If it is true that all primary effects of stimulation consist either in an excitation or depression of the metabolism, and that all other effects of stimulation secondarily follow this primary alteration of the metabolism of rest, then every thorough analysis of the mechanics of reaction must have its beginning in the investigation of these primary processes. I desire to adopt this method here and will analyze somewhat further the primary process of excitation and its immediate and remote sequences. This will be followed later by the analysis of the process of primary depression and its results.
The investigation of the more obscure processes in the living substance places us in a difficult position, for their details cannot be observed by the unaided senses. That which we can perceive is merely the grosser vital action, consisting of a complex combination of the individual processes, the total result of a multitude of different components. For this reason the conception of excitation can only be established by observations based upon the combined vital actions, which are produced by the effect of stimulation upon the complex system. In the beginning, the process of excitation was studied exclusively on the muscle and nervous system. A physical factor served as indicator, such as muscle contraction or production of electricity. These showed, besides the direct and primary effect of stimulation, the secondary process of conductivity. Even graphic registration is merely an expression of the phenomena composed of a great mass of individual elements. The visible course of the phenomena, as shown, for instance, by the latent period by the ascent and descent of the curve of contraction, represents as it were a reflected picture of the actual excitation processes similar to an object seen in a distorting mirror; the first and the last parts of the process are not even perceptible. Later, when organ physiology was extended into a cell physiology the processes of excitation were studied in numerous simple organisms, such as the plant cell, the rhizopoda, the infusoria, etc. Later, in this way, by the use of comparative methods many essential facts were discovered. However, even the single cell, in spite of its minuteness, is, compared with the size of a molecule, a gigantic system, and it would be a grave error if we should consider this system even in its simplest aspect as homogeneous. In order, therefore, to analyze the vital activities in the cell, cell physiology must endeavor to penetrate into molecular conditions. For this purpose the indicators employed must be essentially of a chemical nature, capable of magnifying the processes of molecular dimension to such a degree that we are enabled to base conclusions upon these not otherwise directly perceptible phenomena. To obtain a sufficient magnification we must necessarily place somewhat larger quantities of living substance under observation and apply a stimulus of such frequency or length of duration that the chemical alterations as a result of excitation are so increased as to be plainly perceptible with the aid of our chemical indicators. Unfortunately, we do not possess specific chemical indicators for every individual molecular constituent process of the cell and so cannot dispose with the help of indicators of the combined happenings in a greater quantity of living substance. It remains for us to obtain data concerning the cycle of excitation processes in the living substances by the aid of the combined employment of the most varied kinds of physical as well as chemical indicators. If we use the most varied types of living substance of widely differing properties, showing us the greatest variety of vital manifestations, we may hope by the use of comparative physiological methods, even though with difficulty, to separate more and more the essential details of the general processes of excitation. At present we are still at the very beginning of this task and vast fields of unexplored regions are yet before us. But it is the unknown which has a particular fascination, especially if we succeed from time to time in making new advances.
If we suppose a living system in a state of metabolism of rest influenced by an instantaneously excitating stimulus, the entire course of excitation extends from the first alteration produced by the stimulation until the complete restitution of the metabolic equilibrium, and we will, therefore, differentiate individually the successive stages of this whole process.
The very beginning of the chain of alterations produced by the excitating stimulus cannot be studied by any indicator. The changes must first reach a certain dimension by conduction from the point of stimulation before they influence even the most delicate indicators. The application of the stimulus is, therefore, followed at first by a measurable “latent period,” in which the living substance remains apparently at rest. This latent period has been particularly studied in muscle. After its discovery by Helmholtz[55] it was made the object of innumerable investigations and met with an interest which can only be explained by the exactness of the methods employed. Among others Tigerstedt[56] has made the most thorough study of the influence of various factors on the duration of the latent period. These experiments have established the fact that the duration of the latent period varies according to the intensity of the stimulus, temperature, loading or fatigue. This is apparent when it is understood that the amount of the alterations produced by the stimulus must ascend from the value zero to a certain height before the changes are perceptible, and that under various conditions this amount is, on the one hand, attained in different lengths of time and, on the other, must reach a varying amount before it is perceptible by means of the indicator.
The facts concerning the whole latent period and its dependence on various factors would be incomprehensible if it were assumed that no alterations whatever take place during the latent period although the stimulus is already operative. In reality, the alterations following a stimulus occur with imperceptible rapidity in the form of a molecular interchange, and the latent period is simply an expression of the fact that the primary alterations, being limited in nature, are not registered by our indicators.
The question first arises, In what do these first imperceptible alterations consist? Nernst[57] has evolved the theory for electric stimulus, that the primary effect produced by the electric current is an alteration in the ion concentration on the surface of the living substance. In fact, we know that the surfaces of all protoplasm possess the property of semi-permeable membranes and that changes in the concentration of ions invariably occur when an electric current flows through two electrolytes separated by a semi-permeable membrane, in which the anions and cations have a different rapidity of movement. It is apparent, therefore, that such an alteration in the ion concentration must be followed by further chemical processes in the living substance. According to the theory of Nernst the first impetus for all further alterations, which the electrical stimulus brings about in the metabolism of rest, is the alteration in the concentration of the ions on both sides of the semi-permeable membrane, which represents the surface of the protoplasm. In view of the present findings of physical chemistry, objections can hardly be made to this theory of Nernst’s. It is a question, however, in how far this theory, especially established for the electric stimuli, can be applied to other forms of stimuli and their action. It cannot be denied that the degree of dissociation of an electrolyte can be altered by very different factors, such as heat, light, chemical processes, etc., and in that the surfaces of the protoplasm, acting as semi-permeable membranes, bring about a selective action on the passage of the ions, there arises the opportunity for the development of difference of electrical potential on both sides, and for further chemical alterations in the protoplasm. These observations, however, require further experimental investigations in many fields, before we are justified in extending the Nernst theory of the manner of action of the electric stimuli to a general explanation of the primary alterations produced by all stimuli in the living substance. For the present we must confine our observations to those alterations which are known to be responses to an excitating stimulus; these are the chemical alterations in the metabolism of rest in the living substance.
If it is asked, which members of the entire metabolic chain are increased primarily by the stimulating excitation of a vital system, we should not be able to answer this question generally for all living systems. To begin with, it appears highly probable that the various forms of vital substances in this respect act quite differently. It is to be regretted that, up to the present, this question has not been treated from a comparative standpoint. This inquiry should be extended to the greatest possible number of organisms. Still there is enough material at hand, obtained from the muscles, glands, ganglion cells, nerve fibers and plants, to show that the complexity is by no means so great as one might at first assume.
In considering the two stages of metabolism, assimilation and dissimilation, in their entirety, it appears as a very remarkable fact, that nearly all stimuli produce primarily a dissimilative excitation. We are only acquainted with a primary assimilative excitation, that is, an augmentation of the building up processes, in short, the formation of living substance, occurring as a primary result of stimulation, following increased introduction of foodstuffs extending over a prolonged length of time. With this exception it cannot be proved that any other stimuli, either especially those operative in the activity of the animal organism or any of the physiological nerve impulses which regulate the actions of the different organs and tissues, bring about primarily an assimilative excitation, which leads to an increase of new formation of living substance. The much-discussed teaching of the existence of the trophic nerves has not given us a single case in which there was positive proof that a nerve impulse brought about a primarily assimilative excitation. I have endeavored for nearly fifteen years to discover such a case. My efforts have been, however, without avail. In the most recent critical review by Jensen[58] on the subject of the trophic nerves, the same conclusion is reached although certain facts, as, for instance, the excitation of assimilative processes in the green plant cell, produced by light, seems at the first glance to clearly demonstrate a primary excitation of the building up processes resulting from a stimulation. Nevertheless closer observation invariably shows that these conditions are much more complicated and that primarily assimilative excitating reaction of the stimulus cannot be conclusively shown. There remains, therefore, as a primary assimilative excitating stimulus only the increased introduction of nutrition in a living organism. This excitating effect on the assimilative portion of metabolism is, as we shall see later, a simple manifestation of the law of mass action.
As a result manifold effects of excitating stimulation, which seemed possible at a first glance, are already considerably restricted. The great mass of excitating stimuli produce an acceleration of the dissimilative processes of the metabolic chain. But here our former observations have already shown that certain constituent processes are especially responsive and very readily increase as a result of the most varied adequate and inadequate stimuli. These are the “functional” members of metabolism. These members are particularly labile, so that they are always affected by every influence to which the system is subjected in the form of a stimulus. The functional portion of metabolism of the muscle, which is particularly labile and is always primarily affected by stimulation, consists as demonstrated in increase of formation of carbon dioxide and water, and in the disintegration of the nitrogen-free groups. The innumerable observations on metabolism during the stage of the activity of the muscle, as those of Hermann, v. Frey, Fletcher, Johannson, Thunberg, and many others on the individual muscle, and those by Voit, Fick and Wislicenus, Pflüger, Rubner, Zuntz, Lehmann and Hagemann, Bernstein and Löwy and others on the muscle of the entire organisms, have sufficiently proved this fact. However, we should not apply in detail the conditions existing in the muscle to all living substance. Comparative methods show us, rather, that the functional portion of metabolism is very differently involved in various forms of living substance. The formation of carbon dioxide and water is constant in nearly all forms of living substance. We must, however, exclude certain micro-organisms, which have adapted themselves to unusual vital conditions. Further, there appear in some forms manifold special constituent processes consisting in a disintegration of living substance which are in part converted into very complex combinations. In the gland cells this type is represented in an especially high degree. Here the functional disintegration leads to excretion of proteins, glycoproteins, nucleoproteins, cholic acid, enzymes of various kinds, all of which are complex and at the same time nitrogenous organic combinations. This fact must not be lost sight of. The origin of these special members, however, for the present is completely unknown, while on the other hand, it is self-evident that the general and constant constituents of the process of excitation must claim a first place in our interest. It is just at this point, therefore, that we must endeavor to penetrate somewhat more deeply into the mechanism of the excitation process and analyze in greater detail the acceleration of the functional constituent parts of metabolism produced by the stimulus bringing about the formation of carbon dioxide and water.
The question arises: By what means is the particular labile state of just this constituent part of functional metabolism conditioned? The lability of the functional portion of metabolism, excitated by the stimulus, resembles the processes in the disintegration of explosive combinations. Iodide of nitrogen, for instance, in a manner similar to the living substance in the state of the metabolism of rest, constantly disintegrates even without the influence of an impact. The disintegration is suddenly enormously increased by the result of a jar. An explosion follows. In a like manner the functional metabolism of rest is explosively excitated by the stimulus, the transformation of the energy involved likewise bears a similar relation.