General Physiology: An Outline of the Science of Life

The phenomena of fatigue appear, perhaps, still more clearly upon stimulation by the tetanizing current than by single induction-shocks. If the curve of tetanus of a frog's gastrocnemius muscle, not too strong and weighted, be recorded upon a rotating drum, it is seen that it continues at its original height for a long time, and follows a straight line (Fig. 238). But after some time it begins slowly to fall, and, not rarely at the same time, small irregularities in its course become visible, which are due to the fact that the muscle begins to tremble. The curve continues to fall gradually. If the stimulation be interrupted, the curve usually does not sink at once to the level of its startingpoint, but remains some distance above the latter, and only in the course of a considerable time returns to it. Hence there is a considerable contraction-remainder

in the fatigued muscle after the end of stimulation, and the muscle assumes its original length only very slowly. It is of great interest that microscopic changes have been observed in fatigued muscle. Of a number of wholly similar blue-bottle flies (Musca vomitoria) H. M. Bernard ('94) kept some in continual motion by constantly exciting them, until they fell to the ground completely exhausted. The fatigued flies were at once killed simultaneously with the others, which, in the meantime, had remained at rest. The two kinds of specimens were then subjected to the same treatment. A marked difference appeared between them. While in the resting flies the musclefibrillse showed distinct cross-striation and the various discs of the individual segments showed differences in staining-capacity, in the

FIG. 237. — Curve of fatigue ; decrease of the height of the curves with numerous successive contractions of the flexor muscles of the fingers. (After Mosso.) fatigued specimens only Dobie's line was to be seen clearly, and the whole contents of the segments stained uniformly without any differentiation of the discs being noticeable (Fig. 239). But the granules, or sarcosnmes, lying in the sarcoplasm between the individual fibrillse were enormously enlarged in the fatigued, in comparison with the resting, muscle. It would lead us too far to consider in detail the significance of these changes. Hodge ('92), G. Mann ('94), and Lugaro ('95), have recently made known distinct microscopic phenomena of fatigue in the ganglion-cells of mammals,

FIG. 239.— Wing-muscles of a blue-bottle fly (Musca vomitoria). A, At rest; £, fatigued. The division of the muscle-segments into discs has become invisible and the sarcosomes between the fibrillse are enormously enlarged. (After H. M. Bernard.) birds, and insects, especially in their nuclei. Thus, according to Hodge, in the sparrow, in the morning, after resting, the cells of the brachial ganglia, which innervate the wing-muscles, have clear, round, vesicular nuclei (Fig. 241, A), while in the evening, after

the exertion of the day, they have an indented contour (Fig. 241, B). Likewise in the cat, after stimulation for several hours, the nuclei of the ganglion-cells, which previously were vesicular and round, are shrunken and have an irregular contour, while the arrangement of the contents has changed materially (Fig. 240). According to Mann, and also Lugaro, the change of the ganglioncell during its activity consists essentially in a turgescence of the protoplasm and the nucleus, while during rest a diminution in volume takes place. During work the nucleus becomes poorer in chromatin, and, as Lugaro found, by fatigue the nucleolus can

FIG. 240.— Ganglion-cells of the cat. A, In the normal condition ; £, after five hours' stimulation be made completely to disappear. Here belong, also, the fatiguechanges which Heidenhain ('83) observed a long time ago in salivary glands after stimulation, the cell-nuclei of which, in rest, put out pseudopodium-like processes, but after stimulation assume the spherical form (Fig. 242). The fatigued muscles recover as soon as the stimulation ceases, and the more rapidly, the less was the degree of fatigue. In recovery the irritability gradually increases; the various phenomena of fatigue, which can be seen in the curve of contraction, gradually pass away, and, finally, the muscles are in the same condition as before.

That which appears especially interesting is the fact, discovered by Valentin ('47), and Eduard Weber ('46), that excised muscles also are capable of recovery. This, also, can best be seen by the aid of the graphic record of the muscular movement. If an isolated gastrocnemius of a frog be fatigued by being alternately tetanized for perhaps five seconds and allowed to rest for five seconds, after some time, the intensity of the stimulus remaining constant, the curve begins to fall, until, finally, the stimulation no longer produces any contraction, and the muscle remains at rest in a slightly contracted condition, determined by the contractionremainder. If, then, the stimulation be interrupted and the muscle be left to itself for a considerable time, protected from

drying, contractions nearly equal to those before the fatigue can be induced anew with the same strength of stimulus. The muscle now becomes fatigued more rapidly than before. One factor in the recove'ry, which has recently been established in Richet's laboratory by J. Joteyko ('96), is of interest. This is found in the fact that excised muscle recovers only when oxygen is available ; with the exclusion of oxygen after complete fatigue the muscle cannot be put again into activity. Hence oxygen is absolutely necessary for the restoration of the irritability of muscle. But the fact that after great fatigue excised muscle is able to recover in a medium containing oxygen proves that the musclesubstance, while it can perform contractions for a considerable time independently of the circulating blood, must possess in itself,

also independently of the blood-current which brings in food-stuffs and takes out excretory matters, the factors which, in union with oxygen, are necessary to the restoration of irritability. If we turn from the phenomena of fatigue that are externally visible in the muscle itself to those that develop secondarily in the body as results of very strong muscular effort, we meet with certain facts which bring us a step farther in the knowledge of fatigue.

If we observe the phenomena that develop in our body in the course of strong muscular effort, we notice first a considerable acceleration and deepening of the respiration. At the same time the frequency of the heart-beat becomes increased. The production of heat which is increased by the muscular activity, is essentially compensated reflexly by the outpouring of perspiration, the evaporation of which lowers the temperature. If FIG. 242.— Parotid of the rabbit. A, During rest ; the cell-nuclei are indented. B, After stimulation through the sympathetic ; the nuclei have become round. (After Heidenhain.)

the activity has been very considerable, not rarely a slight fever appears, especially when the body has made no muscular effort for a considerable time previously. The temperature rises, there are attacks of shivering, and a certain increase in irritability of the central nervous system is noticeable. This fact is so well known that there is recognised a " gymnast's fever," which appears in gymnastic work after too strong exertion. This fever of fatigue is also very frequently observed after very exhausting mountain tours and after long riding. Among the subjective symptoms that manifest themselves as a result of very strong muscular exertion, the best known are excitement appearing during the stage of the fever, e.g., in the evening after an exhaustive march, sleeplessness, lack of appetite, and intense muscle pains, which appear usually upon the next day or even later.

These phenomena together present an interesting complex of symptoms, which remind the physician very strongly of the picture of events in acute infectious diseases. The conjecture is strongly suggested that all these symptoms that appear as a result of muscular fatigue appear also as the characteristic complex of symptoms of infectious diseases. Concerning the latter, it is known from the later bacteriological investigations that they are the result of poisoning by certain poisonous metabolic products, the so-called toxines,1 which are excreted by invading bacteria. But, like bacteria, a great variety of other forms of living substance excrete poisonous substances in their metabolism, and hence the assumption is not unjustified that the muscles also produce such toxines, which in the quantity usually present produce no effects, but which, as soon as they accumulate in the body in greater quantity as the result of excessive muscular activity, give rise to phenomena of genuine poisoning. Various experiments have proved directly that this conjecture is correct.

The first important experiments were those of Eanke ('65), who found that he could make a fatigued muscle again capable of performing work by washing it out with a dilute solution of common salt which, as is well known, is completely indifferent to living tissue. Hence there must have arisen and accumulated in the muscle as the result of activity certain fatigue-substances, which act to paralyse the muscle-substance itself, but after the removal of which the muscle regains its capacity for work. Ranke was able actually to confirm this by the following experiment. He made a watery extract of muscles that had been strongly fatigued, and injected it through the blood-vessels into a fresh muscle. The result was that the muscle immediately lost its working capacity and behaved exactly like a fatigued muscle. It is proved by this experiment that phenomena of fatigue are caused by the accumulation of certain metabolic products in the muscle, and can be set aside by the washing-out of the latter. More recently Mosso ('91) performed upon a dog an experiment analogous to Ranke's. When he injected into a narcotized dog blood from a normal dog, the former continued completely normal. But if, instead of this, he used for injection blood from a fatigued dog, whose muscles had been kept in violent contraction by tetanization with the electric current for only two minutes, characteristic phenomena of fatigue immediately appeared : the respiration became accelerated and even dyspnceic, and the heart began to beat strongly. Hence the fatigue-substances that are produced in the muscle do not remain there, but are taken up by the blood and thus go to the organs of the whole body. Hence it comes about that after an exhaustive march not only do the muscles of the legs, but also those of the arms, show phenomena of fatigue.

The poisonous substances going with the blood to the brain-centres that control respiration and the movement of the heart, there first produce an excitation, which results in a powerful increase of the respiration and the activity of the heart, but finally with too great exertion cause a depression, which leads to standstill of the heart and death. The history of the runner of Marathon is a classic example of this course of phenomena. But in seeking the origin of muscle-fatigue, we ought not to attach too much importance to the appearance and accumulation of fatigue-substances in the muscle, as is not rarely done. Al- though it is beyond doubt that the phenomena of fatigue can be produced by the accumulation of fatigue-substances, this is not the sole cause. The chief factor in the production of fatigue is the progressive consumption of substances that are necessary to activity. Accordingly, in muscle and probably in all living substance, two different causes of fatigue may be present. Phenomena of fatigue are observed, on the one hand, when certain substances that are necessary to life are consumed during exhaustive activity more rapidly than they are introduced or reformed ; and, on the other, when certain substances that arise as decomposition-products during activity accumulate in such quantity that they produce a depressing effect. On account of this fundamental difference in the genesis of the phenomena in question, it seems advantageous to distinguish between the two causes by the use of different terms, and to call the phenomena of depression that result from the consumption of the necessary substances, exhaustion, and those that result from the accumulation of and poisoning by decomposition-products, fatigue. The end-result of the two series of phenomena arising from such different causes is the same. Both are characterised by depression of the irritability and the activity of living substance.

Let us first bear in mind that excitation and depression are merely quantitative opposites. The two are merely different degrees of one and the same phenomenon, namely, life, excitation being an increase, depression a decrease of the normal intensity of vital phenomena. It has been seen in a previous section that phenomena of depression can be called out by over-stimulation. This fact is important, for it shows that the same stimuli which with slight intensity or short duration produce excitation, with increased intensity or long duration can produce precisely the opposite effect, namely, depression.

This relation between excitation and depression is very widespread. The phenomena of fatigue are a single example of it. In this respect the effects of anaesthetics form a complete analogy to the phenomena of fatigue. It appears to be a general property of these substances that in very small doses or with very brief administration they produce phenomena of excitation, while with increasing action phenomena of depression become more and more noticeable, and apparently are able to lead to a complete standstill of life.1 This fact is well known in pharmacology. Morphine in small doses and at the beginning of its action produces always a stage of excitation, in which the patients are restless and excited, are not able to sleep, and are haunted by all sorts of illusions. But if the dose given be greater, and the stage of excitation appearing at the beginning of its action be passed, deep sleep comes with total absence of motion and sensation. The same result is seen also with other narcotics and with single cells. In ciliate Infusoria the ciliary motion is increased to furious rapidity under the influence of the vapour of ether or chloroform in small quantity or with brief duration. The excitation of the cilia is so great that the organisms shoot through the water like arrows. But if the dose or the duration of the influence of the narcotic become only slightly increased, the motion becomes slower and slower until, finally, complete paralysis results, and the cells remain motionless. The same phenomena have been observed with the many different kinds of anesthetics, and in all sorts of living substance.

Another example of the fact that with increasing intensity of the stimulus excitation is first increased and then after a certain point gives place to depression, is afforded by stimulation by heat.2 With increasing temperature up to a certain degree, which is very different for different forms of living substance and for different vital phenomena in the same form, all vital phenomena undergo an augmentation to a maximum. But if this degree be overstepped, excitation decreases rapidly, and gives place to complete paralysis in the form of heat-rigor. The fermentative activity of yeast-cells, the growth and development of ova, and the protoplasmic and ciliary motions of unicellular organisms, afford distinct examples of this. Other varieties of stimuli illustrate the same general principle.

But this relation of excitation and depression holds good only for those stimuli which consist in an increase of the factors that under normal circumstances act upon the organism as vital conditions, as, e.g., increase of the surrounding temperature, or those which consist in an incoming of foreign factors, as, e.g., poisonstimulations. Those stimuli, however, which depend upon the diminution of vital conditions, as, e.g., decrease of the surrounding temperature, appear in general with increasing intensity to depress vital phenomena without previous excitation. With the present condition of our knowledge a law covering these facts cannot be formulated with certainty, for a cautious critic requires 1 Cf. p. 379. * Cf. p. 396.

a larger number of phenomena before generalising. Nevertheless, large number of discoveries speak directly in favour of the idea here expressed. E.g., with increasing cold the energy of vital phenomena sinks, until at certain low degrees of temperature, which likewise are very different for different objects, apparently complete paralysis results. The experiments of Kuhne ('64) on Amoeba, in which the protoplasmic motion was at a complete standstill in coldrigor at 0° C., as well as a number of other phenomena previously spoken of, afford examples of this. Further, with decrease of moisture the intensity of vital phenomena sinks, until the latter come to a complete standstill. The behaviour of dried, apparently dead, organisms illustrates this. Finally, with decrease of food and of oxygen vital phenomena are depressed, and, as is instanced by the protoplasmic movement of Amoeba in Kiihne's experiments, cease in an atmosphere of pure hydrogen.

The fact cannot be overlooked that there are cases in which with falling temperature, as in the regulation of heat by warmblooded animals, or with decrease of the water-contents, as in drying nerve and muscle, or with decrease of oxygen, as in the asphyxiation of warm-blooded animals in a space free from oxygen, phenomena of excitation are apparent. But the mode of occurrence of these phenomena, which can be investigated in the cell-community only with difficulty on account of the complexity of the conditions, is in large part still obscure, and many investigations directed toward this point alone, especially in single cells or simple tissues, are needed, before it shall be known clearly whether the principle observed in so many cases, that with decrease of the various vital conditions a gradual depression of vital phenomena comes in without previous excitation, really has general application. The question whether within the two extreme limits of vital conditions living substance possesses but one maximum of excitation is surely interesting. There are doubtless many cases in which both augmentation and diminution of the vital conditions produce depression, and in which between these two points excitation rises to a single maximum.

The inevitable end-result of continual or strong over-stimulation is death, but the manner in which it develops differs in individual cases according to circumstances. With continued, not too strong stimulation death develops fairly gradually, and here the stages of the reaction can be followed best. The effect of narcotics may serve as an example. If, e.g., an infusorian cell, such as the ciliate Spirostomum, be exposed to the influence of the vapour of chloroform or ether, there is seen first a

stage of excitation, in which the ciliary motion becomes strongly accelerated. Gradually with continued action the excitation gives way, and there begins a stage of depression resulting in a complete standstill of the cilia. From this stage by interruption of the stimulus and the re-establishment of the normal vital conditions the organism can be revived. If, however, the action continues still further, this is no longer possible ; narcosis passes directly into death. The same thing is seen in human ganglion-cells in morphine poisoning. At the beginning of the action there is a stage of excitation, which soon gives way to a complete paralysis of the ganglion-cells. With too strong a dose the death of the cells results ; this is seen in a standstill of the functions dependent upon them (movement of the heart, respiration, etc.). The same sequence of actions is produced by the thermal stimulus with continual increase of its intensity. The protoplasmic motion of Amoeba increases with increasing warmth up to nearly 35° C. Here the motion suddenly diminishes ; the organism continues in

FIG. 243.— Pelomyxa palustrls. A, Creeping ; B, contracted as a result of feeble chemical Simulation ; C, undergoing granular disintegration with long stimulation. the stage of contraction and performs at most very feeble motions. With a slightly higher temperature the latter wholly cease. This is the point of heat-rigor. Upon cooling from this point motion returns. But, if the temperature rises above 40° C., the heatdepression passes over into death. With thermal stimulation the whole sequence of reactions from the minimum of temperature up to the maximum is presented with the greatest clearness : standstill of vital phenomena in cold-rigor, increasing excitation, depression in heat-rigor, and finally death.

The complete series does not always appear. Very frequently one or the other stage is wanting. This depends partly upon the special qualities of the living substance, and partly upon the kind of stimulation. Often under the influence of stimuli of very high intensities all stages are omitted, and death results at once. Sometimes there is a brief stage of excitation, but intense excitation is followed immediately by death. If, while Pel.omyxa is creeping quietly, it be stimulated only feebly by acids, alkalies.

chloroform, or other chemical substances, in a few seconds it draws itself together into a ball (Fig. 243, JB), and thus gives the impression of intense excitation of contraction. In the course of a longer, constant action of the stimulus the protoplasmic body begins to undergo granular disintegration from the periphery (Fig. 243, C). If, however, the chemical stimulus be allowed to act in greater intensity upon the resting, extended body, the stage of excitation has no time for its development. The body begins immediately, without first contracting into a ball, to undergo granular disintegration in the form which it had at the moment of stimulation (Fig. 244, B). Here death appears immediately as a result of stimulation, while the other stages of the reaction have not time to develop externally. The same is seen in galvanic stimulation. If Actinosph cerium be stimulated by feeble galvanic currents, the typical phenomena of excitation of contraction appear at the anode. The protoplasm of the pseudopodia forms small globules and spindles, and flows centripetally, until the pseudopodia

FIG. 244. — Pelomyxa palustris. A, Creeping; B, undergoing granular disintegration as a result of strong chemical stimulation. are wholly retracted. If, however, a strong galvanic current be applied suddenly, the protoplasm has not time to contract, but immediately undergoes disintegration at the anode. Granular disintegration of protoplasm as a result of supramaximal stimulation is a valuable aid when, as e.g., in stimulation by galvanic currents, the localisation of the excitation is to be determined in objects in which there is no other distinctly visible expression of it. In such cases it is only necessary to employ supramaximal currents, and the place of excitation is recognised at once in the granular disintegration of the protoplasm. Of course this is possible only in forms of living substance which, at the moment of death, show granular disintegration. There are many forms of cells, especially those that are provided with a solid wall, which in dying do not pass into granular disintegration at all. Yeast-cells, e.g., can be killed in various ways by over-stimulation without any disintegration of the body. Their death is indicated only indirectly, by loss of the power of splitting grape-sugar into carbonic acid and alcohol. But we need not here go more in detail into the different forms in

which death appears, since we have previously l become acquainted with them. Over-stimulation, in its most general significance, is nothing but that which has been termed elsewhere external causes of death. The fact does not require special mention that overstimulation, when it consists either in an increase or a decrease of the factors that act as vital conditions, always results finally in death. It has already been seen that overstepping either the minimum or the maximum of vital conditions leads to a fatal outcome.

In a previous chapter we came to regard life as a phenomenon of nature that, like all other phenomena of nature, comes into existence when a certain complex of conditions is fulfilled. If the conditions become changed, the phenomena also change ; if the former wholly disappear, the latter also cease. In stimuli we have become acquainted with sach changes of vital conditions. Under the influence of stimuli vital phenomena change, and they wholly cease, when the stimuli overstep a certain limit.

If we except the small number of cases, thus far largely unexplained, such as the metamorphic processes of necrobiosis, where vital phenomena are forced into a perverted path and are qualitatively changed under the influence of stimuli, we observe that within certain limits stimuli cause only a single kind of effect, namely, a gradual, quantitative change of the vital phenomena, either increasing or decreasing the intensity of the latter. Hence in the vast majority of cases stimuli do not call out new phenomena, but produce merely an excitation or depression of those general vital phenomena already existing.

It is here especially to be noticed that the different varieties of stimuli produce in the same object wholly similar reactions. An Amoeba may be made to retract its pseudopodia and assume a spherical form by chemical, mechanical, thermal, and galvanic stimuli ; the cells of a ciliated epithelium respond by an acceleration of their ciliary motion to chemical, mechanical, thermal and galvanic stimulation ; and by all of these agencies the production of light can be induced in Noctiluca.