Principles of General Physiology

In the text, a number of illustrations are given to show the different aspects of inhibition, as it affects peripheral muscular organs directly, and as it affects nerve centres acting on these organs through nerves. Also on the nerve centres controlling those peripheral organs, such as skeletal muscle, which have no automatic activity of their own. That the excitatory and inhibitory influences act on the same cell is shown, amongst other facts, by the capability we have of exactly neutralising the effect of stimulation of the one nerve by simultaneous stimulation of the one having the opposite effect.

The state of excitation of a nerve centre causing peripheral inhibition can be itself inhibited by nerves acting on this centre, so that we have "inhibition of inhibition." It seems probable that an intermediate neurone, inhibiting a particular motor neurone, may itself be inhibited by an afferent neurone and thus the inhibition of the motor centre may be taken off. Higher centres in the nervous system influence lower centres, either increasing or decreasing their excitability. Hence the phenomena of " spinal shock " and of " decerebrate rigidity."

Inhibitory effects can be brought about by direct action of chemical agents or by the anode of the electrical current. The phenomena of physical interference of wave motion are incapable of explaining total inhibition, whereas it is an experimental fact that inhibition may be complete. The part played by the refractory period is described in the text. Also an explanation is suggested for the results of von Frey on the vasomotor nerves of the submaxillaiy gland.

It is shown how the theoretical basis of the theories according to which " assimilation " or " anabolism " is associated with inhibition is unsatisfactory, and that, if we look upon cell processes from the dynamic point of view, increase of anabolism seems to necessitate increase of catabolism also, instead of decrease, as such theories of inhibition require. There is no satisfactory evidence that the increase of functional capacity, sometimes found to be present after inhibition, is actually due to an increased building up by the inhibitory stimuli. On the other hand, the fact that fatigue of inhibition in nerve centres is found to occur does not necessarily exclude an anabolic explanation, since the fatigue may be situated in an intermediate excitatory synapse.

The seat both of excitation and of inhibition in nerve centres is in the synapses, so that fatigue must in all probability be here also. There is a fundamental misconception at the basis of the " drainage " theories, namely, that the amount of nerve "energy" present in the neuro-muscular system is a constant, limited quantity. Moreover, the occurrence of inhibition without simultaneous excitation elsewhere is left unexplained by such theories. The possibility of productiop of a " block " and its relation to the permeability changes of the membrane is briefly discussed.

Macdonald's theory of adsorption of ions by colloids is shown to have considerable importance as a contribution to the theory of inhibition and excitation. Inhibition can be changed into excitation by strychnine and similar drugs, while excitation can be changed into inhibition by chloroform. The most satisfactory explanation seems to be that the actual processes themselves are reversed. The possibility of a similar phenomenon being concerned in the reversal of peripheral action, such as that of the vagus and of the chorda tympani by certain alkaloids, is pointed out.

The process of excitation in plants, apart from movement, is shown to be essentially similar to that in animals, being independent of visible effects, and accompanied by electrical negativity of the excited protoplasmic structures. Conduction of excitation in plants appears to be through protoplasmic continuity of cells, since it can be abolished by local application of anaesthetics. The " anti-oxydase " reaction of Czapek, as associated with stimulation in plants, is described.

IN the animal organism, the tissues which have the power of effecting movement by changing their form, " contraction," as it is usually called, are known as muscular. It should be made clear at the outset that the word " contraction " is, strictly speaking, incorrect, since there is no change in volume when a muscle becomes active, merely change of shape, by which its two ends are brought closer together. So that, if one end is fixed, the other end moves nearer to it and, if the latter is attached to a movable object, this object moves with it. If the muscle

is prevented from shortening, owing to attachment to an immovable object, a state of tension is developed in it. The mechanism of movement in the plant is of a different kind, and will be described in a special section later. There are two kinds of muscular tissue, which, in the extremes of the scale, have very distinct properties, namely, the cross-striated, skeletal, or voluntary muscle on the one hand, and the smooth, non-striated, or involuntary muscle on the other hand. There are, however, many degrees of transition between them. The heart muscle of the vertebrate is crossstriated, but exhibits many of the properties of the other class ; the claw muscle of the crayfish is another case. Perhaps the most characteristic difference, physiologically, between the two classes is that the typical skeletal, cross-striated muscle, in its highest form of development, is entirely dependent on impulses from the central nervous system to set it into activity ; the other class possesses an automatic activity, manifested in tone, or in rhythmical contraction and relaxation, even when separated from the central nervous system. It is not to be supposed that the involuntary muscle is not subject to control from the central nervous system ; we have seen the contrary to be the case with the intestine, the heart, the blood vessels in the vertebrate and the claw in the crayfish. This last case is, indeed, a difficult one to classify on any system, since, although possessing automatic tone, it is under voluntary control on the part of the anim'al, like the skeletal muscles of the vertebrate. The organs consisting of smooth muscle in the latter organisms, and also the heart, are not under voluntary control, although acted on reflexly.

Some other differences, rather of degree than of kind, may be mentioned. The rate of contraction of the smooth muscle is usually slow, compared with that a to 6 shows the extent to which the lever was pulled down in order to stretch the muscle. of striated muscle ; it has also a longer latent period. There are two properties deserving mention which both classes of muscle possess, although produced in a different way. The automatic tone of smooth muscle has been referred to above; skeletal muscle, under normal conditions, also possesses a certain degree of tone, but it is of reflex origin from afferent nerves in the muscle itself and the joints, etc., ceasing when the nerves are cut. Again, smooth muscle is caused to enter into contraction by stretching, as shown in Fig. 132 (from Straub's paper, 1900). The possible importance of this reaction to stretching will be discussed under vasomotor mechanisms. The changes in the tonus of skeletal muscle produced reflexly by changes of position of the ends of the muscle (that is, changes in the length of the fibres) were investigated by Sherrington and will be described under the head of "plastic tonus" in Chapter XVIII.

Details of structure, especially in the case of the complex one of crossstriated muscle, are extremely difficult to make out at all satisfactorily. Very little, except the alternate dark and light bands, can be seen in living muscle, and we have no guarantee that the various structures seen by different observers, after treatment with reagents, have any resemblance to the living state. The account given by Macdonald (1908) will be read with profit by those interested in the views that have been put forward.

a, in ordinary light. 6, in polarised light, between crossed Nicols. The wave length is about 25 striae ; the maximum degree of shortening is 8-19 show in a reversed position of dark and light bands, but this reversal is absent from b. Note also the intermediate stage of Nos. 5-7 and 20-22, in which the crossstriation in a nearly disappears. In b it is seen that, in contraction, the volume of the anisotropic part (white) increases at the expense of the isotropic part (black). The

figure should have represented the ratio of the heights as 3 : 1. It seems possible that photographs of the living fibre by ultra-violet light, in the manner described in a previous chapter (page 9), might give valuable information with regard to the structure of muscle. A fact of interest is that the dark bands of striated muscle are doubly refracting, that is, they appear bright on the dark field between crossed Nicol prisms. Tf a fibre is made to contract while under the microscope, the dark band becomes light and the light band dark ; but the double refraction does not alter, that is, it is the light band which is now doubly refracting. According to Engelmann (187.3, p. 166), the isotropic (singly refracting) part diminishes in volume in contraction, while the anisotropic (doubly refracting) part increases ; that is, fluid passes out of the isotropic into the anisotropic elements (p. 167 of the paper). Fig. 133 shows this and other facts. It will be seen, in the

appearance under polarised light, that whereas in the resting fibre the two parts are of about equal size, in the contracted part, in the middle of the portion of fibre represented, the clear part considerably exceeds in volume the dark part. Further, Engelmann holds (1875) that contractility is always associated with double refraction ; in the striated muscle fibre it is the anisotropic part which is the active constituent, and Engelmann has detected double refraction in the contractile parts of Hydra, and of various unicellular organisms. The statement is made (p. 460) that contractility, in whatever form it may occur, is connected with the presence of doubly refracting, positive, uniaxial particles, whose optical axis coincides with the

direction of shortening. The isotropic part is supposed capable of excitation, but not of contraction. Hiirthle (1909) concludes, from the evidence of photographs of living fibr ' th ™> chane of volume occurs MKLA CORRULEA WITH (FIXED) CONTRACTION in tne doubly retractive, contractile WAVE, PHOTOGRAPHED UNDER POLARISING elements. The isotropic parts, on the A, with parallel Nicols. B, with crossed Nicols. expense of the Sarcoplasm. Although (After Engelmann. Schafer's " Essentials the photographs of the living fibres

of Histology," Fig. 166, p. 136.) with waves of contraction are certainly out from them whether the statement is justified (see Schafer's criticism of Hiirthle's views, 1910, pp. 72-73). Fig. 134 shows photographs of living muscular fibres under polarised light. The essential point in the mechanics of muscular contraction is that the properties of the tissue change in contraction, so that, if it be not permitted to shorten, a state of tension is developed. It is a difficult matter to give an adequate mechanical illustration of the process, but perhaps it will assist comprehension if we imagine that we have two spirals, one of hardened steel wire, the other of soft lead wire. We now stretch them to the same extent. The coil of steel wire will be in a state of tension, as felt by the necessity to exert a continuous pull upon it to prevent its returning to its original length, whereas the lead wire will have

no tension, oppose no resistance to stretching, and will not return to its original length when released. When a muscle is stimulated, it changes its physical state from that of the stretched coil of lead wire to that of the stretched coil of steel wire. The fact may also be realised if we allow a muscle to shorten on stimulation and then pull it back to its original length, the stimulation being continued. It will require a certain force to do so ; this force may be measured by the weight which it is necessary to hang on the end of a vertical muscle in order to bring it to its resting length. This is, of course, only a rough measurement, because the weight will passively stretch both the resting and the contracted muscle ; so that it will be found that if the weight is applied which is just sufficient to extend the muscle to its unloaded resting length, the weight will fall somewhat when the stimulus ceases, since it stretches the resting muscle to a greater length than its unloaded one. This is the fact involved in the principle of " after-load" in which the weight is supported at the position of the length of the resting muscle and -does not stretch it until contraction takes place.

As we shall see in considering the heat evolved and also in the theory of muscular contraction, the development of tension is the fundamental fact in the process, so that it is of importance to grasp its meaning clearly. The special case of certain muscles which are able to possess the same degree of tension at different lengths requires separate consideration and will be discussed in Chapter XVIII., as it would tend to confuse the issue of the problem before us here.

It is not my intention to give details of the varied phenomena to be observed, especially in skeletal muscle, when stimulated in different ways or when the load is applied or removed at different stages of the course of a contraction. There are some which are necessary for our further discussion and details of the others will be found in the textbooks of Human Physiology. The articles by von Frey (1909) on striated muscle and by Griitzner (1904) on smooth muscle may be consulted.

When a single electric shock is applied to the nerve of a nerve-muscle preparation, nothing happens that can be seen for a period of two- or three-thousandths of a second, as we have already learned. The muscle subsequently contracts at a certain rate and relaxes again. It is not always remembered that I he processes both of contraction and of relaxation are not instantaneous. The curve can be traced, on moving smoked paper, by a lever to which the muscle is attached. The rise is gradual and so is the return. But mere inspection of the curve does not tell us whether the rate of fall was that of a body falling freely, or whether it was, so to speak, allowed to fall gradually by a gradual disappearance of the state of contraction. Tracings in which the lever is released at the top of contraction show that the rate of its fall in such a case is greater than when connected with the relaxing muscle, so that the state of contraction does not cease suddenly at the top of the curve, but disappears gradually. At the same time, as we shall see later, the active process of contractile" stress, or, in other words, the development of energy, ceases at the top of the curve, so that changes of tension applied after this point, do not affect the total amount of energy developed.

When a muscle is held so that it cannot shorten, its contraction is said to be isometric, since its length does not alter ; when it is allowed to shorten in such a way that it raises a weight or stretches a spring, the weight being applied in a manner such that its inertia does not come into play, or the spring such that its tension remains constant, the contraction is isotonic, It will be obvious that a contraction may be of one type in a part of its course, and of another type in the remainder. Since the tension develops gradually, a muscle is able to raise a weight at a later period of its contraction, which it was unable to raise at an earlier stage. Thus the contraction is first isometric, then isotonic. On the other hand, the weight raised may suddenly come against an unyielding obstacle ; the contraction is then first isotonic, then isometric. The contraction of the heart muscle is first isometric, then, after the aortic valves have

opened, auxotonic, that is, it contracts against an increasing resistance, as the arterial pressure rises. There are several forms of experimental twitch, " arrested," " inertia," and so on, which do not concern us here. The external work done is clearly the weight raised multiplied by the height to which it is raised. Although no external work is done in maintaining the weight at this height, it is a familiar fact that fatigue results and the metabolism and heat of the muscle show a considerable consumption of energy. This point will be returned to in a later page.

When we remember that, with zero load and maximum height of twitch, no external work is done, nor when the load is so great that the muscle cannot shorten, a little consideration will show that there must be a load of a certain magnitude with which the maximal work is done ; this is found experimentally to be the case. When the muscle is allowed to relax again with the weight still on, this weight falls to its original position, so that no permanent work is done. To enable a muscle to perform actual external work, Fick devised the " Arbeitsammler " or " work collector" in which, by a system of catches, the weight is taken off the muscle at the height of contraction, so that the weight does not fall again ; but when the muscle makes a further contraction, it catches the rim of the wheel on whose axis the weight is suspended, and raises it by a further amount and so on (see Fick's book, 1882, pp. 139-143).

Blix (1891, p. 306) has described a muscle indicator, which draws a curve whose ordinates are lengths of the muscle and whose abscissa1 are corresponding tensions. The area of the curve is thus the work done. Similarly, in the indicator of the steam engine, the co-ordinates of the curve are pressures and volumes in the cylinder. In order to measure the work done by an animal or man for the purpose of metabolism experiments, some form of bicycle mechanism or treadmill is generally used. A brake is applied so that the amount of work can be varied and determined. The brake may be f rictional, as in the simple but accurate pattern of C. J. Martin (1914), or it may be in the form of a dynamo, as in the earlier apparatus of Atwater and Benedict (see Atwater, 1904), or again as Foucault currents, produced in a copper disc rotated between the poles of an electro-magnet, whose magnetising current can be varied (see Krogh's article, 1913).

When a second stimulus is applied to a skeletal muscle before the muscle has returned to its original length, the contraction due to this second stimulus starts from the level at which the first contraction is at the time, and so on for subsequent stimuli. Thus a summation is produced, by which the extent of contraction is much greater than can be brought about by a single stimulus, however strong. But each stimulus produces less increase than its predecessor, so that, after a certain number have been applied, no further increase in height results ; a constant level only is maintained. This is known as " tetanic contraction."

An effect of the same kind is produced by reflex or voluntary contraction of .skeletal muscle. A series of disturbances at the rate of 50 per second, in the median nerve of man, is sent out from the centre (Piper, 1912, p. 98). This value was obtained by leading off the muscles of the forearm to a string galvanometer. It is practically the same in the case of all the muscles tested, namely, 40 per second in the quadriceps femoris, 60 in the masseter. The shortest voluntary movements always consist of at least three or four waves. It is interesting that the frequency of these waves in the tortoise is a linear function of />'»///»'/v////v, and, indeed, through the wide range from 4° to 40°. Put in other words, we may say that it is directly proportional to the absolute temperature, just as the simplest physical phenomena, such as the volume of a gas, the osmotic pressure of solutions,

or the electro-motive force of a concentration battery. Yet it would seem absurd to draw the conclusion that the rate of discharge of a nerve cell has no connection with chemical processes. Similar facts in the case of the rate of the mammalian heart beat and other processes have been already referred to (page 43). A further interesting fact found by Piper in the experiments quoted is that, at 37°, the nerve cells of the tortoise have the same oscillation period as those of the warmblooded vertebrate, namely, 47 to 58 per second.

It will perhaps facilitate comprehension of the relationship between the various experimental facts, if we first of all consider a condensed statement of the view of the processes taking place in active muscle, which the work of Hermann and others in the past, but chiefly that of Fletcher, Hopkins, and A. V. Hill in recent years, has made it necessary to adopt. When a muscle contracts, tension is developed and external work is done if the tension is made use of to raise a weight or perform other functions requiring expenditure of energy. It is obvious, therefore, that there must be something in resting muscle which possesses potential energy of some kind, and that, on excitation, some change takes place in this system resulting in loss of potential energy. We know that lactic acid is formed and that the actual contractile process is not associated with the giving off of carbon dioxide nor with the consumption of oxygen. It is not, in fact, an oxidation, so that the " biogen " conception fails here. Although there must be some large molecules, or aggregates, containing the lactic acid group, these cannot be of a protein nature with " intramolecular " oxygen as one side chain and an oxidisable group at another place. It appears that the potential energy must be in the form of surface energy or osmotic energy, or both ; at all events, in some form which is not associated with chemical reaction in the strict sense. At the end of the contraction, the cell machinery possesses less potential energy and the systems actually participating in the change, "inogens," if we may use Hermann's name, though not exactly in his sense, have let loose lactic acid.

Now to restore the system to its original state, with increase of energy content, the lactic acid is put back by another reaction. In this process, the system is restored to its original state of high potential energy, so that the reaction by which it is effected must be one in which a considerable amount of energy is set free. This is shown by the large consumption of oxygen and liberation of carbon dioxide, indicating oxidation of some combustible substance. We have seen already (page 271) that no nitrogen metabolism is associated with muscular work as such ; the oxidised substance must therefore be carbohydrate or fat. It appears that carbohydrate is actually used, but fat appears also to be capable of serving the purpose, perhaps indirectly.

After this condensed and somewhat dogmatic exposition, we may proceed to consider the evidence on which the various statements are made. The production of tension, without shortening, is measured by the various methods of tracing isometric curves, as mentioned above. The principle on which these methods rest is that of arranging the muscle so that it shall pull against a strong spring or twist a stiff wire ; thus the very slightest change in its own length is sufficient to produce considerable tension in the spring. This very slight movement is magnified by a long lever, or better by a reflected beam of light, whose movement is recorded on the surface of a moving photographic plate (" optical lever").