Principles of General Physiology

Reversals of this kind can be brought about without the influence of drugs, as shown more particularly by Magnus (1909). The direction of the movement of the tail of a spinal cat, when the tip is pinched, varies with the position in which it hangs. The movement is always towards the stretched side, so that the same afferent impulse produces, in one position, excitation of those muscles which are inhibited in the opposite position. The condition of the centre must be changed by receipt of afferent impulses from the stretched muscle.

Returning to the action of chemical agents, Dale, Laid law, and Symons (1910) describe how stimulation of the vagus in the cat, under the effect of nicotine, causes marked acceleration instead of slowing of the heart. This may be due to earlier paralysis of the inhibitory fibres than of supposed accelerator fibres, normally masked. Or it may be a reversal of the function of the inhibitory fibres. In the latter case, we should have an instance of reversal of a peripheral muscular mechanism. The authors named are inclined to favour the former hypothesis, but it does not seem probable, a priori, that fibres acting in the same way as the sympathetic supply of the heart should be present in a cranial nerve.

Again, Dale and Laidlaw (1911) found that, after a dose of cytisine, the alkaloid of laburnum seeds, stimulation of the chorda tympani nerve in the cat produces no secretion while the stimulus lasts, but is followed by a copious flow. A renewed stimulation, during this after-flow, nearly stops it, but the course is resumed after the stimulation ceases. The authors suggest no explanation, but it seems to me, although I admit that the suggestion is purely hypothetical, that, if we regard the action of strychnine and of chloroform as actually reversing the sign of the effect on a nerve cell, why should we not accept the possibility of similar reversal in peripheral inhibition and excitation in smooth muscle and heart ? If this be so, the above result on the salivary secretion might easily be explained by conversion of the normal vaso-dilator action of the chorda tympani into a vaso-constrictor one, the diminution of flow being then due to failure of blood supply. This hypothesis might be tested by determining the rate of blood flow under the conditions of the experiment.

Langley (1911) finds that, after nicotine or curare, the normal contraction of the bladder produced by stimulation of the sacral nerves is followed by inhibition, FIG. 128. REVERSAL OF VASO-CONSTRICTOR REFLEX BY CHLOROFORM. Stimulation of central end of hypoglossal nerve in the rabbit. Right-hand tracing— under 3 per cent chloroform in addition. and that the presence of inhibitory fibres is not a satisfactory explanation. Changes in the sign of the movement of ions to or from the membrane is suggested, a process which would be equivalent to reversal of excitation into inhibition.

The fact, discovered by Dale (1906), that ergotoxin converts the normal vasoconstrictor effect of the abdominal sympathetic nerve on the hind leg into a vaso-dilator one is, to my mind, more consistently explained by peripheral reversal than by paralysis of vaso-constrictors leaving unmasked vaso-dilator fibres. I have been quite unable to find any evidence of the existence of such fibres in the abdominal sympathetic chain. But the whole question as to the mechanism of these various reversal phenomena cannot be said to be capable of decision as yet.

Pearce (1913) has described experiments in which the normal vasoconstrictor action of FIG. 129. THREE STIMULATIONS OF THE CENTRAL END OF THE MEDIAN Upper tracing — volume of the kidney. Lower tracing — arterial pressure. Zero is 23 mm. below the upper signal. The first stimulation is under ether alone. There is a rise of blood pressure, with vasoconstriction in the kidney. The second is under chloroform. There is a fall of blood pressure, with vaso-dilatation in the kidney.

Third stimulation after partial recovery from chloroform under ether. Preliminary vasodilatation, followed by a larger vaso-constriction. adrenaline on the arterioles of the frog appeared to be converted into a dilator one in the absence of calcium. These experiments have been already referred to (page 217) and I regret to say that I have been quite unable to confirm them. I found constriction produced by adrenaline even after prolonged perfusion with Ringer's solution free from calcium, although addition of calcium increased the effect to a small degree. On the heart, also, I found the usual augmentation and acceleration to be produced on the auricle when the calcium was reduced as far (as possible without causing complete cessation of the beats. Of course, under these conditions, conduction is bad, so that one is apt to find the ventricle following only each alternate auricular beat, when they are accelerated by adrenaline.

The mechanism by which movements are produced in plants, especially in the higher plants, will be discussed in the next chapter. The nature of the excitation process concerns us here, That it is essentially similar to that in the animal is indicated by the fact that vegetable protoplasm, in a state of excitation, is electrically negative to that at rest. This is shown by the observations of Hormann on Nitdla (1898, pp. 69-79). A stimulus at a point sets a wave of excitation in progress, accompanied by a state of electrical negativity. This electrical state, so far as could be ascertained, precedes the cessation of movement caused by the stimulus. In these cells, the streaming movement corresponds to the contractile properties of a muscle fibre and is, as we have seen, something added on to the simple excitatory process as it shows itself in nerve. Similar conclusions are to be drawn from the work of Burdon- Sanderson on the leaf of Dioncea muscipula (1888), whose leaves shut up rapidly

Fio. 130. ELECTRICAL CHANGES IN THE LEAF OF DIONJEA. — Corresponding points on the under surface of each lobe led off to capillary electrometer. a, Stimulated mechanically four times on right side. Diphasic effect due to excitatory process arriving when a fly touches certain sensitive hairs on the upper surface. By placing electrodes on opposite lobes, and stimulating the neighbourhood of each electrode in turn, it was shown that the excited spot becomes first negative, then positive, as the wave of excitation reaches the other electrode (see Fig. 130); just as was described above for nerve and muscle. It is pointed out that this wave of excitation precedes the change of form and travels at a much faster rate. Visible change of form was prevented by a cross-bar fixed between the lobes.

It is a familiar fact that plants in general, root, stem, leaves, and flowers, respond to gravity and to light, and in various ways. Certain of them, as the climbing plants, and especially the " sensitive plant," and Dioncea, respond to touch by more or less rapid movements. Now this response is not confined to the part actually stimulated, but the excitation is conducted to more distant parts. For a description of the various phenomena concerned, the reader is referred to the book of Pringsheim (1912). We are chiefly interested here in the excitatory process itself.

It is found that a stimulus, such as gravity or light, requires to act for not less than a certain time in order to have any effect at all. This minimum time is known as the " presentation time." Further, however long a stimulus is applied, no effect is produced until an interval of time has elapsed since the beginning of the stimulation. This is the "reaction time." There are no special channels for conduction of excitatory processes like the nerves of animal organisms. Conduction appears to take place through the cell protoplasm, which must be living. In the stem of Tradescantia virgitnca, the curvature which takes place under the stimulus of gravity takes effect on the next internode below the one stimulated, and the transmission is abolished by local anaesthesia of a spot between the two. Similarly, light stimulus acting on the stem of the Dahlia is transmitted to the root. A curious fact, whose probable explanation will be given in Chapter XVII. on receptor organs, is that, at the temperature of 0° or in an atmosphere of hydrogen or carbon dioxide, no effect is produced until the temperature is raised or oxygen supplied, respectively. But, although the actual stimulus may have ceased before the change of conditions, the effect shows itself.

When light stimulus and gravity stimulus act together, the former, as a rule, completely overpowers the latter. The manner of conduction has been a subject of dispute. In the case of the sensitive plant, it was originally held by Pfeffer and by Haberlandt that the transmission was mechanical, by a movement of water in tubes of the vascular bundles ; but the abolition of power of conduction by local anaesthesia is strong evidence that it takes place through protoplasmic structures. It is known in many cases that the protoplasm of neighbouring plant cells is united by strands passing through holes in the cell walls (see especially the work of Gardiner, 1884). Fig. 131 shows the structure of a tissue of this kind. Further details as to the mechanism of conduction will be found in the essay by Fitting (1906).

In connection with the increase of permeability which we have seen to occur in the state of excitation, the mechanism of the movements of the sensitive plant, investi gated by Pfeffer (1873), is of interest. As we have seen, the vegetable cell is maintained in a state of turgor by means of the osmotic pressure due to the presence within it of substances in solution, and to the impermeability of the cell membrane to these solutes. Since the cell wall surrounding each is incapable of any considerable stretching, a pressure in the interior results. A mass of cells with such a turgor well developed exists at the lower side of each movable joint in the leaf of the plant. The cells on the upper side are less turgid. When stimulated, the cell membrane of the lower cells suddenly loses its semipermeable character, as regards the solutes of the cell contents, with the consequence that the internal pressure can release itself by filtering solution through the membrane. Drops appear on a cut surface and the weight of the leaf, being no longer supported by the distended cells, causes it to fall.

Another phenomenon, which may be in some way connected with changes of permeability, is the oxidation reaction, described by Czapek and Bertel (1906). If longitudinal sections are cut from the root point of lupin seedlings, it is found that their cells become brown on boiling with ammoniacal silver nitrate, owing to the presence of a reducing substance. If the root has been stimulated geotropically, the dark stain is more intense. Investigation showed that this reducing reaction was due to the presence of tyrosine, although indirectly, being actually given by homogentisic acid, apparently produced by the action of an enzyme on tyrosine. Now the difficulty is that tyrosine has an OH group in the para-position as regards

The protoplasts, contracted by the action of alcohol, adhere to the transverse wall, and that of each cell is connected to the other by delicate protoplasmic filaments, passing through the pores of the cell wall. the chain, whereas in homogentisic acid it is in the meta-position. If, however, the OH be first removed from tyrosine, phenyl-alanine is formed, and from this, by de-amination and oxidation, homogentisic acid might be produced thus : —

Phenyl-alanine. Phenyl-a-oxypropionic Uroleucic Homogentisic After the action of gravity, then, there is more homogentisic acid found in the root than normally. This is interpreted as follows : homogentisic acid is oxidised to carbon dioxide and water in the resting cells ; under the action of gravity. an " anti-oxidase " is formed, which inhibits the normal oxidation process. Since, as we have seen, the existence of specific anti-enzymes is extremely doubtful, it would be more correct to say that the action of gravity caused the appearance of some substance which retards the action of the oxidase. A similar effect was found to be produced in heliotropic stimulation. It is a result of excitation, not of movement, since mechanical prevention of the latter does not alter the reduction reaction.

Homogentisic acid plays a part in the normal oxidation of tyrosine in the animal organism (see Garrod, 1909, pp. 41-81), since, in certain inborn errors of metabolism, the enzyme responsible for the further oxidation of homogentisic acid is absent, and administration of tyrosine increases the output of homogentisic acid. In Garrod 's book (p. 78) another mode of conversion of tyrosine into homogentisic acid, through para-oxyphenyl-pyruvic acid, is given.

Automatic cell processes require the provision of means of regulation in two directions, increase and decrease. The former is called "excitation" and the latter, " inhibition." A process which is set into action by influence from without may also be stopped by inhibition of the external influence. Processes of a non-living nature are also capable of modification in two directions by external action, as in the familiar case of reversible reactions.

Strictly speaking, all living protoplasm is able to respond to external changes (" stimuli "), but the name of " excitable " tissues is given for convenience to those which, like muscle and nerve, respond by rapid changes. Nerves are especially present for the purpose of conducting a stimulus from the place of application to more distant parts of the organism and bringing the various constituent parts into relation with one another. They really constitute the excitable tissue, par excellence, since they have no other function to perform.

A nerve when disturbed at a point conveys some sort of change, the propagated disturbance or nerve impulse, along its course to the place where the nerve fibres terminate, and the tissue in which the fibre ends is excited or inhibited according to the particular manner in which the fibre is connected. Of course, the kind of activity which is set going or stopped depends on the cell, nerve cell, muscle fibre or gland cell, etc. There is no visible change in a nerve as the impulse traverses it. Indeed, one kind of change only has been definitely shown to take place, an electrical one, in which a spot in activity is electro-negative to one at rest. Certain conclusions as to the nature of the process can be drawn from this fact, taken in connection with

the way in which the nerve responds to stimulation. There is no heat produced, and the evolution of carbon dioxide is questionable. The various practical methods of setting up a propagated disturbance in excitable tissues are described in the text. There are no differences of degree in the state of excitation of a nerve or muscle cell in a given state ; a stimulus either produces the maximal effect that the tissue is capable of in this condition, or no response at all, in the way of a propagated disturbance, Nevertheless, a stimulus too weak to do this leaves behind a local change at the point of application. Degrees of contraction, produced in a muscle by different intensities of stimulation, are due to the activity of a larger or smaller number of fibres in the nerve or muscle.

A narcotised region of nerve reduces the intensity of a propagated disturbance as it passes along it, so that, if long enough or sufficiently deeply narcotised, it abolishes the disturbance altogether. But, if any state of excitation is left at all, the disturbance returns to its original magnitude when it enters a normal region again. It appears, then, that the degree of activity of a tissue supplied by nerves depends only on the number of tissue cells acted upon, and on the state of these particular cells ; not on any difference of degree in the stimuli reaching a given cell. It should be mentioned that this view is not accepted by all investigators so far as it applies to reflexes from the central nervous system.

All excitable tissues are incapable of response to a second stimulus applied at a short interval of time, differing in different tissues, after a previous one. This is the " refractory period," and consists of a first part, where no strength of stimulus whatever will excite ("absolute refractory state"), and of a second part ("relative refractory state "), where stimuli stronger than normal are required. The disturbances set up in this latter period are smaller than normal, but cannot be made greater than those set up by a stimulus just sufficient to excite, however the stimulus is increased. Their magnitude increases progressively up to the end of the refractory period.

The refractory state is not only local, but follows the propagated disturbance as it passes along the nerve fibre. The question of fatigue of nerve fibres is somewhat disputed. There is some evidence, not altogether convincing, that oxygen is necessary for the continuance of the excitability of a nerve fibre. The electrical negativity associated with the passage of an impulse is followed by a state of increased positivity, the explanation of which is not yet clear.

The passage of the nerve impulse takes time, the rate being increased by rise of temperature.. The temperature coefficient is 1*79 for 10° C. There is evidence that the state of excitation is accompanied by increased permeability of the cell membrane. If the membrane be impermeable, at rest, to one only of the ions of an electrolyte within the cell, the membrane is " polarised," and the " current of rest," " injury current," or " demarcation current," is accounted for. If this semipermeability is abolished in excitation, the "negative variation" can be accounted for, and also the diminished polarisability in this state.

A certain formula was put forward by Nernst to express stimulation by an electrical current. The basis of this expression is a movement of ions to or from a semipermeable membrane and is suggested as an approximation only. Taking further known facts into consideration, A. V. Hill modified the formula in a way which was found by Keith Lucas to satisfy most cases of experimental test. The factors playing a part are the number of ions and their charge, the distance between the membranes, and the distance of the place where the concentration takes place from the membrane under consideration, the rate -of movement of the ions, and a factor expressing rate of " recombination " of ions. This last factor is probably an adsorption in the sense of Macdonald's theory.

Various excitable tissues differ in the rate of incidence of their "optimal stimuli, that is, the stimulus which excites with the least expenditure of energy. This is Waller's " characteristic," and is included in the modified Nernst formula. The function of the medullary sheath is still problematical, although it appears to have a function in connection with the growth of fibres. The axis cylinder is probably of a liquid nature, but colloidal. There is no evidence of the existence of " neuro-fibrils " in the living state.

The nerve impulse, as it travels along a fibre, seems to be a reversible, physicochemical process, not associated with metabolic changes ; but the question is not, as yet, altogether decided. A distinction must be made between the local process at the spot stimulated and the propagated change. The former is confined to the stimulated spot, and requires a certain small expenditure of energy to set it up. When set up, if sufficiently intense, it produces a propagated disturbance. There is no convincing evidence that the latter is attended with any consumption or evolution of energy.

In muscle there is an excitatory process essentially like that in nerve, and, superadded to this, a contractile process, which has a latent period and is associated with metabolism, with its accompanying heat production and fatigue. The former process may be present without visible contraction. There are certain other excitable substances which intervene between nerve and muscle. These are called " receptive substances " or the " myo-neural junction." Their existence can be shown by their reaction to various drugs, and by their different optimal rates of stimulation. The muscle fibre has a low optimal rate, the nerve trunk one of a rather higher value, while the intermediate substance has a very high one. These optimal rates have been shown by Keith Lucas to be functions of the rate of diffusion of the ions concerned in the excitation process, according to the conception of Nernst.

There is a membrane intervening between the nerve ending and the muscle fibre supplied by it, as also between one neurone and the fibre connecting it with another neurone. This membrane is called by Sherrington the "synaptic membrane." The essential processes connected with inhibition must be of an opposite kind to those connected with excitation. Various theories have been propounded, from different points of view, as to what is the basis of inhibition.