle, they were slowed or stopped altogether. The original communication is, unfortunately, published in an Italian medical journal difficult of access (Omodei's Annali di Medicinal), But in 1846 Eduard Weber wrote an article, " Muskelbewegung," for Wagner's " Handworterbuch der Physiologic," which included an account of the work. It was found that stimulation of the vagus nerve inhibited the heart, not only in the frog, but also in fish, birds, the cat, dog, and rabbit. It is well to transcribe the words used : " Eine auf das Mannichfaltigste abgeanderte

Reihe von Versuche, welche ich gemeinschaftlich mit meinem Bruder Ernst Heinrich aufgefiihrt habe, hat uns zu der Entdeckung geftihrt, dass durch Reizung der Nervi vagi oder der Hirntheile, von dem sie entspringen, das Tempo der rhythmischen Bewegungen des Herzens verlangsamt und sogar das Herz ganz zum Stillstand gebracht wird" Since the work of the Webers, a large number of investigators have taken up the question of the action of the vagus on the heart, but we do not yet know what the nature of inhibition is. The problem has been discussed in some preceding pages of the present work (pages 418-427). I wish here to draw attention to some aspects of it as affecting the heart, referring the reader especially to the article by Gaskell (1900) for further details up to the date of the article.

Fio. 232. ACTION OF VAGUS ON CONDUCTION FROM AURICLE TO VENTRICLE. — Dog's heart. Middle signal, artificial stimulation of auricle by single shocks, five per second. Lower signal, time in seconds. Before the stimulation of the vagus, the ventricle follows each auricular beat, with an occasional omission. During stimulation of the vagus, it responds to each alternate As Engelmann pointed out (1899), the action of the vagus is shown under four aspects : —

2. On the strength of the beat (" inotropic "). Shown in the auricular 3. On the capacity of the muscle for conducting excitation (" dromotropic "). Shown for the turtle in Fig. 231, and for the dog in Fig. 232 (see the descriptions of the figs.). 4. On the excitability to direct stimulation (" bathmotropic "). Mac William showed that the heart muscle, in some cases, is inexcitable under How far these different effects are aspects of the same fundamental change is not definitely known, but it seems probable.

In the mammal, Cohn and Lewis (1913) have shown that the left vagus has more effect on the junction between auricle and ventricle than the right one has. On the other hand, the right nerve affects production of impulses in the auricle more than the left one does. The facts are of interest in connection with what we have seen as to«the facts of impulse formation in the sino-auricular node, together with the conducting function of the tissues in which the auriculoventricular node is situated. The former is at the mouth of the superior vena cava, and the latter at the opening of the coronary sinus, which are the representatives, respectively, of the right and left ducts of Cuvier of the embryo. Thus, the right and left vagi act preferentially, each on that structure with which it would naturally be expected to be in morphological relationship.

Colin and Lewig are of opinion that these results favour the view that the FIG. 233. ACTION OF ACCELERATOR NERVES IN- IMPROVING CONDUCTION. 1, Ventricle stimulated at the rate marked by the lowest signal, namely, 22 shocks in five seconds. The auricle does not follow until the accelerators are stimulated as shown by the top signal. At the end of the tracing the artificial stimulation of the ventricle is stopped, and the normal rate of the beat is seen (17 in five seconds). Time in seconds given by the middle signal.

2, At the beginning the natural rate of the heart beat is seen (14 in five seconds). During the period shown by the middle signal, the auricle was stimulated at a rate of 25 in five seconds. The ventricle is unable to follow, until the accelerators are stimulated (top signal). Time in seconds by bottom signal. particular aspects of vagus action, obtained reflexly by Engelmann, depend on the particular attributes of the tissue in which the fibres end, rather than on different functions of the same muscle.

Thos. Lewis (1914) further finds that the effect is more profound upon the auriculo-ventricular node than upon the sino-auricular node. Some important conclusions as to the mode of action of the vagus on the ventricle are to be drawn from the work of Mines (1914) on the frog's heart. It is shown that atropine, applied to the sinus, eliminates the action of the vagus <m the rate of the beat, while the effect on the auriculoventricular junction and the ventricle remain. In these conditions the vagus decreases the rate of transmission from auricle to ventricle, and diminishes the duration of the state of excitation in the muscle fibres of the ventricle. This is associated with weakening of contraction in all parts of the ventricle, and not to failure of some of them to get excited at all. This diminution of duration of excited state by the vagus explains why it changes the sign of the final T-wave in the electro-cardiogram, if we admit that the negativity of the base indicated by this wave is due to the greater duration of the excitatory state at the base than at the apex. The action of the vagus being more powerful at the base than at the apex, it has the effect of reducing the duration of the excited state at the two to approximate equality, and thus tends to produce a simple diphasic effect. The application of atropiue to different parts of the ventricle, by which the vagus endings are paralysed locally, confirms the conclusions arrived at.

Augmentor Serves. — Like smooth muscle, the heart is supplied with two kinds of nerve fibres, inhibitory and excitatory. The latter were discovered by Von Bezold (1863), and their existence proved in a convincing manner by Von Bezold and Bever (1867). A tracing of their effect on the heart of the toad is given in Fig. 114 (page 406). In general, it may be said that the effect of the accelerator nerves is exercised on the rate and the strength of the beat, and on the conducting power of the muscle and, in all cases, in an opposite direction to that of the vagus. Fig. 233 shows the improvement of conduction. Increase of excitability has not, so far as I am aware, been demonstrated directly.

These nerves arise from the sympathetic system. Their antagonistic relation to the vagi has been discussed above (page 407). Reflexes to Heart Serves. — Both the vagus and accelerator nerves can be excited reflexly. It is not yet definitely known whether there is reciprocal innervation, such as that of the vasomotor reflexes, in the reflexes to the heart. Whether, for instance, when reflex slowing of the heart is produced, there is, along with excitation of the vagi, inhibition of tone of the accelerator centre. Bainbridge (1914) finds that reflex acceleration of the heart is produced by inhibition of vagus tone, together with excitation of accelerators, but could find no evidence of inhibition of accelerator tone in reflex slowing. Possibly there was no tone in the accelerator centre, although the heart was apparently beating at a maximal rate. This may, however, have been from its own pace-maker, when relieved from vagus control.

The heart reflexes are closely interconnected with those to the blood vessels, and further facts with regard to them will be referred to along with the latter. Exact investigation of the phenomena of the circulation was impossible until Ludwig (1847) invented the graphic method of recording blood pressure. His portrait will be found in Fig. 234. Owing to the necessity of the pump being rhythmically active, the fact that the blood vessels possess elastic walls has considerable importance. Since the blood cannot pass through the arterioles as rapidly as it is driven into the aorta, if the arteries were rigid and unable to accommodate, temporarily, the excess of blood driven in by the contraction of the heart, it is plain that the efficient action of the heart would be put to great strain, owing to the incompressibility of the blood. Moreover, much less blood could be expelled at each beat. The result of the stretching of the arterial wall by the beat of the heart, owing to the elastic reaction when the aortic valves are closed, is to convert the rhythmic flow from the heart into a continuous one through the capillaries.

A further necessary incidental result of the elasticity of the arterial wall is the pulse wave. As the fijjst portion of the system is distended by the blood, it tends to close again, having, in fact, a certain period of vibration. This distension, therefore, disappears at one point and passes on to the next at a rate depending on this period of vibration. Details of the form of the pulse wave have not sufficient general interest to warrant description here, although they have considerable practical importance, as indicating states of the heart and blood vessels. It must be clearly understood that the wave of distension travels along the arteries at a much faster rate than the blood current itself. That the progression of a wave is independent of the current of the fluid itself is well

shown by observing a sea-gull floating on a fairly calm sea. It will be seen that it merely rises and falls as the waves pass under it, without any change in its position otherwise. Httrthle (1912 and 1913) believes that he has found evidence that there is an active contraction of the arteries at the latter part of each systolic, wave, so that the blood is forced onwards by it. On the assumption that the rate of the current of blood through a certain length of artery is proportional to the difference of pressure between the two ends, it was found, under certain conditions, that the rate of the current was greater towards the end of the systolic part of the pulse wave than corresponded to the difference of pressure at this time. It is also stated that the amplitude of the pulse wave, instead of decreasing towards the periphery, as it does in the dead animal, is increased in the living animal, especially when the blood vessels are constricted. The interpretation of the facts is difficult, and further investigation is required. There is, of course, the possibility that the muscle of the arterial wall may respond to distension by a contraction, as that of the earthworm and the frog's stomach does (page 436). This idea is supported by some observations by Carl Tigerstedt (1913), who found an electrical change in the carotid artery with each heart beat. The direction of the deflection was such as to imply that the electrode nearest the heart became negative before the more distant one.

The nature of this, as conditioned by the internal friction of the blood, has been explained above (pages 241-242). The blood of the dog has a viscosity about five times that of water. How far changes in this property occur in physiological conditions and their effect on the blood pressure have not received much attention. According to Burton-Opitz (1911), the viscosity of normal blood is much higher than that of defibrinated blood. Deep narcosis with ether increases the viscosity, which falls again as the narcosis is diminished. Carbon dioxide also increases the viscosity; hence venous blood, in addition to the effect of loss of water, has a slightly higher viscosity than arterial blood. The viscosity, also, as would be expected, increases with the number of corpuscles per unit volume ; and that of laked blood is less than that of the same blood before laking. Of course, dilution of the blood, as happens after loss of blood, has a considerable effect in reducing the internal friction.

The general effect of the existence of the peripheral resistance is to enable the heart to produce a high arterial pressure, with the advantages as regards regulation of blood supply to organs following therefrom, as already pointed out. It is scarcety necessary to say that the peripheral resistance must not be stated to be the cause of the blood pressure, which is due to the energy produced by the muscular contractions of the heart. It has been shown by Dreyer and Ray (1910) that the volume of the blood in mammals is satisfactorily given by the formula —

k where B is the blood volume in cubic centimetres, W the weight of the animal in grams, n approximately §, and k a constant varying with the particular species. In other words, the blood volume is a function of the surface and would be exactly proportional to W* if the animal were spherical. The formula also implies that smaller individuals of the same species have a relatively greater volume of blood than the larger ones. This relation is obviously an important fact when doses of toxin or drugs are

to be given and it is required to know their concentration in the blood. It may therefore be useful to give the values of the blood constant, k, as far as determined:— The relative dosesr of drugs for adults and children can also be calculated on a more accurate basis than heretofore. If the arterioles of an organ are caused to dilate, the volume of the blood flowing through the organ is increased, and the pressure in the capillaries raised. Coincidently, the peripheral resistance is decreased, so that, if the region in which the dilatation occurs is a considerable fraction of the whole circulation, the aortic pressure falls, unless the heart beat is increased to compensate for it.

Methods of Investigation. — In order to measure the state of the circulation in an organ, we may take tracings of the changes in its volume, due to greater or less distension of its blood vessels, by some plethysmographic method. In this method the organ is enclosed in an air-tight box, provision being made that the nerves and blood vessels are not compressed, and the interior of the box is connected to some instrument which records by its movement the amount of air sent into or removed from the recorder as the organ alters in volume. It has been suggested that changes in general venous pressure would interfere with the correct interpretation of the results. In actual fact, it has been found that experiments by the plethysmographic method and by determination of the actual rate of flow of blood give the same results. Of course, due account must be taken of changes in the general arterial pressure, which alters the rate of flow apart from local changes. If, for example, along with fall in arterial pressure, the organ decreases in volume, no information is obtained as to any active changes in the blood vessels of the organ itself. But, if the organ expands with a fall of arterial pressure, no other interpretation is possible than that its blood vessels have actively dilated. If the organ contracts, with a fall of arterial pressure, we cannot draw the conclusion that local vaso-dilatation is absent, because it may be too small to counteract the effect of the general fall of pressure in draining away blood.