Principles of General Physiology

There is no reason to suppose that there is any difference between the components of the electro-cardiogram other than that due to the different times of arrival and duration of the excitatory state at the various parts of the heart muscle. * Tn the skin of the frog, it has been shown that the electrical change can still be obtained when the saline solution in the leading off electrodes is replaced by water ; so that a clear proof is given that the electrical effect is not merely due to the electrolytes of the leading off solution. In accordance with the membrane theory, we find that both here and in the case of plant tissues the electromotive force is modified by the concentration of the cations of the leading off solution.

A brief account is given in the text of the electrical fish, and the interest of the phenomena from the general point of view, as regards reflex co-ordination and so on, is pointed out. The electrical phenomena in plants are readily explicable in terms of changes of permeability of the cell membrane. IN organisms of microscopic dimensions there is obviously sufficient opportunity for interchange of soluble materials by diffusion, without the necessity for special provision to enable the products of the activity of one organ to reach another organ with due rapidity. With increase in size this is no longer the case, and is especially important with regard to the supply of oxygen.

Fl(5. 218. A I'ACE FROM THE REPRODUCTION OF HARVEY'S MANUSCRIPT NOTES. Accordingly, we find more or less rudimentary methods of causing iow of body fluids from one part to another in early stages of evolution. The objects of such currents, which later become developed into those of a special fluid, the blood, in a system of closed tubes with a pump, the heart, may be said to be, in general, threefold : — 1. The supply of food, inclusive of oxygen, to all parts of the organism.

2. The removal of waste products of activity, which would paralyse function if allowed to accumulate. 3. The carriage of chemicai substances from an organ in which they are produced in order to influence the activity of other organs. This function has (Photographed by Elliott & Fry from the picture by Mierevelt in the Council Room of University College, London. The original is in the possession of University of London, University College. Reproduced by permission.)

come especially into prominence in recent years in the theory of internal secretions, or hormones. In the early stages this fluid is not confined to special channels, but passes through interspaces in the tissues. A kind of pump, the heart, is very early met with, even in such simple vascular systems, and it serves to accelerate the flow. In some organs in the higher vertebrates there are remains of this lacunar system of circulation, in the spleen, for example.

History. — It is a matter of common knowledge that Harvey (1616 and 1628) (From the reproduction in Jl. R. Micron. Soc., 1913, part 2. By the kindness of the Council. ) was the first to grasp the fact that the function of the heart is to drive the blood along the blood vessels and back to the heart in a circle. This knowledge he gained by experiments on living animals, combined with deductions from the direction in which the valves of the heart and of the veins allowed the blood to flow. The first statement appears to be in the manuscript notes of lectures given in 1615 to the College of Physicians of London. These notes have been published in facsimile by the College of Physicians, at the instance of the late Sir Edward Sieveking. The reader may be interested to glance at Fig. 218, in which a page from this facsimile is reproduced. The statements to which Harvey affixes his initials, he intends 4o claim as his discoveries. The transcription of

the first eight lines of this passage, as given in the book referred to, reads thus : — " WH constat per fabricam cordis sanguinem per pulmones in Aortam perpetuo transferri, as by two clacks of a water bellows to rayse water constat per ligaturam transitum sanguinis ab arteriis ad venas unde A perpetuum sanguinis motum in circulo fieri pulsu cordis." It is to be remembered that these notes were only meant to be used by the lecturer to assist his memory, so that a translation must be somewhat free. It may be given thus : " WH shows, by the way the heart is made, that the blood is perpetually driven from the lungs into the aorta, ' as by two clacks of a water bellows to rayse water.' He shows, by means of ligature, the passage of the blood from arteries to veins. Hence it is demonstrated that the perpetual movement of the blood takes place in a circle, owing to the beat of the heart."

The more complete demonstration was given in the book published in 1628. A portrait of Harvey is given in Fig. 219. The demonstration of the actual passage of blood from arteries to veins in the peripheral parts of the circulatory system was first given by Leeuwenhoek in 168G (see H. G. Plimmer, 1913, p. 130). He saw it in the tail of the tadpole by the aid of the microscope which he had invented. A portrait of Leeuwenhoek will be found in Fig. 220.

Malpighi in 1661 (see Foster, 1901, p. 97) saw the capillaries in the dried lung of the frog, but it was Leeuwenhoek who first detected, in the living animal, the blood actually passing from artery to vein through the capillaries. Although the first clear presentation of the circulation of the blood was made by Harvey, it is plain that Leonardo da Vinci (1452-1519) was not far from the discovery. It seems evident from his descriptions in the " Quaderni d'Anatomia " that he realised that the function of the heart is to drive the blood into the arteries. One of his drawings of the heart and blood vessels in man is given in reduced size in Fig. 221, and some sketches illustrating observations made on the movements of the heart of the pig, when killed by inserting a " piercer " for wine casks into the heart, in Figs. 222 and 223. In the description of these observations he states, " il core nella sua espulsione del sangue si racorta," " the heart shortens itself during its expulsion of the blood " (" Quaderni d'Anatomia," I. p. 22. Line 8 of Fig. 223).

In Fig. 221 the curious "mirror" writing used by Leonardo will be noticed. It is sometimes stated that this is a proof that the artist was left-handed. This view is confirmed by the fact that his shading is always drawn from left to right downwards. Others hold that it is much more probable that he could use either hand equally well, and adopted the mirror writing as a protection against ecclesiastical interference, since the nature of the writing was not discovered for a considerable time, and it was thought to be a cipher.

Since the blood vessels, as they get further from the heart, divide up into smaller and smaller branches, it will be clear, from the account given on page 241 above, that the internal friction of the blood causes considerable resistance to the flow. A somewhat high pressure is thus required in the main arteries to drive the blood at an adequate rate through these small vessels. It may be repeated here that it is in the small arterioles that the chief resistance occurs, on account of the fact that the rate of flow is great here, and the friction is proportional to the square of the velocity. In the capillaries, although they are, individually, narrower than the arterioles, the rate of flow is small, owing to the sectional area of the bed being greatly increased by the great increase in their number. A high arterial pressure is also of advantage when the arterioles of an active organ are dilated. The high blood pressure enables a considerably greater flow to take place through the organ, without notable diminution of that through other organs. Moreover, a much more

FIG. 221. COPY OF THE DRAWING BY LEONARDO DA VINCI OF THE ANATOMY OF THE HUMAN VASCULAR SYSTEM. — Reduced in size. delicate adjustment of flow can be effected with a high driving pressure than with a low one. The fact that mammals possess a high arterial pressure was shown by Stephen Hales (1733). The second volume of his book, " Hsemastatics," opens with the description of his famous experiment, which I will give in his own words : — " In December I caused a mare to be tied down alive on her back . . . having laid open the left crural artery about 3 in. from her belly, I inserted into it a brass pipe whose bore was 1 of an inch in diameter ; and to that, by means of another brass pipe which was fitly adapted to it, I fixed a glass tube, of nearly the same diameter, which was 9 ft. in length : then untying the ligature on the artery, the blood rose in the tube 8 ft. 3 in. perpendicular above the level of the left ventricle

of the heart : but it did not attain to its full height at once ; it rushed up about half way in an instant, and afterwards gradually at each pulse 12, 8, 6, 4, 2, and sometimes 1 in. : when it was at its full height, it would rise at and after each pulse 2, 3, or 4 in. ; and sometimes it would fall 12 or 14 in., and have there for a time the same vibrations up and down, at and after each pulse, as it had, when it was at its full height; to which it would rise again, after 40 or 50 pulses."

The circulatory system, then, consists of a branching system of tubes, the arteries, arising from a pump, the heart. After dividing up into a fine network of capillaries in the various organs, the vessels reunite to veins, which enter the heart again at the opposite end. In mammals there are what amounts to two separate circulations with two pumps, although the two pumps are combined together side by side in the heart, where they are called right and left auricles and ventricles, respectively. Fig. 225 is a schema of the circulation in birds and mammals. In the fish there is only one circulation. The venous blood, arriving at the heart is sent first through the aerating organs, the gills, from which it is distributed to the arteries

of the body in general. In the amphibia and reptiles, part of the blood only passes through the lungs, which may be considered to be one of the parallel paths of the diagram. There are, however, arrangements by which a more or less perfect separation of the aerated blood from the venous blood is effected, so that the organs may have the benefit of that which contains most oxygen. Details of these arrangements may be found in the textbooks of comparative anatomy. In the schema, the blood which has lost its oxygen to a great extent, and taken up excretory products, is represented black. As is well known, this blood appears blue by reflected light through the skin. "Blue blood" is that which is of comparatively little use for the demands of the organism.

As remarked above, Leonardo da Vinci realised that the heart is an organ which, by its active muscular contraction, decreases periodically in its volume, and thus drives out the blood which has run into it during the time in which it was relaxed. Owing to the high pressure necessary to drive the blood through the peripheral arterioles, it is clear that, unless there were valves at the origin of the aorta to prevent the blood flowing back, this pressure could only last for a moment, during the contraction of the ventricle, and also that no -blood, or very little, could run in from the veins, since the ventricle would fill up from the aorta. In fact, there would be a very inefficient circulation. Valves are obviously necessary between the auricles and ventricles also, to enable the energy of the ventricular contraction to drive the blood into the aorta or pulmonary artery against the pressure existing there, and not backwards to the veins.

Owing to its great importance, the physiology of the heart and the circulation has probably attracted more attention than any other branch of the science. It is clearly impossible to refer to the whole of this work, so that I must confine myself to facts which seem to be of the most general interest. Further details may be found in the book by Starling (1912). The general properties of the muscle of the heart have been described on pages 45 1-454 above.

The energy given out by the muscular contraction of the ventricles is, apart from the heat produced, used in raising the pressure in the aorta and in giving to the mass of blood a certain velocity. The former is mainly expended, to begin with, in stretching the elastic walls of the arteries. The kinetic energy of the latter is only a small fraction of the whole work when the output is small. According to the data given in Starling's book (1912, p. 1032), in the human heart the kinetic energy only amounts to 0'7 grammetre per beat ; whereas the former, measured by the product of the volume of the blood driven out by the pressure to which it is raised, amounts to about 81-6 gram-metres. On the other hand, when the output is large, as in muscular work, the kinetic energy of the blood current is an appreciable fraction of the total external work of the ventricular contraction. Evans finds, for example, that with an output of two litres per minute, the kinetic energy amounts to as much as 16 to 18 per cent, of the whole. In the case of the right ventricle, owing to the low pressure in the pulmonary artery, the product of volume and pressure is probably a much smaller fraction of the whole work than in that of the left ventricle. The pressure here is taken as the mean between the aortic pressure at the moment of opening of the aortic valves and that when they close again as the ventricle begins to relax. It is obvious that, for an accurate estimation, we need to know the time course of the pressure and to determine the integral of it.

In order to determine the time curve of the pressure change, a manometer is necessary which is capable of following exactly the changes of pressure without distortion by inertia of moving parts, and so on. The first approximation to such an instrument was made by Starling and myself (1894), and the curves we obtained were very similar to those which Piper (1912, 2, and 1913, 2 and 3) has published as the results of a much more perfect method. This method, also an optical one, is described in the first of the papers

named. Fig. 226 is a reproduction of a simultaneous tracing of intra-ventricular PRESSURE CURVES FROM AORTA (UPPER TRACING) AND LEFT VENTRICLE (LOWER TRACING). — To be read from right to left. Note that the aortic pressure does not begin to rise until the intra-ventricular pressure has risen to the level of S\. The wave at S\ on the ventricular curve lies in time between K and 8-2 of'the aortic curve. The notch J of the aortic curve is considerably later than the beginning (IF) of the fall of pressure in the ventricle.

(Piper.) and aortic pressures, and Fig. 227 a diagram showing the relations between FIG. 227. CURVES SHOWING SIMULTANEOUS CHANCES OF PRESSURE ORDER FROM ABOVE DOWN.— To be read from left to right. a, Closure of auricula-ventricular valve. 6, Opening of aortic valve. 4, Slow rise of pressure in auricle, due to inflow of blood from the veins. This pressure falls again as soon as the relaxed ventricle allows blood to enter it. are that the auricular contraction (1) produces only a slight increase of pressure in the ventricle, since the latter is quite lax. As the ventricle contracts, there is a small rise of pressure in the auricle, due to pressing back of the mitral valve as it closes. The ventricular pressure rises rapidly, without any increase in aortic pressure, since the semilunar valves are closed by the greater pressure in the aorta. As soon as the intra-ventricular pressure is slightly greater than that of the aorta (at 6), these valves open and the aortic pressure rises simultaneously with the further rise in the ventricular pressure, the two curves being practically parallel, until the ventricle commences to relax. Since blood is flowing from ventricle to aorta during this period, the pressure in the former must be somewhat higher than in the latter, and we notice that it is not until the ventricular pressure has fallen somewhat, at the line c, that the semilunar valves close, marked by a series of vibrations on the aortic curve. The further course of the ventricular pressure curve is independent of that of the aorta. The significance of the remaining points marked on the curve will be found in the description of the figures. The actual shape of the top of the ventricular pressure curve, during the time of driving blood into the aorta, varies according to the resistance in the arterial system. It may be dome-shaped or have indications of waves on it, but, on the whole, it is a kind of plateau, compared with the rapid rise and fall. It appears, then, that the form found by Chauveau and Marey, and confirmed by Bayliss and Starling, is the correct one, although the waves are somewhat exaggerated in these, especially in Chauveau and Marey's.

The more or less sharp-peaked curves, obtained by some investigators, are due to insufficient accuracy of response of the instrumental method used. It is interesting to note that there is no change in length of the muscle fibres of the ventricle until nearly the full height of contraction is reached. It will be remembered that A. V. Hill (page 443 above) showed that the maximal external work is obtained from skeletal muscle if not allowed to shorten until the full state of tension is developed, so that the heart muscle works, in this respect, under nearly optimal conditions. Owing to the curvature of the heart, however, it is clear that only a part of the force of the contraction is exerted in the direction required, namely, inwards, so that the fibres act at a considerable mechanical disadvantage.

The researches of Patterson and Starling (1914) show that the work done by the heart is determined by the amount of blood flowing into the ventricles from the venous side. Up to a very high rate of inflow, the power of raising this volume to the aortic pressure is fully adequate. The limit at which this power fails is much higher than had been supposed from previous experimental work, in which sufficient venous supply was not provided. Put in another way, the energy produced in a ventricular contraction is in direct proportion to the length of the muscle fibres at the time when contraction begins. Thus the heart muscle obeys a similar law to that of skeletal muscle, in which we saw (page 443 above) that the energy developed is in relation to the magnitude of certain action surfaces in the fibres.

Patterson, Piper, and Starling (1914) show in more detail how the length of the muscle fibres during contraction determines the output. The energy of each systole is proportional to the preceding diastolic volume. This view is found to explain all the facts. The same relationship was shown by Kozawa (1915) to hold for the heart of the tortoise. The heart sounds have for centuries attracted attention, chiefly owing to their use in clinical diagnosis. Thos. Lewis (1913, 2), by an improvement in the microphone method of Einthoven, has obtained interesting records with the string galvanometer, using two parallel strings, so that the electrical change of the muscle can be recorded at the same time. This addition to the instrument has shown itself very valuable also in comparing the electro-cardiograms from different leads. Fig. 228 gives three records, one a normal record from the

Fio. 228. RrcoRDS OF HEART SOUNDS; — Taken simultaneously with the carotid pulse? Lowest curve, movements of a second string of the jralvanometer, connect cd witli a inicro]>lione OMT the The carotut pulse is interjwsed between the other two. Time in s'nth sec. Tincontinuous vertical line marks the lie^iiinin^r of the ventricular systole, the dotted line the end. II, Heart sounds from a ]>atient with incompetent mitral valve. The murmur (systolic) is at SJ/., of

rapid rate of vibration, and in the niiddle of the ventri<-nl;ir systole. C, From a case of incompetent aortic valres, trivinjr a musical murmur during the whole of diastole. dog, one from a human patient with a systolic mitral murmur, due to escape of blood through the imperfect valve during systole, and a third in which there was a musical murmur during diastole, due to incompetence of the aortic valves. The second sound, a sharp one, is caused by the sudden tension put on the aortic valves as they are shut by the aortic pressure when the ventricle begins to relax. The first sound, of a softer and more prolonged character, appears to be due to two causes ; one, the closure of the auriculo-ventricular valves, the other the muscular contraction, since it can be heard in the excised, empty heart. The pitch of this second element is the same as that of the resonance of the ear passage, which exaggerates the vibrations which correspond to its own period.

Some facts relating to this question have been already given (page 612). The work of Rohde (1912) and of Rohde and Nagasaki (1913) requires a little more detail. In order to be able to control the conditions, the isolated perfused heart (cat or rabbit) was used in the method described in 1910, with the improvement of placing the whole in a thermostat. The object was to determine the relation between the activity and the chemical changes, including the consumption of oxygen and of glucose, the production of carbon dioxide and of other end products.

The first result is identical with that of A. V. Hill, already mentioned, on skeletal muscle, namely, that there is a direct proportionality between the oxygen consumption and the pressure developed in isometric contraction, in which the volume of the heart does not change. An important point is that, although the pulse rate is considerably lower at 15° than at 36°, the oxygen consumption per millimetre pressure developed is the same, within the limits of experimental error, namely, 427-436 x 10~7 c.c. of oxygen. This fact of the absence of temperature effect on the conversion of chemical to mechanical energy is, no doubt, an important one from the point of view of energetics ; what it means is not yet clear, although the surface energy as a " limiting factor " is indicated.

From the work of Zuntz and his co-workers on the whole animal we know that we can convert the oxygen consumed into its equivalent of oxidised food-stuff, in the proportion of calories developed. This was found to hold in the heart. The ratio of pressure developed to calories produced by oxidation was the same, whether glucose with a respiratory quotient of 0'98, or the "reserve stuff" of the heart itself, with a respiratory quotient of 0-80, was consumed.

In short, the ratio of the chemical energy of oxidation, or calories, to the amount of pressure developed is a constant number. To obtain further insight into the mechanism of the energy change, experiments were made in which the heart was placed under abnormal conditions, narcotics, want of oxygen, the influence of muscarine, of veratrine, etc. It was found that the heart muscle worked less efficiently ; that is, less pressure was developed in proportion to the oxygen consumed. As a first step towards the analysis of these results, the behaviour of the heart as regards different food-stuffs was investigated. When glucose was present in the circulating Ringer's solution, the carbohydrate was consumed along with certain reserve materials present in the cells themselves. As to the chemical nature of these " reserve stuffs " we have little information. There is no evidence that protein is consumed in muscular contraction. In fact, the experiments of Athanasiu and Gradinesco (1912) seem to show that it is not. They kept the excised heart of a frog beating normally for thirty-three days, giving about 360,000 beats, in Ringer's solution containing glucose and oxygen only, in addition to the salts. Any store of protein, if used for energy purposes, must have been exhausted early in the experiment. If any was used, it could only have been the minimal amount required for repair of the machine. See also the work of Evans and Matsuoka (1915) as regards the relation of oxygen consumption to the production of energy.