Principles of General Physiology

The opposite effect of chloroform is well shown in Mathison's curve (Fig. 128, page 428, and in Fig. 129). The question of the nature of the automatic tone in the vasomotor centres has been touched upon above (page 546). It is well known that a considerable rise of arterial pressure occurs in asphyxia, and we have referred to Mathison's results on the action of asphyxial products in an earlier page (page 632). The experiments of Sollmann and Pitcher (1911) may be added. They find that the asphyxial stimulation of the bulbar vasomotor centre is due to carbon dioxide, and is absent if accumulation of this acid is prevented, although oxygen is absent. We may regard it as possible that the normal stimulation of the centre is brought about by the carbon dioxide tension of the blood, like that of the respiratory centre.

Chemical Regulation of the Blood Flow. — The appropriate sensibility of the blood vessels to the products of the activity of cells, by which an automatic vasodilatation is caused, has been referred to in speaking of the coronary circulation (page 680). The importance of the action of metabolites in this respect was first clearly realised by Gaskell (1880, pp. 66-70). As acid products, and especially carbon dioxide, are the usual results of cell metabolism, it is natural to look for direct evidence of the effect of increase of hydrogen ion concentration. Gaskell showed that lactic acid produces decrease of tone, and I showed later (1901, 1) that carbon dioxide has the same effect. The work of Hooker (1911-1912) confirmed these results, and was extended to the action of other substances. It should also be mentioned that Severini (1876-1881) had already described dilatation of capillaries by carbon dioxide and constriction by oxygen. The fixed acid products come chiefly into play in deficiency of oxygen supply, as in asphyxia, or when oxygen is consumed at a rapid rate in great activity of the cells. Hooker showed that oxygen and also calcium ions increase vascular tone, and that carbon dioxide, 'urea, sodium, and potassium ions decrease it. Schwarz and Lemberger (1911) found that the injection of 1 cub. cm. of O'OOl molar hydrochloric acid into the central end of the left subclavian artery caused obvious dilatation of the vessels of the submaxillary gland, although, of course, only a part of the acid reached the gland. Comparing the action of different acids, their action was not found to correspond to the H ion concentration.

But, as the authors point out, and as we have seen above (page 200), the effect is really produced by carbon dioxide driven off from the bicarbonates of the blood, which would naturally be proportional to the total molar amount of the acid introduced. Acids weaker than carbon dioxide, such as glycine and alanine, were inactive. This local effect, it will be noticed, is opposite to that on the centres, on which, as we have seen above, carbon dioxide has an exciting influence, and Mathison showed (1911) that the direct action of potassium salts on the centres is also excitatory.

There is often present, in extracts of tissues, especially when prepared by boiling, some substance or substances which have a powerful dilator effect on blood vessels. This is the case with acid extracts of the mucous membrane of the small intestine. Now Barger and Dale (1911) have shown that such boiled acid extracts contain the salt of a base, which is also obtained by the splitting off of carbon dioxide from histidine, and is /3-iminazolyl-ethylamine. This compound is present in the cells when scraped off, since it can be extracted by alcohol (Bayliss and Starling, 1902, 1, p. 335), but whether it is actually present in the living

cells, or is given off in their normal metabolism, is not known. It is interesting to note that the vaso-dilatation, seen in the cat and dog, is replaced by v;is<> constriction in the rabbit and guinea-pig, so that it would be rash to assert that this substance plays the part of a general metabolite to bring about vascular dilatation in active organs. In contradistinction to the usual dilator action of the products of tissue metabolism, the secretion of the suprarenal bodies contains an extremely potent substance, adrenalin*, which causes vaso-constriction in all cases where there is a supply of sympathetic vaso-constrictor nerves. This " hormone " will come up for further discussion in the next chapter. Reference is made to it here since, in many cases in which reflex rise of blood pressure occurs, there is a turning out of adrenaline into the blood vessels, which assists in the rise of pressure. The secretory nerves to the suprarenals are excited simultaneously (see especially the work of Anrcp, 1912, 1).

It might occur to the reader that, perhaps, this production of adrenaline is the cause of all rise of blood pressure in pressor reflexes : if so, the existence of a vasoconstrictor centre would be superfluous. Hoskins and Wheelon (1914), however, find that four to six hours after tying off' both suprarenal bodies, although there is weakness of the skeletal muscle and the heart, the blood pressure is not lowered, and pressor reflexes from a sensory nerve are still to be obtained. Thus, excitation of vasoconstrictors occurs in the absence of stimulation of secretion of adrenaline.

Similarly, the vaso-dilator nerves have been supposed by some, Barcroft (1914, p. 148), for example, to be of comparatively small importance, even if their existence is not doubtful. The products of metabolism are supposed sufficient to account for the functional dilatation. But when vaso-dilators are excited through the depressor nerve in order to relieve the heart by fall of blood pressure, it would seem a remarkable way of bringing it about if it were necessary to set a multitude of organs into activity. It must be admitted, however, that the vasodilators do not appear to play a great part in the reflex fall of blood pressure, since inhibition of constrictor tone is usually sufliciently effective. The decision of the question obviously rests on the proof that vaso dilatation can occur on stimulation of a nerve apart from increase of metabolism. The effect of the chorda tympani on the atropinised submaxillary gland, in which vaso-dilatation is obtained without visible secretion, has been brought forward in evidence, but Barcroft (1914, p. 147) rightly points out that there may be stages of cell activity, preliminary to extrusion of secretion, which are not paralysed by atropine. In fact, he obtains increase of oxygen consumption. The data given seem to me to show that, although metabolites are a partial cause, there is a nervous effect in addition, since the degree of dilatation is not in proportion to the increase of oxygen consumption. Thus a 109 per cent, increase in oxygen consumption coincides with a 488 per cent, increase in blood flow, while a 50 per cent, increase coincides with an increase in blood flow of 812 per cent., that is, a larger dilatation with a smaller consumption of oxygen.

Some recent experiments by Anrep and Evans (unpublished) show that it is possible to obtain vaso-dilatation in the tongue, on stimulation of the peripheral end of the lingual nerve, without any increase in oxygen consumption. In some cases an increase was found, but this was probably due to secretory activity of the glands in the tongue. Anrep's experiments, referred to on page 349 above, show that when the secretin used to stimulate the pancreas is free from the depressor substance, there is little or no sign of vaso-dilatation in the gland, associated with secretion. The products of metabolism of active glands have not, therefore, universally a vaso-dilator action.

It was mentioned above (page 345) that the cervical sympathetic in the cat gives abundant secretion of saliva. Disregard of the fact that metabolites cause dilatation led some observers to state that the cervical sympathetic contains vaso-dilators. Now the drug, ergotoxine, obtained by Dale (1906) from ergot, paralyses sympathetic constrictors and secretory fibres, but does not affect vasodilators. After ergotoxine, Stimulation of the cervical sympathetic fails to

produce dilatation in the gland vessels. The conclusion seems justified that the failure is on account of the absence of secretion. Some observers appear to have obtained, normally, vaso-dilatation from the cervical sympathetic, not preceded by constriction. This has not been my experience. I find constriction at first, followed by dilatation, as the secretion becomes more copious. Reaction to Changes of Pressure. — I had observed (1902, 2), that if the general blood pressure is suddenly raised while a plethysmographic tracing is being taken of an organ, that the first passive expansion of the organ is followed by a considerable contraction. Since it was known that smooth muscle in various situations responds to stretching by contraction, I interpreted the effect as being due to a similar reaction on the part of the muscular wall of the arterioles. The fact that stimulation of the splanchnic nerves, or asphyxia, excites the flow of adrenaline into the blood current was not known at the time, and Anrep (1912, 2) has shown that the methods used by me to cause a rise of blood pressure were such as to cause this flow, and that the results are sufficiently accounted for by it. Of course, the reaction to stretching may also take place, but my experiments did not prove it. Anrep was unable to confirm the result which I had obtained by raising the pressure inside an excised piece of artery, but my recollection of this experiment is so clear that I am unable to believe that the particular piece of artery used then did not really contract. If I understand Anrep's description of his method correctly, it does not seem possible for the artery to contract when it was distended by pushing in the piston of a syringe. In the same paper I also described the opposite reaction of blood vessels to fall of pressure, in which it appeared that dilatation took place in response to diminution of tension. The effect of adrenaline is excluded here, and Anrep explains the result as due to asphyxial metabolic products. I do not feel quite satisfied with this explanation, but I was unfortunately unable to see Anrep's experiments. No doubt the prolonged stoppage of circulation in his experiments was sufficient to afford such metabolites, but if Fig.

250 be consulted, it will be seen that a compression of the abdominal aorta for eight seconds produces a subsequent dilatation of nearly as great a degree as one of twenty seconds, and it is difficult to believe that deprivation of blood flow for Upper curve, volume of hind leg of dog, constrictors and dilators cut. Lower curve, pressure in femoral artery. Zero at level of upper signal. The abdominal aorta was compressed twice, the first time only being marked by the signal. The blood pressure curve shows the actual duration of the fall of pressure in the limb vessels in both cases.

The first fall in volume, due to deprivation of blood, is followed by a large dilatation. The magnitude of this dilatation does not seem to have any relation to the duration of the anaemia, and it is difficult to understand how an anaemia of only eight seconds' duration in a curarised animal under artificial respiration could produce sufficient asphyxial metabolites to cause so large an effect. The dilatation is followed by a constriction, which may possibly be a contractile response to the sudden inrush of blood into the dilated vessels.

eight seconds should cause an appreciable accumulation of metabolites in a resting, curarised leg. It is to be remembered that the blood was fully oxygenated. It is desirable that compressions of still shorter duration should be tested. If, however, we accept a reaction of the muscle cells of the arterial wall tofall of pressure, it is necessary to suppose that they must previously have been in a state of contractile response to the normal high pressure. Further, if the electrical change described by Carl Tigerstedt (page 687 above) be accepted as due to arterial contraction, it shows that the larger arteries respond to the heart beat by a contraction, although small.

Kesson (1913) was unable to find any reaction in isolated arteries. Regulation of Supply to Organs. — Summing up the facts of the previous pages, we may say that the blood flow through an organ in activity is increased in the following ways : — 1. By rise of general arterial pressure, produced by constriction in other 2. By vascular dilatation in the organ itself. These two effects are The natural tonus in arterioles is maintained in three, or perhaps four, ways : —

1. The natural property of smooth muscle to be in a state of partial 2. The continuous vaso-constrictor impulses sent out by the tonic excita- 3. The contraction set up by adrenaline in those arterioles supplied with sympathetic nerves when this substance is present in the blood. (4. The contraction by which they respond to the normal stretching force of the blood pressure, possibly.) The fact that the blood, when it leaves the blood vessels and comes into contact with the tissues or external objects, sets into a kind of jelly is familiar to all.

The value of this process to the organism appears to be to lessen loss of blood when blood vessels are injured. It is impossible to give an account here of the great mass of work that has been done on the process. In point of fact, it cannot be said that it is yet understood. Much of the research done has led to little more than the multiplication of names given to supposed substances held to take part in it, but these have not been isolated as chemical individuals, and the names really refer to aspects of phenomena (see the remarks on pages 107 and 328 above).

As an illustration, I would refer to the paper by Collingwood and MacMahon (1912), where we find the following names used as applying to definite substances : fibrinogen, prothrombin, prothrombokinase, anti-thrombokinase, thrombokinase, anti-thrombin, and antiprothrombin. These are supposed to be present before clotting. After clotting we have : fibrin, thrombin, thrombokinase, anti-thrombin ?, anti-prothrombin, anti-thrombokinase, and prothrombin.

On the whole it appears that the point of view originally taken by Wooldridge (1887-1893) and developed by Nolf (1906-1908) has the most evidence in its favour. According to this theory, the phenomenon is essentially an interaction of colloids under the influence of electrolytes, especially calcium salts. There is reason to suppose that the so-called " fibrin-ferment " is not an enzyme, although some enzymes of a proteoclastic nature may be concerned in the later liquefaction of the clot.

In invertebrates there are two kinds of processes, one associated with breaking up of amoeboid corpuscles, the other with a coagulation effect in the plasma. The papers by Hardy (1892) and by Tait (1910) may be consulted. The existence of something which prevents or retards the process of coagulation has been referred to in speaking of the extract of the heads of leeches (page 360). A similar " anti-thrombin " can be obtained from the liver, as shown especially by Doyon (1912).

On account of the difficulty and expense of procuring hirudin, it would seem worth while to attempt to prepare an anti-thrombin from the liver by Doyon's method. It would require removal of the toxic impurities present in the crude mixtures hitherto obtained. The substances in question seem to make the colloidal system more stable, so that the coagulation process induced by rough surfaces is prevented. Zak (1912) shows that the " lipoids " of the plasma play a considerable part in the phenomena of coagulation, a fact which points to the intervention of surface action. This investigator shows that the hypothesis of a " thrombokinase " is superfluous.

The object of the circulation of a fluid through the larger organisms is to supply food, especially oxygen, to the tissues, and to bring about effective interchange of chemical products. The function of the heart as a pump to drive blood into the arteries was shown by Leonardo da Vinci, but the actual fact of the movement of the blood in a circle back to the heart was first demonstrated by Harvey. The passage of the blood through the peripheral capillaries from arteries to veins was first seen by Leeuwenhoek.

A high arterial pressure is necessary, and was shown to exist by Stephen Hales. This is in order to ensure a sufficiently rapid flow through the fine branching tubes of the various organs. In the higher vertebrates there are two pumps in series, having the lungs between them ; one is to drive the aerated blood from the lungs to the organs in general ; the other to drive the venous blood, returning from these organs, through the lungs, in order that it may take up oxygen and lose carbon dioxide. The two pumps are combined in one organ, the heart, but their cavities are separate.

The greater part of the work done by the heart muscle is expended in raising the pressure of the blood driven out, and may be measured by the product of the volume and pressure.. Determination of the time course of the pressure curve in the ventricle shows that no blood is expelled until the maximum tension is developed. The muscle, therefore, works at its best efficiency. During the expulsion of blood into the aorta, the pressure in the ventricle remains nearly constant, the curve showing a flattened top.

The inflow from the veins is, practically, the determining factor in the work done by the heart. The human heart, indeed, can deal with as much as 21 litres per minute. Thus it is the length of the fibres that determines the energy given out. The oxygen consumed by the heart is in direct proportion to the energy of the tension developed, and is the same at 15° as at 36°. The actual amount of oxygen used depends on whether the "reserve-stuff" of the heart itself is oxidised, or the glucose of the solution perfused ; but the relation between the energy produced by oxidation and that of the tension developed is constant. The effect of excess of carbon dioxide is to prevent the conversion of chemical to mechanical energy ; similarly, the presence of calcium is necessary for the due conversion of this chemical energy into that of tension.

The muscular tissue of the vertebrate heart initiates -the heat, and is also responsible for the transmission of excitation from one part of the heart to another. In the mammal, a localised bundle, that of His, conveys the excitation from auricles to ventricles. The rate of the automatic rhythm is greatest in the sinus tissue, so that this acts as the pace-maker. In the mammal, a remnant of sinus tissue, the " Keith-Flack " or " sino-auricular " node, is the initiator of the beats, and is in direct connection with the nerves controlling the rate of the heart beat.

The heart requires an abundant supply of oxygen, which is provided by the copious flow of blood through the coronary circulation. The arterioles of this system are very sensitive to the dilating action of products of the muscular metabolism. The inhibitory action of the vagus nerves may show itself in different ways, on rate, strength, conducting power, or excitability of the muscle. These effects appear to depend chiefly on the particular function of the tissue in which the fibres end. The duration of the state of excitation is lessened by vagus stimulation, a fact which explains the abolition of the T-wave of the electro-cardiogram by the vagus, since its action is naturally more pronounced at the base.

There are also excitatory nerves, the accelerators, supplied to the heart muscle ; their action is directly opposed to that of the vagus nerves. The importance of the elastic nature of the walls of the arteries is pointed out. It accommodates, temporarily, the blood driven out by the rhythmic beats of the heart, converting the flow through the capillaries into a continuous one. Incidentally, it gives rise to the pulse wave. This wave is due to the elastic recoil of the arterial wall, and must not be confused with the actual mass movement of the current of blood.

The resistance to flow in the blood vessels is due to the internal friction of the blood, so that changes in the viscosity of the blood change the resistance. The total volume of blood in an animal is a function of the outer surface of the animal. A brief description is given of the methods used for the investigation of changes in the heart and circulation. The arterioles are supplied with two kinds of vasomotor nerves, vasoconstrictor or excitatory, and vaso-dilator or inhibitory, in respect of the normal tonus of the arterial muscular wall.

The constrictor fibres are all of sympathetic origin. That of the dilators is more varied. In some organs it is peculiar, the vaso-dilator impulses being conveyed by the ordinary sensory fibres in an " antidromic " direction. These fibres to blood vessels are, apparently, lateral branches of the sensory fibres, and can thus give rise to axone reflexes, as in inflammation. While stimulation of sensory nerves in general causes rise of blood pressure by reflex arterial constriction, there is one set of nerve fibres, arising from the aorta and the heart, which always produces reflex fall of blood pressure. These are known as the fibres of the depressor nerve.

In reflex rise of blood pressure, excitation of the vaso-constrictor centre is combined with inhibition of the tone of the vaso-dilator centre. In -reflex fall, excitation of the vaso-dilator centre is combined with inhibition of tone in the vaso-constrictor centre. Reciprocal innervation holds, therefore, as in the case of skeletal muscle. Stimulation of the central end of the afferent nerve from an organ causes reflex dilatation in the organ itself, with constriction elsewhere, thus ensuring the maximal supply of blood to the organ.