Principles of General Physiology

Absorption of Fats. — These fatty acids and glycerol are taken up by the cells covering the villi and, in their interior, are synthesised into neutral fats again, probably by the reverse action of lipase. In the form of fine droplets, the neutral fats are passed into the central lymphatic space of the villus, and thence in the stream of lymph into the lacteals and thoracic duct and so into the blood stream. In the blood they can be observed by ultra-microscopic methods of illumination as the " blood dust," with its vigorous Brownian movement. It is difficult to see precisely why fats should be hydrolysed only to be resynthesised in the villi, but it must clearly be for the purpose of facility of absorption.

Absorption of Water and Salts. — Water can be absorbed by the intestinal mucous membrane to practically any extent. The regulation of the water content of the organism is carried out by the kidneys. No water is absorbed from the stomach, most in the small intestine and a certain amount in the large intestine. If it were pure water that is to be absorbed, the osmotic pressure of the constituents of the blood-plasma would suffice to explain the fact ; but it actually happens that isotonic saline solutions can be absorbed. Even hypertonic solutions are ultimately absorbed after a preliminary dilution by pure osmotic action. There must, therefore, be some active intervention on the part of the absorbing epithelial cells, by which energy is consumed. This process is thus a kind of inverse of that involved in secretion. It is perhaps most strikingly shown by the fact that the animal's own serum can be absorbed. At the same time, physical factors have considerable effect on the rate of absorption and a discussion of the part played by these factors will be found in the article by Starling (1909).

In animals, food requires treatment, mechanical and chemical, before it can be absorbed. Digestion mechanisms ensure this, and also provide for efficient absorption of the products. In unicellular organisms, the solid food particles, mostly living algje or bacteria, are attacked inside the cell. They are first killed in acid medium, then digested by enzymes in alkaline medium. Similar statements apply to the phagocytes of the higher, niulticellular animals. There is no evidence of prehensile, pseudopodial attack ; chance contact with bacteria leads to adhesion and engulfing by the action of surface forces. " Opsonins," as specific chemical entities, in all probability have no existence.

The general plan of the digestive system in the higher animals is a long tube with dilatations in places and arrangements for enclosing food, temporarily, in various sections, in order to enable the enzymes, which are secreted into these sections, to act for a sufficiently long time. Two kinds of movements are required. One to pass the food along the gut, the other to send it backwards and forwards in a particular section. The former is provided for by nerve centres in the wall of the alimentary canal itself; these

centres are responsible for the myenteric reflex, or "law of the intestine." This consists in the production of a relaxation, with inhibition of movements, below the spot at which a mass of food is found, and an increase of tone, together with more powerful contractions above the spot, thus moving onwards the contents of the intestine at this spot. This reflex can be prevented by a set of nerve fibres, in the splanchnic nerves, arising from the central nervous system. Another set of fibres, in the vagus nerve, produces increased movements. In this way, all kinds of movements are provided for.

The normal movements can be best investigated by the aid of the Riintgen rays. The secretion of the various digestive juices is excited in two ways — chemical, by the presence of a substance in the blood which has been produced by the action of something contained in the food mass, when it arrives in a particular section of« the alimentary canal ; or nervous, by reflexes excited by the sight, smell, or taste of food. The relative part played by these two mechanisms changes from the mouth to the large intestine in such a way that the glands nearer the head are more under control of nervous reflexes. It is doubtful whether secretory nerves play any important part, in normal conditions, in the cases of the pancreas, liver, and small intestine.

The food is first disintegrated mechanically, sometimes with the aid of bacteria. Carbohydrates are then converted into their constituent hexoses or pentoses by a series of enzymes, contained in saliva, pancreatic juice, and succus entericus. Cellulose is usually converted into glucose by the action of bacteria in the large intestine and is probably absorbed in this stage before the bacteria have converted much of it into more degraded products, such as hydrogen or marsh gas. In a few animals, an enzyme capable of hydrolysing cellulose has been found in the secretion of digestive glands.

Sugars are chiefly absorbed in the small intestine ; when arising from cellulose, in the large intestine. Proteins are converted first into proteoses and peptones (higher polypeptides) by the pepsin of the gastric juice, and these into amino-acids and some di-peptides by the trypsin of the pancreatic juice, and finally completely into amino-acids by the erepsin of the succus entericus. Proteins are not absorbed in the stomach, but their absorption is practically complete by the end of the small intestine.

Fats are hydrolysed in the small intestine by the pancreatic juice and absorbed as glycerol and fatty acids, the latter for the most part in solution in bile. In the epithelium of the villi they are resynthesised to neutral fats, which pass into the lymph of the lacteal system and thence to the blood in a finely emulsified state. Water and salts are absorbed by the mucous membrane of the intestine. Active intervention on the part of cell mechanisms must be postulated to account for the absorption of solutions isotonic with the blood.

WHEN a process of any kind takes place continuously of itself without intervention from without, it is clear that, for purposes of due regulation in the living organism, there must be means of modifying it in both directions ; there must be some power of either increasing it or decreasing it according to necessity. Cases of physiological processes of this kind are the muscular coat of the small arteries and other places where we find that kind of muscular tissue known as smooth, pale, or involuntary muscle. This, in its usual state, which may be regarded as "resting," since it is the condition taken on when unaffected by nervous impulses, is in a state of partial contraction or "tone." This tone is capable of being increased by certain nerves supplying the tissue and diminished by another set of nerves. In the preceding chapter we saw how the automatic movements of the intestine can be stopped by the splanchnic nerve and increased by the vagus. For our present purpose it is immaterial whether these movements are due to periodic discharges of nerve cells in Auerbach's plexus, or inherent in the muscle cells themselves, although the work of Gunn and Underbill (1914) shows that the latter is the correct statement. In either case, the responsible cells can be either restrained or excited. Such double effects play a fundamental part in the mechanism of nerve centres, as we shall see later. Perhaps the most striking instance that can be given is that of the heart. As is well known, this organ continues its regular series of beats even when cut out of an animal ; but, in its natural state, it can be ^topped by the vagus nerve or excited to increased rate and force by the " accelerator " nerves from the sympathetic system.

This capacity of being affected in two opposite directions is not confined to living matter. Consider again our old example of an ester system in equilibrium. As we have seen, if we add more water, there is increased hydrolysis ; if we remove water, there is increased synthesis, or diminished hydrolysis, of ester. The effect of a catalyst should also be kept in mind, as consisting merely in the acceleration of the attainment of equilibrium, by addition or subtraction of water ; that is, it increases both hydrolysis and synthesis ; which of these effects will be the more obvious one depends on circumstances. But again, the accelerating action of a catalyst can be itself increased or diminished. Pepsin hydrolyses proteins at the greatest rate in the presence of a certain definite concentration of hydrogen ions ; suppose that this concentration is somewhat less than the optimal one, it is plain that we can increase the rate of hydrolysis by adding more acid or diminish it by adding alkali.

, — The duality of phenomena illustrated in the last example reminds us further of the opposition in general chemical properties between hydrogen and hydroxyl ions. The existence of positive and negative electricity may also be mentioned, although perhaps the final word has not been said on this question. In discussing the phenomena of metabolism, we saw how two processes might be distinguished, the building up of a complex system or substance of high potential energy, "anabolism," and the breaking down of such a system, "catabolism," giving off energy in other forms. Such a case we saw in the secretion of the salivary glands and shall meet with again in muscular contraction. The tendency of much recent work, however, is to throw doubt on the universality of this opposition of anabolism and catabolism as explanatory of physiological activity

in general, since it appears that many protoplasmic processes may IK- compared rather to the utilisation of fuel in a petrol motor, where the fuel does not I income built up into a chemical complex with the mechanism, but gives up its energy by means of the mechanism. The mechanism acts upon it from without, in a certain sense. Further discussion of this question will be necessary later. The name "excitation" is usually given to the increasing or setting into action of a process, and that of "inhibition" to the opposite phenomenon of stopping a process or decreasing its activity.

In the strict sense, all living protoplasm is "excitable," that is, it is capable of being affected by external forces, as was clearly pointed out by John Jirown (1788, p. 3 of 1795 edition) and, in more detail, by Claude Bernard (iss.\ I, p. 242), who defines "irritabilite," which is equivalent to the name " excitability " as used above, as "la propriete que possede tout element anatomique (c'est a dire le protoplasma qui entre dans sa constitution) d'etre mis en activite et de reagir d'une certaine maniere sous 1'influence des excitants exterieurs."

Nevertheless, it is usually the custom to apply the name especially to such tissues as respond to stimuli by a rapid change of some kind and more particularly to nerve and muscle. As animals in the course of evolution increased in size and complexity, means of communication between different parts became more and more necessary. To a certain extent, such intercommunication is effected in a chemical way, through the blood, or similar fluid. But this is not sufficiently rapid for many purposes, the fact of contact of a solid object must be conveyed to the muscles of locomotion, so that the organism may react rapidly enough to avoid it. Hence we find the presence of nerves at a very early stage of evolution of multicellular animals. Even in Crelenterates, the complexity at the nervous channels is considerable. The effect of something happening at one end of such a thread is conveyed with great rapidity to the other end of the nerve, wherever it may be. Our study of the phenomena of excitation will begin with that of the nerve fibre. In some ways, it is the simplest case ; in others, more difficult. Nerve fibres ha\e no other function than that of conveying excitations. When left alone, they are, as far as we know, in complete rest, so that their activity does not require inhibitory influences to quell their state of excitation. When set into activity by some influence, called a " stimulus," the disturbance set up disappears spontaneously after a certain very short time, if the stimulus ceases to act.

If we take what is known as a "nerve-muscle preparation," that is, the gastrocnemius muscle of the frog, with the nerve, the sciatic, supplying it, we find that if we lightly pinch the end of the nerve distant from the muscle, the latter enters into contraction, and, as it seems, simultaneously with the stimulus. Nothing to be seen has happened in the nerve, yet something must have passed along it from the point at which it was pinched, otherwise the muscle would have been unaware of anything having taken place at the other end of the nerve. It is usual to speak of a " propagated disturbance " passing along the nerve, or sometimes a " nerve impulse." But how are we to detect it and investigate it in the nerve itself, apart from the indicating muscle 1

The most careful investigation with the most sensitive apparatus has only In en able to detect with certainty one kind of change accompanying the passage of the " propagated disturbance," namely, an electrical effect. The production of heat in any quantity that would have any significance at all is definitely excluded by the experiments of A. Y. Hill (1912). By the use of a method by which changes in temperature of six-millionths of a degree could be detected, no effect was obtained by twenty-five seconds continuous stimulation. This result means that a single propagated disturbance does not result in the production of more than 1° x 10~8 C., that is, a hundred-millionth of a degree. Hill calculates that heat of this amount would be afforded by the consumption of 1 molecule of oxygen by a volume of nerve of 3'7 p. cubic measure,

a volume easily visible under the microscope and, if filled with oxygen as atmospheric pressure, would contain 3 x 109 molecules, since 1 cm. contains 4-5 x 101(i. This result makes it impossible to suppose that any chemical process resulting in an irreversible loss of energy, such as an oxidation, can be involved, and indicates that a reversible physico-chemical one of some kind is to be looked for. Moreover, it makes it a matter of necessity to examine with care statements that have been made as to the production of carbon dioxide by nerve in activity.

Waller (1896) noticed that the action of small amounts of carbon dioxide on nerve was to increase the extent of the electrical changes and that tetanisation had the same effect. The natural conclusion was that carbon dioxide was produced by the nerve in its own activity. It will be clear, however, that it is quite possible that the effect of prolonged electrical excitation may have nothing to do with the effect of carbon dioxide, but perhaps be a consequence of some direct effect of the current, electrolytic or other effect. A recent paper by Tashiro (1913, 1) claims to have proved by a direct method that carbon dioxide is formed by nerve fibres as a product of their activity. A very delicate method was used for the estimation of carbon dioxide (1913, 2), dependent on the formation of a film of barium carbonate on the surface of a drop of barium hydroxide solution. The quantities found were, of course, very small, and the possibility that they were merely dissolved in the tissue is not satisfactorily excluded. Small amounts were given off very slowly by the resting nerve. The extra production on electrical excitation would easily be accounted for by the heat resulting from the passage of the current. It is to be remembered that a nerve trunk consists not only of nerve fibres themselves, but of connective tissue in which are living cells, which would contain carbon dioxide from their own respiration, so that, although the production of carbon dioxide on their part might not be increased by electrical excitation, that dissolved in them would be partly given off in consequence of the heat produced by the exciting current itself. We note also that there was a regular falling off in the output of carbon dioxide by resting nerve, even during the time in which there is every reason to suppose that the excitability was undiminished.

Killing the nerves by the action of steam abolished their power of giving off carbon dioxide, both resting and YIG. 101. DIPHASIC CURRENT OF ACTION on excitation ; but this does not show that it was a IN OLFACTORY NERVE OF PIKE, AS vital phenomenon, since carbon dioxide dissolved in SHOWN BY THE CAPILLARY ELECTRO- on the origin of carbon dioxide from the metabolism ^"^f °nofwj*a8; "gle break mductlon shock of the nerve itself, since they show that it is higher Tim^ ;„" '^ ^"nd.

than that of an equal weight ot muscle. Until (After Garten.) experiments are made in which the source of error referred to is excluded, I fear that we cannot accept the conclusions of Tashiro. The source of the effect in Waller's experiments may also have been from carbon dioxide dissolved in non-nervous tissue. We are thus limited to the electrical change. Fortunately, this can be measured with accuracy and its time course determined. For the present, we will omit discussion as to its cause, and limit ourselves to the fact that a spot in a state of excitation behaves as if electrically negative to a spot on the nerve at rest ; that is, if the two points are connected to a galvanometer, a current flows through the instrument from the resting to the excited spot, as if the former corresponded to the copper of a Daniell battery and the latter to the zinc. We find that the electrical change set up at one point by a momentary stimulus lasts only for a short time at this point and passes along the nerve, making each point in turn electro-negative to the rest. Suppose that two electrodes lie on the nerve at different points and that a stimulus is applied near the one electrode ; the electrical response will consist of a current in one direction as this electrode becomes negative to the more distant one, followed by a current in the opposite direction as the wave, having left the first electrode, arrives at the second, making it negative to the other. If we call the electrodes A and B, we have, first, A negative, B positive, then A positive, B negative. This form of electrical response is called "diphasic" (see Fig. 101). If electrode B is on a spot which has been killed, the wave of negativity, as it is commonly called, disappears in the killed area, so that the only electrical effect seen is that due to the becoming negative of spot A and consists, therefore,

of only the first half, as it were, of the diphasic response ; it is, in fact, " monophasic." We know, then, that a propagated disturbance can be set up in a nerve fibre and we have next to inquire how such a " nerve impulse " is excited for. experimental purposes. The agents which do this are known as " stimuli " and, for practical purposes, electricity is the most useful, since its strength can be accurately and conveniently graduated and measured. In the application of a single stimulus, consisting of a definite quantity of electrical energy, we must remember that energy is made up of two factors, quantity and intensity, so that we can make up the same amount of electrical energy by varying the two inversely. Now it was found by Waller (1899) that this is not a matter of indifference. There is a certain definite ratio, different for different excitable structures, and different conditions, such as temperature, at which a smaller quantity of energy will excite than at another ratio, in which either the quantity or the potential is higher or lower. This is called by Waller the " characteristic " number. How is it to be explained ? Investigations of this kind can be best made by the use of condenser discharges. When two metallic plates, separated by a non-conductor, are charged to a different potential by connection to a source of electricity, the quantity required to produce a given potential difference between them depends on their size, distance apart and the dielectric constant of the medium between them, as we saw on page 180. This is known as the "capacity" of the condenser. By taking condensers of different capacities and charging them to different potentials, we can obtain all the varieties required. The energy in ergs of the discharge of a condenser is given by the formula, 1/2 U2 C, where U is the potential difference between the plates in volts and C the capacity in microfarads.

The expression, it will be noted, is analogous to the ordinary one for kinetic energy. When a certain quantity of electricity is discharged through a high resistance, such as a nerve, there is a perceptible difference in the time taken for the discharge, according to the potential at which it commences. The formula when there is no considerable self-induction in the circuit. E0 is the potential difference between the plates before commencement of

discharge. Ej is that after the lapse of time, t, during which the condenser has From this formula it will be seen that, other things being constant, the time taken for discharge is proportional to R or to C. In the paper by Hermann (1906, p. 554), a series of curves will be found, showing the different steepness of the curves of discharge of condensers of different capacity. The reader may be reminded that the capillary electrometer, used so frequently in the investigation of the electrical changes of tissues, behaves as a condenser in its time curves of charge and discharge. In the determination of the constants in these cases, as in general, where the process starts rapidly and becomes slower and slower as the final state is approached (Newton's " law of cooling," see above, page 157), it is customary to make use of the time taken for half the process to be completed, since the curve is changing its shape most rapidly at this period. Towards the end, measurements are difficult and inaccurate on account of the slow change. In the case of a condenser charged to a potential of 1 volt, the character of the discharge is given by the time taken to fall to half a volt. In the excitation of nerve, in fact, the steep and only active part of the discharge is well over before this time ; slowly changing currents have no exciting effect, as will be seen later.

It appears from Waller's experiments, that there is a particular steepness of curve which produces its effect with least expenditure of energy, and it seems justifiable to connect this fact with the rate of movement of some constituent of the nerve system, somewhat as a push of a given strength, applied to a resting heavy pendulum, will have a greater effect if the rate at which its energy is imparted to the pendulum coincides with the vibration period of the latter.

In the practical use of the condenser, it is important to remember that the insulation is never perfect, so that if any delay occurs between the charge and the subsequent discharge through nerve, the most effective part of the discharge, namely the steepest fall of potential, will have been lost. For this reason, the best arrangement of the circuit is that given in Fig. 102, ascribed by Hermann (1906, p. 540) to Radakovid The condenser c is connected to a source of adjustable potential through the nerve N. When the key K is closed, a chosen fraction of the potential difference of the battery B is sent into the condenser through the nerve. As long as the key remains closed, the full charge of the condenser is kept up to the potential required, but the moment that the key is opened, discharge takes place through the nerve and the part of the slide wire between A and P. If either the charge or the discharge is not intended to pass through the nerve, a short circuit is made for the time being between D and K.

Although the condenser is the most perfect means of delivering accurately measured stimuli to a nerve, it requires somewhat complex apparatus when a rapid series of stimuli is required. For ordinary use, the induced currents produced in a coil of fine wire, by the make or break of a current in another coil of larger wire at an adjustable distance from it, are substituted. This arrangement, when fitted with an automatic interrupter, " Wagner's hammer," is known as "Du Bois Reymond's

Coil," after its inventor. The currents induced by the make and break of a current in the primary coil differ in their time course, owing to the fact that the establishment of the current in the primary coil is retarded by self-induction, which is naturally absent at break, since the circuit is no longer complete. The break shock is therefore of a higher potential than the make shock. Further details of the various methods of electrical excitation will be found in the article by Garten (1908). One or two facts may be mentioned here. The current used to excite must obviously enter the nerve at one electrode, and leave it at the other. It is always found that excitation takes place at the cathode when the current is established and, if it has lasted for some time, at the anode when it is broken. These facts can be made out best by the use of constant, unidirection currents, which can be kept closed as long as desired. Of course, when other than alternating currents are used, the electrodes must not be capable of polarisation, 'ihe construction of non-polarisable electrodes will be found in Garten's article (1908, pp. 333-339). A very convenient form is the modification of Ostwald's calomel electrode described by Noyons (1909), or that of Philippson (1912). No excitation occurs during the passage of a current as long as it remains

unaltered ; in fact, there must l>e a change of potential in order to excite, and this change must not be too gradual or it will not excite at all, nor too rapid, as the extremely rapid alternations of the Tesla currents, which are practically inactive in proportion to the energy which they contain. These currents are produced by induction from the rapid natural oscillatory discharge of a condenser, such as a Leyden jar, charged to a high potential by connection to a large induction coil or influence machine. A current of nearly half an ampere, sufficient to light an incandescent lamp in the same circuit, can be sent through the human bndv without exciting nerves therein. It appears, indeed, that what effects are produced by these so-called "high-frequency" currents are merely due to the heat into which they are converted in the tissues through which they flow.

A convenient method of application of currents of different time course is by the rheonome of von Fleischl, described in Garten's article (1908, p. 406). Keith Lucas (1907, 1) describes a simple form of rheonome, formed by an ebonite diaphragm with a hole, which is moved across another hole in a second shutter, which separates two compartments, each containing saturated solution of zinc j Kisses by means of a zinc electrode in each compartment.