Principles of General Physiology

The relaxation of tone in smooth muscle is another aspect of the negative temperature coefficient of surface energy. Pauli (1912) has developed a theory on the lines of the colloidal chemistry of the compounds of proteins with acid. I find it difficult to bring this view into connection with what we know from other lines of investigation, and must be content with referring the reader to the lecture itself. There is one point that requires some attention. We know from the work of Ryffel (1909) and others that, in considerable muscular work in man, lactic acid appears in the urine. This must be due to the fact that the oxygen supplied in the blood is insufficient to replace in the muscle system the whole of the lactic acid formed by the vigorous contractions before a part of it is washed away by the blood current. Now this part is lost to the muscle system and must be replaced from some source. It can readily be formed, as we have seen, from glucose or from alanine, but its actual origin is unknown. The fact that the excretion of nitrogen is not increased in muscular work appears to be against the latter possibility. It seems possible that experiments might be made to see whether removal of lactic acid by perfusion of active muscle would or would not affect the final amount to be obtained in heat rigor, and whether there is any evidence of more carbohydrate being used under these conditions.

In excessive work, as opposed to normal vigorous work, there is evidence of a certain amount of nitrogenous breakdown of the structure itself, as we have already seen (page 272). Food Used. — Locke and Rosenheim (1904) found that glucose, added to the perfusion fluid of a mammalian heart preparation, gradually disappeared ; but, as Evans (1914, 1, p. 408) points out, this fact does not satisfactorily prove that it was -consumed, since it might have been converted into glycogen or some other substance of less reducing power than glucose. The proof was afforded by Evans himself, in the paper referred to, by showing that the respiratory quotient (see p. 279) was raised by the addition of glucose. Rohde (1910) had shown that the respiratory quotient in the first period, after setting up the preparation, was dependent on the previous diet of the animal, so that it was lower after a flesh and fat diet than after one of carbohydrate. The result was confirmed by Evans, and appears to show that the heart can also utilise fat. Experiments of Palazzolo (1913) show that the fat content of frog's muscles is diminished by tetanisation to exhaustion. If the muscle actually has the power to use fat for energy purposes without previous conversion to carbohydrate, we have a further argument that the oxidation reaction may make use of various combustible materials indifferently, and therefore that the contractile system so built up is not a chemical one.

Campbell, Douglas, and Hobson (1914) show that muscular work is associated with a rise in the respiratory quotient, which is not merely due to production of lactic acid driving off carbon dioxide, since it remains raised during the performance of work, and, on cessation of work, there is at first a further temporary rise to nearly one. It subsequently falls to below normal. This seems to show that carbohydrate is burned. The late fall to below normal might be due either to the carbohydrate store having been exhausted or to formation of new carbohydrate from other substances.

Benedict and Cathcart also (1913, p. 94) find that there is a rise in the respiratory quotient during work ; thus showing that there is an increased consumption of carbohydrate. But the fact that the respiratory quotient very rarely rises to 0-98, as they point out, prevents the conclusion being drawn from these experiments that muscular work is performed exclusively at the expense of combustion of carbohydrate. Moreover, the more severe the work, the heavier is the draft upon the carbohydrate material of the body. So that, in the subsequent resting period, a lower proportion of carbohydrate is burned for the purpose of the total energy output of this period. These workers state that their average results suggest that the energy for muscular work is afforded exclusively by the oxidation of carbohydrate. They were unable to find any evidence of the conversion of fat to glycogen during muscular activity (p. 146).

Efficiency. — We have already seen that the potential energy of tension can practically be all converted to external work, a very small fraction only being degraded to heat in the process. In other words, nearly the whole of the energy is "free." In the engineer's sense, the "efficiency," that is, the proportion of the work done to the total energy change, is nearly 100 per cent. This value is only to be obtained in optimal conditions, but its importance is obvious. If, on the contrary, we include the heat given off in the restitution phase, as must be done when we consider the muscle as a machine performing work by means of food supplied, the efficiency is only about 50 per cent., .since, in the second phase, the heat given off is about equal to the work of the first phase, while no external work is done (A. V. Hill, 1913, 2, p. 465). But even this compare^ favourably with the most efficient heat engine yet made.

This high efficiency of striated muscle applies only to the single twitch, or the act of raising a weight as opposed to that of keeping it supported: While the process of raising a weight, that is, the performance of actual external work, is a very economical one, that of keeping it suspended, without performance of further external work, is much less efficient. In the frog, as A. V. Hill has shown (1913, 4, p. 322), to maintain a particular state of tension in the sartorius muscle it is necessary to liberate six or seven times as much energy per second as that required to produce it. This fact suggests that the state of tension must be maintained less wastefully in other forms of muscular structure, and perhaps in striated muscle in natural modes of stimulation, a question to be discussed in Chapter XVIII. on " Tonus." It may be that the state of shortening is kept up without tension.

This consumption of energy in processes by which no external work is performed renders the calculation of the efficiency of the whole animal as a motor a matter of considerable difficulty. The experiments of Zuntz, Benedict, and others, on the heat and respiratory exchange of men doing measured amounts of work, are beyond the scope of this book. The paper by Macdonald (1913) may be mentioned, together with that by Glazebrook and Dye (1914), in which Macdonald's results are used to obtain mathematical expressions relating to heat and work. In the case of a particular individual, the efficiency comes out as 25 per cent. The detailed researches of Benedict and Cathcart (1913) should also be consulted by those interested.

It will be clear that the calculation of the efficiency of an animal as a motor depends on how this estimation is made. Owing to the low efficiency of the maintenance of tension, it will make considerable difference whether the calculation is made by taking the difference between the heat evolved in maintaining a weight at a constant height, and that evolved in raising it from this height to a further one, and again maintaining it at this position. The tension being the same in the two maintenance positions, the heat production will be the same, and the difference will be that associated with the performance of the external work. In this way a high efficiency is arrived at. Similarly, Zuntz calculates his values on the basis of the difference between the carbon dioxide output when walking on the level and that when walking up hill. The whole question is discussed by Benedict and Cathcart (1913). The efficiency found by them, under most accurate conditions (p. 142), that is, comparing the efficiency obtained under moderate work with that of heavier work with the same apparatus, was as high as 33 per cent. In this way an accurate base line for the increased metabolism was obtained. In other words, " the increase in the effective muscular work may be as high as 33 per cent, of the increase in total heat output."

According to Macdonald (1914), the rate of heat production, Q, associated with cycling at a uniform rate, but with varied performances of mechanical work, is expressed by the formula : — where x is the heat production associated with uniform rate of movement, and y the rate of performance of work. where V is the rate of revolution of the bicycle per minute. This expression is also found to be related to the weight of different subjects thus : — It shows that there is a particular rate of performance of work at which the total efficiency is maximal ; above and below this rate, the efficiency falls.

In connection with the heat developed in tetanic contraction, the fact described by A. V. Hill (1913, 4, p. 317), that the heat-production per unit of tension is independent of the frequency of stimulation between 17 and 100 per second, is of interest. It indicates that "the rise of tension is due to the presence of chemical substances, liberated in conjunction with heat, by the processes called forth by excitation. The presence of a definite amount of these substances in the neighbourhood of certain surfaces or interfaces in the muscle, calls forth the same amount of tension independent of the exact rate at which the stimuli occur. These chemical substances are removed or destroyed at a rate proportional to their concentration at any moment ; and, therefore, if they are produced (and removed) at a greater rate by an increased frequency of excitation, their concentration in the muscle must be increased proportionally. This increased concentration, however, is accompanied by an increased tension, and, therefore, the tension developed remains proportional to the rate of heat-production."

If a muscle is caused to work at a greater rate than the lactic acid produced can be replaced by the oxidation process, it becomes " fatigued," that is, incapable of full activity, or even of any at all. Naturally, this result comes on more rapidly in the absence of oxygen. From the experiments of Fletcher and Hopkins, and of Peters, referred to above, the amount of lactic acid found in a muscle, stimulated to fatigue, only amounts to about one-half of that obtained in heat rigor. The power of contraction ceases before the whole of the "excitable substance" is used. up.

This fact suggests that the lactic acid has a toxic effect, or that the process is of the nature of a balanced, reversible one. Certain experiments by Lipschiitz (1908) show that the spinal cord of the frog, after fatigue in absence of oxygen, can be restored to a certain extent by perfusion with Ringer's solution carefully deprived of oxygen ; so that it seems probable that the same fact would be found in the case of muscle. It would be interesting to know whether more lactic acid could be formed by stimulation, if that produced were washed away as formed. As mentioned above, such experiments would also throw light on the question of the formation of lactic acid from carbohydrate in the muscle.

It is important to note that fatigue of voluntary contraction, as investigated by the ergograph, or similar method, is not situated in the muscle tissue itself. Artificial stimulation of the motor nerve can still cause contraction when fatigue to voluntary inner vation has set in. We have already seen that direct stimulation of muscle will cause contraction after the synapse between nerve and muscle has lost its excitability. The effect of the first stimuli after a period of rest is usually less than that of the subsequent ones ; thus a series of stimuli gives, first, a rise in height of contraction (Buckmaster, 1886), then a period of maximal height, and, finally, a diminution owing to fatigue. It appears that the presence of a small quantity of products of activity is favourable. We shall see immediately that this phenomenon is especially marked in the heart muscle.

The Heart. — There are certain important characteristics of muscular structures which are particularly well shown by the heart muscle, while there are other characteristics which have, as yet, been investigated in the case of this organ only, although they have, in all probability, a general application. It may be noticed that certain of these were, at one time, supposed to be peculiar to heart muscle, although later work showed them to be also present in nerve and in voluntary muscle. In the following pages, some facts concerning the general properties of the muscle as a contractile tissue will be mentioned ; its function as a pump for the maintaining of the circulation of the blood, together with the

(|iirstion of the origin and regulation of the beat, will be described in Chapter XXIII. "All or Nothing." — This fact was discovered by Bowditch (1871) in the heart FIG. 138. REFRACTORY PERIOD IN FROC'S VENTRICLE. — Spontaneous contractions with artificial stimulus applied at various intervals after a contraction, as indicated by a rise in the signal line. The succeeding lines show gradual decrease of latent period (shaded part) of the extra contraction

which takes place at this period. The "compensatory pause," after the extra systole, is shown in lines 4, 5, 6, 7, and 8. of the frog. On account of its interest and importance, the words used by the investigator himself may be given, in translation, thus : " An induction shock produces a contraction or fails to do so according to its strength ; if it does so at all, it produces the greatest contraction that can be produced by any strength of stimulus in the condition of the muscle at the time" (p. 687).

We have seen that the phenomenon is shown by voluntary muscle and by nerve. The law applies also to the movements of plants (Burden-Sanderson, 1882, p. 42). Staircase. — This phenomenon was also demonstrated by Bowditch (1871, p. 669) in the frog's heart. Buckmaster (1886) found it in voluntary muscle and, as we have seen (page 391), the local effect left behind by an inadequate stimulus to nerve, as shown by Adrian and Lucas (1912), seems to be a similar condition. This latter summation of inadequate stimuli ("summation of excitation," as it is sometimes called) is shown by various muscular tissues and must be distinguished from the summation of contractions observed in the superposition of tetanus, where a contraction takes its start from a position of incomplete disappearance of the one preceding it.

Refractory Period. — This can easily be detected in the heart muscle. If a stimulus is put in at various points on the course of a previous contraction, natural or excited by artificial stimulus, no effect is produced until a certain stage is reached and it is found that, within limits, the stronger the stimulus, the earlier is a second contraction capable of being excited ; as already mentioned, in the very earliest part of this period no contraction can be produced by any stimulus whatever. If any effect at all is produced, it is the maximum one that the tissue is capable of giving at that stage of recovery (see Figs. 138 and 139)T.

Summation of Contraction. — Mines (1913, 1, p. 22) shows that, in the ventricle of the Selachian fish, Torpedo, an artificial stimulus, at a short interval after a normal beat, produces a greater response than the normal one, and that this response may occur at so short an interval that the previous contraction has not completely disappeared, so that superposition may occur. As the interval increases, the height of the second contraction decreases, until, at the normal interval between spontaneous beats, the normal height of contraction is given by an artificial stimulus. These facts and the relatively short refractory period associated with the phenomenon are shown in Fig. 139 (page 453). The increase of height is, no doubt, a similar phenomenon to that observed in skeletal muscle, and is probably due to an increase of hydrogen-ion concentration to its optimal value by the lactic acid formed in contraction (see the following section below).

Action of Ions. — The powerful effect of certain inorganic ions has been referred to above (page 143). A few additional facts are of interest in the present connection. The part played by lactic acid suggests that hydrogen ions have an important share in the phenomenon. Mines (1913, 3, p. 221) finds that the optimal concentration of hydrogen ions for the heart is 10~72. If slightly above this, say 10~6-8, the beats become slower and weaker, the duration of the electrical change is diminished, while the rate of transmission from auricle to ventricle is decreased (see also Fig. 55, page 187).

Since increase in frequency of beat results naturally in increase of hydrogenion concentration, the above effects may be expected to be met with in such a case. Similarly, with increased rate of stimulation of skeletal muscle, we may expect corresponding results. The action of calcium ions is of much importance. We have already described Ringer's work in some detail (pages 207-209). Although calcium is necessary for the occurrence of contractions, it was noticed by Locke and Rosenheim (1907) that a heart at rest, owing to absence of calcium, still continued to consume glucose, and that the electrical change still remained strong. This latter observation was confirmed by Mines (1913, 3, p. 224), and further analysed. It was found that calcium has two effects. It is well known that, as far as its effect on the contractile function is concerned, it cannot be replaced by magnesium. Thus, if we replace a normal fluid by one containing magnesium in place of calcium, the effect on the size of the contractions and on the transmission from auricle to ventricle is the same as if we had merely removed calcium ; but the primary quickening of the rhythm, which is the first effect of a solution devoid of calcium, is absent. So that, as far as this latter effect is concerned, magnesium can replace calcium. It appears that the contractions fail in the absence of calcium because the actual contractile mechanism, on which lactic acid plays, is thrown out of gear in some way. A point of interest, upon which further information is required, is whether there is production of heat, which would be expected to occur when glucose is consumed. It does not seem to me to be a satisfactory explanation to suppose that the contractile substance is in the forms of strands of a calcium salt of some colloidal material, which contracts when acid is formed in contact with it. The various facts referred to on previous pages indicate rather an electrical effect on surface energy, but dogmatic statements are out of place at present.

Contractile Muscles and Arrest Muscles. — In many animals, as we shall see in more detail in Chapter XVIII., the two functions of shortening and of maintenance in the state of shortening arrived at, appear to be assigned to separate muscle fibres of different characteristic properties. In the bivalve molluscs, there is a small quickly contracting muscle which closes the shells ; but the shells are kept closed by a strong, slowly acting muscle, which follows up, as it were, the rapid contraction of the other and holds the shells together. This last effect seems to be done by some kind of an arrangement which may be compared to a ratchet, the process being attended with no consumption of energy. A description of certain of these mechanisms will be found in the book by von Uexkilll (1909, pp. 92 and 144). The question is discussed in Chapter XVIII.

In skeletal muscle it is important for sensitive grading of contraction that the fibres should act separately. In smooth muscle and in the heart, excitation can travel from one fibre or cell to another, so that there are waves of contraction passing over the mass of muscle. In the heart, the separate fibres are connected by bridges of muscular structure, but, in the typical smooth muscle, such as the intestine, it is more difficult to ascertain the mode of transmission from cell to cell. In both cases, however, it can be seen that a stimulus applied to a point starts a wave of contraction, which travels in all directions from the point stimulated.

It is very instructive to lead off the quiescent ventricle of the frog, or better of the tortoise, by two electrodes to a capillary electrometer, the electrodes being as far apart as possible, say on the apex and base, respectively. If an induction shock is applied close to one of the electrodes, say that at the base, a diphasic electrical response will be seen, indicating by its direction that a negative wave has started at the base and been propagated to the apex. The neighbourhood of the electrode at the apex is then stimulated ; we see again a diphasic response, but this time the negative wave starts at the apex and is propagated to the base, so that, if the first phase in the first experiment was an upward movement of the mercury, in the second experiment it will be downward.

It is not to be taken for granted that the muscular systems of the lower invertebrates necessarily behave in the same way as the smooth muscle of the vertebrate. It is important for their movements that accurate control should be exercised over separate fibres and, accordingly, we find that (von Uexkiill, 1909, p. 79), even in the Medusae, the contraction produced by an electrical stimulus remains, in certain cases, limited to the spot excited ; the excitatory process does not spread from one fibre to another. This applies to the ring of muscle around the edge of the umbrella of Rhizostoma. On the other hand, in Aurelia, as Romanes has shown (1876), the umbrella can be cut up into a spiral or other shape, and a contraction produced by stimulus applied at one end is conducted to the other end. Romanes (1885, p. 77), however, regards it as proved that the excitatory process is conveyed by the nerve network and not by transmission from muscle cell to muscle cell directly. The properties of such nerve networks will be discussed in the next chapter.

The time relations of the production of heat in muscular contraction have been described above. We saw that, in the restitution process, or reaction by which lactic acid is restored to its place in the system, which is thus given a store of potential energy, a certain amount of chemical energy is degraded to heat, and also that the contractile tension developed on excitation, if unused for the performance of external work, is transformed to heat in the muscle itself.

Now, in the warm-blooded animal, this heat must not be looked upon as entirely wasted, since it serves to keep up the temperature of the organism. The importance of this raised temperature for the hastening of chemical reactions, in response to changes in the environment, has been pointed out. Muscular contraction is, in fact, the chief, if not the only, source of heat of practical importance to the animal organism. Of course, heat is produced in other chemical reactions, especially those of oxidation, but they make up but a small part of the total.

Even cold-blooded animals and plants produce heat, but they are not provided with arrangements for keeping their temperature constant, so that it is usually only a fraction of a degree higher than that of their surroundings. Hence they are called " poikilothermic," of varying, temperature, whereas the higher vertebrates, birds and mammals, are " homoiothermic," that is, of uniform temperature. Under certain circumstances, as in a hive of bees, the temperature of poikilothermic animals may rise considerably.

In a warm-blooded animal, even at rest, there is a considerable production of heat by muscular contraction, which is always present in the form of reflex tone. This is naturally less in sleep, and we can observe the care taken by animals to avoid loss of heat when asleep. We know also how much more rapidly we become cold when asleep than when awake. There are always certain muscular movements going on, as those of the heart and muscles of respiration.

Calorimetry. — The apparatus used for determining the output of heat is, like that used for the same purpose in physics and chemistry, called a calorimeter. It may be made on various principles, but the only satisfactory one for use with large animals, such as man, is that described by Williams (1912), as an improvement on that of Atwater, and by Macdonald (1913). The principle on which this apparatus is constructed is to absorb the heat produced by the animal by means of a current of water circulating through ribbed tubes in the chamber. When the amount of water flowing and the temperature difference between the inflow and outflow are known, the quantity of heat can be calculated. A. V. and A. M. Hill (1913 and 1914) have arranged apparatus of a similar kind for automatic registration over long periods of time and have avoided the difficulty of loss of heat, by conduction and radiation, by the use of large vacuum-jacketed flasks for small animals, and double-walled tanks for larger animals, the heat insulation in the latter case being provided by sawdust and "kapok wool." The heat produced is removed by a current of water and the difference of temperature between thermo-electric junctions in inlet and outlet is registered by a self-recording galvanometer. The micro-calorimeter of A. V. Hill (1911 2,) is used for very small production of heat.