Irritability: A Physiological Analysis of the General Effect of Stimuli in Living Substance

by Max Verworn

Considering the close correlation of the individual part processes it would appear very strange, however, if a single one of these could undergo an alteration of its rapidity without the course of the rest of the processes being in the least influenced. One cannot comprehend such absolute independence of a process brought about by functional stimulation from all the other constituent processes, particularly when this is of prolonged duration and involves to a considerable extent the alterations in rapidity, for the individual constituent processes are dependent in a high degree upon the quantity of the particular chemical substances of which the living system is composed. The cycle of the individual constituent processes of this system is determined in the most delicate manner in its rapidity and extent, by the relative quantities of the individual substances. Associated with an alteration in the rapidity of an individual constituent process, there would also be a relative alteration quantitatively of the substances. And with the increase in the quantity of the disintegration products, and also the increase of the substances for their replacement, there would result, during this time, an alteration in the amount of interaction of the molecules of the other constituent processes, so that these processes secondarily suffer an alteration in rapidity which is perceptible after long continued involvement of the functional part of metabolism.

In fact, in the previously mentioned case of the functional stimulation of the muscle, the proof has been furnished that a long-continued increase of the functional metabolism is followed, although to a less extent, by an increase in the entire cytoplastic metabolism. Argutinski showed this on himself in 1890 in Pflüger’s laboratory. He found, namely, that after the exertion of a long walk in a hilly district, a considerable increase of nitrogen excretion in the urine took place, which extended over the succeeding two or three days. This increase of the nitrogen metabolism in its totality is not nearly as great as that of the breaking down of nitrogen-free substances, but it is, nevertheless, present and shows us that functional metabolism cannot experience a lasting excitation without being followed by secondary results in the entire cytoplastic metabolism. This fact is even more strikingly illustrated in the alteration of the entire volume of a living organism as produced by the lengthened duration of functional stimulation. It has been long known, that the muscle as the result of frequent functional excitation by means of adequate nerve impulses, that is, prolonged activity, is considerably increased in size, whereas in the absence of such it loses more and more in volume. A hypertrophy of activity, produced by functional stimuli, and the atrophy of inactivity, the result of the discontinuance of the functional excitation, is universal and can be observed in the various tissues of our body. We see it, for example, in the glands; we see it in the skin and we see it in the elements of the nervous system. Berger,[51] for instance, established the fact that the ganglion cells of the optic lobe in the cerebrum of newborn dogs only reach their full development when functionally excitated by adequate light stimuli (Figure [9], B), coming from the eye, whereas they remain in the embryonic state when these light stimuli are eliminated. (Figure [9], A.) The cytoplastic increase of volume of the neurons under the influence of functional stimuli is a fact of fundamental importance for the entire happenings of the nervous system and forms the physiological basis for reinforcement of reflexes, which, in its turn, is essential for all acts of memory and intelligence. For the increase in volume of the ganglion cell body is, when functionally activated, accompanied at the same time by an increase of specific capabilities and the intensity of discharge. Its excitation impulses can, therefore, be conducted through a greater number of neurons, with which it is connected, than would be the case if development of the volume of the ganglion cell increased to a less extent.

Fig. 9.

A—Undeveloped ganglia cells in the optic lobe of a dog, the eyes of which have been sewn up immediately after birth. B—Fully developed ganglia cells in the same region of a normal dog of the same age. (After Berger.)

The increase in volume under the influence of stimuli further shows the relation between the group of those solely catalytic effects of stimulation consisting in mere alterations of rapidity of the specific vital process, and that of the metamorphotic effects of stimulation, which manifest themselves in qualitative alterations of the vital process. Simple observation shows us that a qualitative change of individual constituent processes must necessarily result from the increase of volume of a cell, and that considering the close correlation of all the individual processes a profound alteration of the entire metabolism must be produced. I have already at another place[52,] [53] treated these conditions more in detail and will, therefore, only briefly refer to them here. If we study the growth of a ball-shaped cell, we find that the surface then increases as a square, and the volume as the cube. It therefore follows that, by progressive volume increase, the conditions for the interchange of substance with the surrounding medium must become more and more unfavorable for those cell portions situated in the interior, whereas those at the exterior are at much greater advantage. This must lead to a constantly increasing difference of the rapidity of the metabolic processes between the peripheral and central portions. Accordingly, the intricate interworkings of the individual constituent processes, the rapidity of action of all which is intimately connected, are, therefore, followed by corresponding alterations in the entire metabolism. Sooner or later a stage is reached in which the individual constituent processes become so limited that certain metabolic products, which previously were broken down as soon as formed, can be no longer eliminated and remain in the cell acting as foreign bodies. In this way the relative quantity of the individual cell substances become more and more altered, and as the course of chemical processes occurs in accordance with the law of mass action, the whole metabolism is directed into another channel, so that finally new constituent processes take place, which were formerly not possible. These in their turn produce deep-seated alterations of the relations of the cell to its surrounding medium, etc. Hence this mere increase of volume of the cell in growth forms the source of an infinite mass of alterations in the activities of cell metabolism, which we briefly term its “development,” and which by constant progression, leads either to a process of cell division, and with this to a correction of existing disorder, or finally to irreparable disturbances ending in death. In this way an inseparable relation exists between increase of volume and the development of living substance. We have seen, however, that the catalytic reactions of stimulation, which at first only produce an alteration of rapidity of the individual constituent processes, if of prolonged duration or of frequent recurrence, secondarily effect a change of volume of the entire living organism. One can, therefore, hardly reject the conclusion that seeing the close interworkings of the individual part process of metabolism, every change of rapidity of a single member, if of prolonged duration or of frequent occurrence, must finally lead to qualitative alterations of the entire metabolism. In consequence there results an important dependence between catalytic stimulation and metamorphic reaction. Indeed, it is not unlikely that the metamorphic reactions, which are especially seen in the continued effect of weak stimuli, result from alterations of rapidity, which the individual members of the vital processes have primarily undergone from this influence.

It is perhaps expedient to cite a concrete instance in illustration. A simple example is furnished by asphyxiation. If oxygen is withdrawn from any living organism, the result is a depression of its oxydation processes. Here there is primarily only a change in rapidity, especially a retardation of oxydation processes. The metabolism, however, proceeds, the disintegration of living substance continues, although at a slower rate, but produces an accumulation of other products. Whereas formerly during the existence of a sufficient supply of oxygen an oxydative disintegration of nitrogen-free groups into carbon dioxide and water took place, both of which could easily be eliminated from the cell, the anaërobic disintegration furnishes only complex products, having a higher carbon content, such as lactic acid, fatty acids, aceton, etc. These, being more difficult to excrete from the cell, accumulate. These asphyxiation products have in their turn a depressing effect and so on. In this way the whole metabolism is forced into a wrong course. The accumulation of fat in those tissue-cells with an insufficient blood supply, as we have seen in the case of the fat metamorphosis, is doubtless brought about in the same manner by relative oxygen insufficiency. The fatty acids accumulate as products of an incomplete combustion and combine with glycerine to form neutral fats. In like manner it may be that the accumulation of amyloid substance in amyloid metamorphosis, of lime salts in arteriosclerosis, etc., is produced by a primary depression of the individual constituent processes of the particular cells.

The relation here described, of the catalytic stimuli to the production of the metamorphic processes, leads us to the distinctions between primary and secondary effects of stimulation. Should the general fact be established, which has up to now only been pointed out in individual cases, that all the metamorphic processes are merely secondary results of primary alterations in rapidity of individual metabolic constituent processes, then the primary reactions of every stimulus would consist purely in the excitation or depression of the directly concerned constituent. Whether or not, as may be assumed, this primary effect of stimulation applies to all stimuli, is a question which only the future can answer.

The metamorphic processes are not, however, the only secondary effects of stimulation. The influence of long-continued excitation of the functional constituent processes upon the entire cytoplastic metabolism can be looked upon as a secondary response. Therefore, they may be considered as a secondary effect of stimulation which, in contrast to this primary excitation, may be called the secondary excitation.

Further: While the secondary excitation and metamorphic processes are generally produced by the continued existing effects of weak stimulation, we also observe as the result of a stimulus of short duration or frequently repeated at brief intervals, but otherwise not exceeding the physiological limits of intensity, a secondary effect, which plays a very important part in the activity of the organism. I refer to fatigue. Here a secondary depression is developed in connection with the primary excitation, for fatigue of a living organism must be characterized as a depression of activity. This case shows that we have to distinguish between a primary depression, as for example, produced by temperature reduction, withdrawal of food, deficiency of oxygen, etc., which occurs as a direct effect of stimulation, and secondary depression, which as in fatigue is an indirect result of primary excitation.