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

by Max Verworn

In both instances the transformation of energy, constant in the resting state, is by the impact of the stimulus suddenly increased. The dynamic method of investigation of the excitation process with its physical indicators, forms, therefore, in many respects an excellent addition to the chemical analysis. A development, that is, exothermic formation, of energy can only occur in a chemical process when the chemical affinities which are to be combined are stronger than those which have been separated. When this process is brought about by a simple impact, the energy value of which bears no relation to that of the quantity of energy in the process itself and which occurs with explosive rapidity, then it can be simply a question of a liberation process, that is, a process by which the impact brought about a conversion of latent chemical energy into that of kinetic energy. The comparison of the functional excitation process with that of an explosion does not, therefore, consist in a merely superficial analogy, but is founded on the same dynamic principles.

When we study the chemical process which occurs in the explosive transformation of potential into kinetic energy we find two types of chemical processes. The first type includes the synthetic processes. For this, the synthesis of water from explosive gas may serve as a simple example. Here the weaker affinities in comparatively simple molecules (H + H and O + O) are separated and stronger affinities are combined in the formation of more complicated molecules (H + O + H). The second type represents the process of cleavage. As example for the latter, the explosive disintegration of nitroglycerine may be quoted. Here the atoms, held together in a complex molecule by weaker affinities, are changed by transposition of nitroglycerine. For instance, the hydrogen atoms loosely combined with carbon enter into strong combinations with oxygen and the oxygen loosely combined with the nitrogen enters into strong combination with carbon, so that water and carbon dioxide are formed and nitrogen and oxygen set free.

In the functional disintegration of living substance, the last type is realized. Living substance contains loose complex combinations, and we know that functional disintegration is accompanied by the consumption of these organic combinations. In the functional disintegration of muscle substance the nitrogen-free groups are concerned, and we must, consequently, first consider the carbohydrates. However, without further study we should not generalize from that which is true in the case of muscle. There are other forms of living substances which contain different combinations, which disintegrate as a result of the contact of a stimulus and yield carbon dioxide. A clue as to which combinations in individual cases undergo disintegration as a result of excitating stimulation, is furnished by the metabolism of rest in the particular substance. Plants and micro-organisms have been investigated more thoroughly in this connection than animals. Plant physiology has demonstrated that the material employed for the CO₂ formation and with it the production of energy is carbohydrate, but that, on the other hand, various plant organisms and protistæ also use a quantity of other substances, such as fats and protein, indeed even such comparatively simple organic combinations as alcohol, formic acid and methane. It may be accepted that in all these various instances of excitation of the functional metabolism as a result of stimulation, the specific respiratory material of the substance concerned is used in greater amount in the decomposition and likewise invariably yields carbon dioxide.

The point of most essential interest for the analysis of the excitation processes is, above all, the mechanism of the organic combustion and the associated energy production. Here we may base our observations on the disintegration of carbohydrates, which is most extensive in the animal as well as in the vegetable kingdom. We may now ask how dextrose, for instance, disintegrates in the living system into carbon dioxide, for it is this, or a sugar of similar chemical nature, which is generally concerned. Plant physiology, which here, as in many other respects, is in advance of animal physiology, has indicated two ways by which this can be accomplished in the living substance. One is oxydative, the other, anoxydative disintegration.

In the oxydative disintegration of dextrose, taking place in aërobic organisms, if sufficient quantities of oxygen are present, there occurs a splitting up of the carbohydrate molecule, as a result of the introduction of oxygen, into simpler substances and finally into carbon dioxide and water, just as the dextrose molecule, when subjected to oxydative processes, is split up into simpler molecules. In the living substance the oxydases play the important rôle of oxygen carriers. It cannot be denied, however, that up to now no carbohydrate splitting oxydases have been obtained from living substance. This, of course, does not prove its nonexistence. But this deserves consideration in connection with an assumption very widely spread among plant physiologists in regard to the aërobic disintegration of the carbohydrate molecule, which I shall touch upon presently. If we suppose that oxydases exist, which bring about primarily the oxydative disintegration of the dextrose molecule, its first point of attack must obviously be sought in the aldehyde group. Here would be situated the activator, as it were, for the whole carbon chain, from which, as by a spark, the entire series of links would be ignited.

In an anoxydative disintegration of dextrose as observed in anaërobic as well as in aërobic organisms, provided the latter have an insufficient supply of oxygen, the dextrose molecule, by enzymic action as a result of the splitting off of carbon dioxide, is converted into substances having a comparatively large carbon content. The best-known example of this anoxydative disintegration is the formation of alcohol by fermentation in which the dextrose molecule is split up by the yeast into alcohol and carbon dioxide. (C₆H₁₂O₆ = 2C₂H₅OH + 2CO₂.) Instead of the production of alcohol and CO₂ we may have other enzymic actions with the formation of other carbon-containing disintegration products, such as lactic acid, fatty acids, hydrogen, etc. Of course in such an anoxydative disintegration, which does not lead to the formation of such simple combinations as carbon dioxide and water, the quantity of energy set free is much less in amount than in complete oxydative decomposition, the energy production of the alcohol fermentation being only 11 per cent of the latter. In order to produce the same amount of energy as in the former, a much greater number of molecules is required. We find, therefore, that the anoxydative type of disintegration develops either only where the respiratory substances are present in sufficient amounts, as for instance, in the case of yeast cells, existing in nutritive solutions rich in sugar; or where the chemical and energy transformations occur only to a limited extent, as, for example, in the presence of low temperature. In this respect Pütter[59] has demonstrated in the leech that at a higher temperature, the oxydative, at a lower, the anoxydative, decomposition predominates. These are important facts in that they show us the superiority of oxydative to that of the anoxydative disintegration in the cell economy. This is of particular interest when we consider those organisms in which great demands are made upon the capability of movement, above all, in homothermous forms, the metabolism of which takes place on a continuously high level. For this reason, in homothermous animals the respiration of oxygen is the almost exclusive source of energy production.

The previously mentioned facts make it clear that in one and the same form of living substance both oxydative and anoxydative decomposition processes are found, depending upon the conditions. This does not apply merely to the individual organic forms, such as the facultative anaërobic organisms, but generally to all aërobic living substance. If oxygen is withdrawn from an aërobic organism the disintegration does not cease in consequence. In place of the oxydative we have anoxydative decomposition. The various aërobic organisms are, however, adapted in very different degrees to the possibility of an anaërobic existence. While the facultative anaërobic organisms can continue to exist without oxygen, the homothermous animals become asphyxiated in a very short time in the absence of oxygen, in that they are poisoned by the products of the anoxydative decomposition, which are eliminated with much more difficulty than carbon dioxide and water. The fact, however, that disintegration also continues in an anoxydative form, if oxygen is withdrawn, has given rise to the thought, which has been accepted especially by plant physiologists with great readiness, that the decomposition of organic respiratory substances of the aërobic organisms invariably takes place in two stages; in that the dextrose molecule—to again use this as an example—is split up first by an enzyme into larger fragments, which then in the second stage of the process undergo combustion to the formation of carbon dioxide and water. Such a possibility cannot be repudiated. I wish, however, to state that one should be very reluctant in generalization of this assumption for all aërobic organisms. The types of metabolism in the different organisms are so manifold and of such immense variety that we should be very careful in our generalizations before being in possession of material extending over a great number of groups of organisms. Above all, it does not seem justifiable to also accept this type for life existing at higher temperatures, and still less to apply it to those instances in which the production of energy following stimulation is suddenly increased to great amounts. Let us suppose that the disintegration process occurs in two phases, the first of which after the type of the fermentation of dextrose separates the molecule into larger fragments, while in the second phase these fragments are split up through oxydation into the formation of carbon dioxide and water. We can then say with certainty that in the first stage only a comparatively small amount of energy production occurs, for energy production by enzymic processes of this kind is never great; the second phase, on the other hand, must be associated with a very considerable energy production, for by the addition of oxygen and the formation of carbon dioxide and water the strongest affinities possible are combined. With this assumption in certain cases, as, for instance, in the sudden production of energy in muscle contraction, which necessarily occurs in the purely oxydative phase of the whole process, the view is forced upon us, that, in these cases, the entrance of oxygen into the molecule from the very beginning, even the first impact, produces oxydative decomposition of the whole molecule. The view that, in the reactions of warm-blooded animals, which occur with great rapidity and considerable energy production, the oxygen primarily explosively breaks up the whole carbon chain, certainly presents no more difficulties than the supposition that the simpler substances are attacked secondarily, provided sufficient oxygen be present. This method would be obviously the simplest. This is, however, mere speculation and a definite decision between the two possibilities cannot be made at present. However, whether the process takes place in two phases, an anoxydative and an oxydative, or simply in an oxydative phase, in any case, the sudden discharge of energy in the aërobic organism set free by the stimulus, is brought about by the addition of oxygen.

This is a highly important fact and as such requires the most thorough confirmation, and is best accomplished by the investigation of the state of excitation of aërobic substances on the withdrawal of oxygen. Experience gained by observation in this respect on a great number of living substances shows that excitability decreases upon the withdrawal of oxygen. In this connection I should like to cite some particularly significant instances.