Organism and Environment as Illustrated by the Physiology of Breathing

The step from secretion to the processes which we commonly designate as cell nutrition or cell respira-' tion is only a short one. The microscopic study of secreting cells shows that the substances secreted, or their immediate precursors, are often stored up for some time until the moment for their discharge comes. This storage is comparable to ordinary growth. In his famous book on Secreting Glands, published in 1830, Johannes Miiller expressed the opinion that secretion and growth are merely different aspects of one kind of activity; the sole difference being that in secretion the product is removed, while in growth it remains. Miiller was a vitalist, and his ideas on secretion were for the time swept away by the whirlwind of mechanistic speculation which passed over physiology about the middle of the last century; but in the main he was right. We now know that even in ordinary nutrition nothing remains still and inactive. Living structure is really alive and full of molecular activity: it is the expression of the directions and velocities which this activity takes. Substances are constantly being taken up from and given off to the environment; and even when these substances do not seem to be used up in adult nutrition, as for instance in the case of inorganic salts, there is a constant molec- ular interchange between the cell and its environ- ment. This is proved by the fact that, as was first shown in particular by Sidney Ringer, the tissues are

extremely sensitive to the slightest changes in the concentrations of inorganic salts in their environment. Cell-secretion, cell-respiration, and cell-nutrition are clearly only different aspects of the same whirl of molecular activity. Where secretion or nutrition seems to be stationary, there is in reality only a balance between ingoing and outcoming molecular streams. Instances of this occur when the kidney is not secret- ing chlorides, or when no oxygen is passing into or out of the swim bladder, or when all external activity is latent, as in a dry seed. The apparent stand-still is similar to that in a blood corpuscle in a test tube of blood half saturated with oxygen, when the stream of oxygen molecules entering the corpuscle is balanced by the stream leaving it. The unstable oxyhaemo- globin molecules in the blood corpuscle are constantly losing oxygen molecules and as constantly regaining others, so that the half saturation of the blood cor- puscle with oxygen represents the average of the gains and losses of the haemoglobin molecules. This we can understand. But what conception can we form of the molecular streaming in the living cell and the strange co-ordination which the different molecular streams exhibit? I have tried to indicate how this problem, which will be followed up in the next lecture, rises directly out of the fact of oxygen secretion. But meanwhile we must follow further various other facts relating to respiration.

The evidence existing at present is strongly against the theory of active secretion of COg outwards by the lung epithelium. Krogh's experiments gave very defi- nite results on this point. In any case we should hardly expect to meet with active secretion of COg, considering that the breathing is regulated by the COg pressure in the arterial blood, and that the oxygen supply to the lungs is dependent on this regulation. During very excessive muscular work it seems to be the oxygen supply to the body that first begins to fail. This is indicated by the fact that in very hard work the alveolar CO2 percentage begins to fall, and may even become lower than during rest.

The delicate and exactly regulated organization by which CO2 is removed from the blood in the lungs, and oxygen supplied, would quite clearly be of little service to the body if there were not also a regulation of the circulation of blood so as to keep the removal of CO2 from the body tissues and their supply of oxygen correspondingly steady. We must now, therefore, consider what is known as to the circulatory regula- tion. Knowledge on this subject is unfortunately still very fragmentary, mainly because physiologists have failed to appreciate the delicacy of organic regulation, or have even lost sight of it altogether when investi- gating various matters of detail.

The blood brings to the tissues the various sub- stances required for their normal life, and removes from them substances which are then carried to other tissues or to secretory organs. It is also a carrier of heat. The carriage of oxygen and CO2 is thus only one of its many functions. Hence we must not expect that the circulation will be solely regulated with refer- ence to the carriage of these gases. Bernard noticed that during active secretion of saliva by a salivary gland the venous blood issuing from the gland was of a bright red colour, owing to quickening of the circu- lation ; and Barcrof t found that owing to the quantity of liquid and COg abstracted from the blood during salivary secretion the absolute quantity of oxygen in a given volume of the venous blood may be greater, while that of CO2 may be less, than in the arterial blood. As one constituent or another assumes greater or less importance in the exchange between blood and tissues we must expect the circulation to vary accordingly, and there is no doubt that it does so vary. The gaseous exchange is, however, every- where of such immediate importance that we may be sure that the circulation is to a large extent regulated with reference to the gaseous exchange.

The flow of blood through any part of the body depends partly on the difference in blood pressure be- tween arteries and veins, and partly on the resistance to the flow of blood from the arteries through the capillaries to the veins. Now the difference between the pressures in the main arteries and veins at any given body level is nearly constant. This is so because, if we neglect such part of the pressure as is accounted for by the mere height above or below the heart, the pressure in the larger arteries is high, and nearly con- stant, while that in the veins is so low as to be insigni- ficant in comparison with the arterial pressure. Hence it is through variations in the resistance that variations in the rate of flow are brought about. But variations in the resistance depend almost entirely, so far as we

know, on variations in the calibre of the small arteries, caused by variations in the degree of contraction of the circular muscular coat with which they are pro- vided. It was discovered by Bernard that the muscu- lar coat is under the control of the nervous system through the vaso-motor nerves supplying the arteries. It is apparently, therefore, by these nerves that the rate of blood flow is controlled, though it may be that there is also some non-nervous means of control, due to the direct local action of chemical stimuli.

But how are the vaso-motor nerves themselves excited? It is known that there is a centre in the medulla oblongata in connection with afferent nerves by the excitation of which a widespread reflex aug- mentation or inhibition of the impulses which are con- stantly passing from the centre to the arteries is brought about. When this centre is destroyed or its connections severed there is also a great general fall in arterial blood pressure owing to dilatation of the arterioles. But the action of this centre does not explain the local regulation of blood flow in different organs in accordance with local requirements. That such local regulation occurs is known from observa- tions of the local blood flow ; it is known, also, that there are subordinate nerve centres controlling local blood supply, the response of these centres being to afferent impulses passing to the centres along locally distributed nerve-fibres. The afferent nerve-endings are apparently excited by excessive accumulation of products of metabolism or by deficiency of the sub- stances used up. It may be that the products of

metabolism act directly on the walls of the small arteries, but it is somewhat difficult to imagine how this could be brought about. Be this as it may, there is no doubt that in some way the blood flow through different parts of the body is regulated in accordance with the requirements of each part, so that during extra activity in any part there is a correspondingly greater blood flow. Measurements of the circulation through various organs have been recently carried out, in particular by Barcroft and his associates, in connection with simultaneous measure- ments of the oxygen consumption in these organs. The general parallelism between increased oxygen consumption and increased rate of circulation is evi- dent from these measurements.

To measure the circulation rate of the body as a whole by direct means is impossible without opera- tive procedures which hopelessly disturb the physio- logical conditions. Indirect methods have, however, been introduced recently. One of these is to measure in the lungs by a rapid method the gas pressures of the whole venous blood entering the lungs. From the gas pressures the gas contents can be calculated, as already seen, and a comparison of the venous with the arterial gas contents gives a direct measure of the ratio between oxygen consumption or CO2 produc- tion and blood flow. If the amount of oxygen being taken up and CO2 given off at the time is known, the blood flow itself can also be calculated. Using this method in man both Dr. Boothby of Boston and I have found that the blood flow increases proportion-

ately with the consumption of oxygen or production of CO2. Accordingly the differences in gas contents be- tween arterial and venous blood vary far less than does the rate of metabolism. To judge from observations on myself, the venous gas pressures are practically constant during rest. The differences in gas pressures between the two kinds of blood differ only slightly with great differences in the consumption of oxygen. The gross regulation of the circulation is of such a nature as to keep the venous gas pressures nearly steady, while regulation of breathing keeps the arte- rial gas pressures nearly steady. Hence although the pressure of oxygen is lower, and that of CO2 higher, in the venous than in the arterial blood, yet in each case the pressure is relatively steady. How the pecul- iar forms of the dissociation curves of oxyhaemoglobin and of the compounds which CO2 forms in the circu- lating blood contribute toward this result has been explained in the previous lecture.

The rate of the total circulation depends of course on the amount of blood pumped round by the heart; and it might seem at first as if the heart were the prime regulator of the circulation. This mistake has, in fact, been made by many physiologists through failure to look at physiological knowledge as a whole. Under normal conditions the heart simply maintains the pressure in the large arteries by pumping more, or less, blood according to the rate at which the blood- vessels allow blood to escape. It is thus the state of contraction of the blood-vessels in the various parts of the body that governs the rate of circulation.

The heart itself could not act as the prime regu- lator of the general circulation rate without pro- ducing great variations in the arterial blood pressure, so as to drive the blood at varying rates through the resistance of the arterioles. These great variations do not normally exist, as is easily shown by measure- ments of the blood pressure. Nor would primary regulation of the blood flow by the heart be of much use, since any regulation brought about in this way would apply to all parts of the body alike, whereas the increased or diminished requirements for blood are purely local, according as one part or another of the body is in a state of greater or less functional activity.

The heart is known to be provided with two sets of nerve fibres through which its action is controlled, and which reach it as branches of the vagus and the sym- pathetic nerves. The vagus fibres, when excited, exer- cise an inhibitory action, reducing both the frequency and the strength of the heart beats. The very signifi- cant discovery of this inhibitory action was made known by the brothers Weber in 1845. Excitation of the sympathetic fibres, discovered by von Bezold in 1862, increases the frequency and strength of the heart beat.

The inhibitrry influence of the vagus fibres is at once increased reflexly if the blood pressure in the aorta (the great artery leaving the heart) rises, and diminished if it falls. As an additional preventive to excessive arterial blood pressure there is a further nervous connection through which excessive rise of blood pressure causes reflex dilation of the arteries of the intestinal area, so that the pressure is relieved. The accelerator or augmentor nerve fibres are, ac- cording to recent investigations by Bainbridge, brought reflexly into action by rise in the pressure in the great veins opening into the heart.

It is clear also that the amount of blood pumped by the heart must depend on the supply of venous blood, and there is experimental evidence, first brought by Yandell Henderson, that fall in venous blood pressure may actually limit the heart's output of blood, so that the frequency of the heart beats is no measure of the rate of circulation, just as the frequency of breathing is no measure of the amount of air breathed. In this connection the state of con- traction or relaxation of the walls of the veins is a factor of great importance. Yandell Henderson's observations, part of which are not yet published, though communicated to me verbally, seem to indi- cate that contraction of the peripheral veins dams back blood in the capillaries. Less blood passes on to the great veins and the pressure in them becomes insufficient for the adequate filling of the heart.

The immediate causes of contraction of the walls of the veins are not yet exactly known ; but the obser- vations of Yandell Henderson on the influence of the pressure of COg on the circulation are extremely sig- nificant. When the body is greatly impoverished in CO2 by excessive artificial respiration the circulation fails, apparently from an inadequate supply of blood to the heart. The simplest explanation of the facts seems to be that the tonic contraction of the walls of

the veins is dependent inversely on the pressure of CO2 in the blood. Accordingly deprivation of CO2 leads to contraction of veins, with resulting congestion of capillaries and a decrease in the volume of the blood in active circulation equalling that induced by haemorrhage. On the other hand, any condition, such as muscular work, which is accompanied by increased pressure of CO2 and diminished oxygen pressure in the blood leads to dilation of the veins, and consequent increased rapidity in return of blood to the heart, with increase of venous blood pressure. What part, if any, the nervous system plays in this process, or what other substances beside CO2 are of influence, there are as yet no data to enable us to decide. From the circulatory phenomena in asphyxia due to breath- ing air deprived of oxygen (when there seems to be a great increase of both arterial and venous blood pressure) we may, however, infer that want of oxygen is one such factor.

The state of tonic contraction of the unstriped muscle such as is found in the walls of blood vessels depends, doubtless, on many other conditions besides nervous control. Recent investigation shows that one of the most interesting of these conditions is the supply to the blood of adrenahn, a specific product of the activity of the suprarenal glands. This discovery illustrates in a striking way the interdependence of different parts of the body — a subject to which I shall presently return.

When we review what is known as to the regulation of the circulation it is evident that it is not primarily the heart, or the nervous system, which is the regu- lator, but the metabolic activity of the body as a whole. The blood circulates at such a rate as is sufficient to keep its composition approximately constant at any part of the body, and the rate of flow seems to be greater or less at any one part in proportion as the causes tending to disturb the composition of the blood are greater or less at the same part. Among the chief of these causes is consumption of oxygen and libera- tion of COg. Hence the circulation rate is to a large extent determined by the activity of the latter pro- cesses, and varies, just as the breathing varies, in such a way as to keep the gas pressures in each part of the body approximately constant.

This is not an isolated fact in physiology. Claude Bernard pointed out in 1878 in his Legons sur les phenomenes de la vie that the blood is a fluid of re- markably constant composition, and practically pro- vides a constant internal environment for the living cells of which the body of a compound organism is made up. He seems to have been led to this conclu- sion by his well-known studies on the sugar of the blood. While still under the influence of the old ideas of the blood as a very variable liquid he began his investigations under the expectation that the amount of sugar in the blood would vary in proportion to the sugar absorbed by the intestine, and would disappear when no sugar or other food was taken. To his astonishment, however, he found sugar still abun- dantly present in the blood during starvation, and that any increase which he could produce in the blood

sugar, by feeding with sugar or sugar-forming mate- rial, was slight. If sugar was introduced in very large quantities it was simply excreted in the urine. He then discovered the part played by the liver in regu- lating the concentration of sugar in the blood, and he soon saw that other conditions of life are similarly regulated. This led him to express the opinion that **all the vital mechanisms, varied as they are, have only one object, that of preserving constant the con- ditions of life in the internal environment."

Bernard's teaching has been to a large extent for- gotten or obscured in masses of unconnected detail, but in reality has been strikingly confirmed by the progress of physiology since his time, and not merely in connection with the physiology of respiration. Let us look at some of the facts. I will refer first to the regulation of the amount of water in the blood, since this is a subject which Dr. Priestley and I have quite recently been investigating. It is well known that when large quantities of water are drunk an increasing secretion of urine follows. This increased secretion is evidently the expression of what may be called metaphorically the effort of the body to rid itself of unnecessary water. We made a study of the water excretion by the kidneys on the same lines as we had followed in studying the regula- tion of breathing.

The increase in secretion of urine a short time after drinking a large quantity of water is very remarkable, the increase being usually to about twenty-fold or more, so that as much urine may be secreted in an hour as is usually passed in twenty-four hours. The urine consists of nearly pure water, containing only what are relatively speaking traces of the ordinary urinary constituents. Now this fact in itself is very remark- able. The blood plasma contains a considerable amount of sodium chloride, and usually there is more sodium chloride in the urine than in the blood plasma ; but in the urine secreted after water drinking there is hardly any sodium chloride. The sodium chloride is held back, while the water passes in large quantities.

What we wished, however, to investigate specially was the change in the blood to which the increased secretion was a response. One would naturally look for evidence of dilution of the blood by the water ; and dilution would be shown by a diminution in the percentage of haemoglobin, since this can be measured with great accuracy and none of the haemoglobin is excreted or destroyed. There was, however, no diminution in the haemoglobin percentage during the period of most rapid excretion of the urine. Evi- dently the blood was not diluted, in spite of the fact that sometimes a volume of liquid exceeding that of the whole of the blood had been carried by the blood from the intestines to the kidneys in the course of a few hours.

Dr. Priestley then determined the electric con- ductivity of the blood serum, as this gives a very sensitive measure of the concentration of salts in the blood. The result was that there was a very slight but constant diminution of the conductivity during the extra secretion. This proved that though the blood was not diluted as a whole there was a very slight diminution in the proportion of salts to water. Some of the salts had presumably passed from the blood into the water contained in the intestine, with the result of decreasing very slightly the percentage of salts in the blood. The enormous extra secretion of water was the response of the kidney to this very slight change. At the end of the extra secretion the conductivity had returned to normal.

When, instead of pure water, a dilute solution of sodium chloride in water was drunk, there was again an enormously increased secretion of urine. This was accompanied by an easily measurable dilution of the blood, and the slightly increased conductivity showed that not only water but also salt was in slight excess over the other constituents. Both water and salt pass out in the urine, though at first very little of the salt goes, indicating that the excretion of the extra water is a process independent of the excretion of the extra salt.

After prolonged sweating, so as to deprive the body of much water, the urine becomes very scanty and concentrated. But in this case the blood may not become measurably more concentrated, even though the body has lost by sweating a quantity of water nearly equal in weight to the whole of the blood. The regulation of the proportion of water in the blood can thus be placed side by side as regards deli- cacy with the regulation of its reaction and compo- nents : its pressures of COo and oxygen, its percentage of sugar, urea, salts, and albuminous substances. Had

we the means of determining the innumerable other substances present in blood we should doubtless dis- cover a similar delicacy of regulation. All parts of the body seem to participate in this regulation. We have already seen how this is so in the case of breathing, circulation, and the activities of the kidneys and liver. Recent investigations reveal the same thing in connection with such organs as the thyroid, suprarenal and pituitary glands. The regu- lation of the blood temperature in warm-blooded ani- mals is one of the most striking instances. During muscular exertion the heat production in the body may be increased six or eight fold, but the tempera- ture of the arterial blood is only increased by a quite insignificant amount, as increase in the skin circula- tion and in the evaporation of moisture from the body compensates for the increased production of heat; while if the external temperature is varied the effects on the body temperature are also compensated by changes in the skin circulation and evaporation, and by variations in the heat-production of the body. The regulation is through the central nervous system, and is exactly comparable to the respiratory regulation of the blood.

The phenomena observed after bleeding or transfu- sion of blood are of great interest in this connection, and have recently been studied in some detail by Boycott and Douglas, using the new method available for determining the total haemoglobin and total blood volume in the body during life. After bleeding the total blood volume in the body is very rapidly recov- ered. The capillary walls seem to take up the liquid and solid material required, and this material is at the same time reconstituted so as to produce blood plasma of normal composition. But the regeneration of the lost red corpuscles is a much slower process, so that the new blood is at first very deficient in corpuscles, and several weeks may be needed for their complete regen- eration. If, however, the bleeding is repeated at inter- vals the process of regeneration of corpuscles becomes faster and faster, so that frequent re-bleedings can be easily borne by the animal. Similarly, if blood is transfused from one animal to another the liquid part of the injected blood is rapidly eliminated, but not the red corpuscles. Hence for a considerable time the blood is abnormally rich in corpuscles. If, however, the transfusion is several times repeated the excess of corpuscles disappears more and more rapidly. The capacity of both the blood-forming and the blood-de- stroying process is thus increased by use. Young red corpuscles are known to be formed in the bone-mar- row, while the products of destruction of red cor- puscles are found in the liver and excreted in the bile. The capacity for formation or destruction of corpus- cles is thus associated with the physiological activity of these parts of the body, but this activity is evidently regulated with great exactitude.