FOOTNOTES:
[62] Arch. de physiol. norm. et path., 4 e série, 2, 1888, p. 93; 5 e série, 1, 1889, p. 253.
[63] Arch. für exp. Path. u. Pharm., Bd. XXXVI, S. 293, 1895.
[64] Arch. für exp. Path. u. Pharm., Bd. XLII, S. 250, 1899.
[65] MacCallum, J. B.: University of California Publications, Physiology, Vol. I, 1904, p. 125.
[66] Leçons sur les propriétés physiologiques et les altérations pathologiques des liquides de l’organisme, II Tome, Paris, 1859. Deuxième Leçon.
[67] Archiv für die gesammte Physiologie, Bd. 61, 1895, p. 378.
[68] Loc. cit.
[69] Chemische Centralblatt, Leipzig, Bd. II, 1895, S. 310.
[70] Bock and Hoffmann: Arch. für Anat., Physiol. und wissenschaftl. Med. (Reichert und DuBois-Reymond), p. 550, 1871.
[71] Külz: C. Eckhard’s Beiträge, Bd. 6, S. 117, 1872. (Quoted by Pflüger, Arch. für die gesammte Physiologie, Bd. 96, 1903, S. 313.)
[72] M. H. Fischer: University of California Publications, Physiology, Vol. I, pp. 77 and 87, 1904.
[73] Loeb, J.: Festschrift für Fick, 1899; Pflüger’s Archiv, 1902, XCI, p. 248.
[74] MacCallum, J. B.: University of California Publications, Physiology, Vol. I, 1904, p. 125.
[75] Leçons sur les propriétés physiologiques des liquides de l’organisme, T. II, 1859, p. 74.
CHAPTER IX.
Mode of Action of the Saline Cathartics.
Since the discovery of sodium sulphate by Glauber in the middle of the seventeenth century, and the preparation of the double tartrate of sodium and potassium at Rochelle some fifteen years later, the saline cathartics have been in constant use among physicians. Attempts have been made also from the first to explain in some way their mode of action; but it was not until the discovery of the osmotic property of salts that any explanation which seemed satisfactory was made. Poiseuille[76] and Liebig[77] both advanced the theory that the purgative action of salts was due to their power of attracting water into the lumen of the intestine, i.e., to their power of endosmosis. This seemed at first sight to be very satisfactory and to account well for the increased amount of fluid in the faeces following the administration of a saline cathartic. The theory did not, however, take into consideration other substances whose osmotic power is as great as that of the purgative salts, but which have no purgative action whatever. It was later, however, supported by Rabuteau[78] in an experiment in which he claimed to have found that the intravenous injection of a large quantity of sodium sulphate produced constipation, while the same salt given by mouth causes purgation. This he ascribed to the flow of fluid towards the salt in each case due to its osmotic pressure. This experiment lacks confirmation, and indeed it has been shown above that sodium sulphate and other saline cathartics produce increased peristalsis and in some cases increase of fluid in the intestine when introduced intravenously or applied on the serous surfaces of the intestine. And these evidences of a purgative action appear much more rapidly and with smaller doses than when the salt is placed in the lumen of the intestine. Claude Bernard[79] states in his criticism of this theory that the intravenous injection of sodium sulphate causes purgation, and further draws attention to the fact that on this theory of the endosmotic action of cathartics, sugar, which has a high osmotic power, should be among the more powerful purgatives. It was further shown by other investigators that of several purgative salts, the most powerful was not the one with the highest osmotic power.
Headland,[80] believing that all medicines must first pass into the circulation before they act, claimed that the saline purgatives are absorbed from the intestine and are again excreted lower down in the intestine, and in being excreted they stimulate the glands to secrete.
A little later than this it was shown by Moreau[81] and others that solutions of purgative salts placed in loops of intestine which had been tied off caused an increased secretion of fluid into the intestine. Brieger[82] further confirmed this with better methods and showed that the fluid was a real secretion, and not an inflammatory exudate, or a transudation.
Thiry in a series of experiments was unable to produce increased secretion of fluid from a Thiry-Vella fistula by the introduction of sulphate of magnesia. He therefore concludes that the action of saline cathartics is due solely to an increase in peristaltic activity. Radziejewski[83] held a similar theory and made many experiments in an attempt to prove that an increase in peristaltic activity was the main result of the administration of a saline purgative. In connection with this it may be noted that van Braam-Houckgeest[84] concluded from his experiments that saline purgatives do not increase the peristaltic activity of the intestine. It is difficult to imagine how these results could be obtained.
Hay[85] quotes Aubert, Buchheim, and Wagner as holding the theory that in addition to causing an increased peristalsis, the salt is slowly absorbed, and tends to prevent the absorption of fluid from the intestine. This theory was held also by Schmiedeberg,[86] who claimed that the purgative salts were absorbed with difficulty and reached the lower parts of the intestine unchanged. In the large intestine the salts, according to this hypothesis, prevent the faeces from becoming compact by inhibiting the absorption of water from the lumen. This explanation of the action of cathartic salts has been widely accepted and has been supported by Wallace and Cushny,[87] who claim in addition that the salts of acids which form insoluble compounds with calcium are especially active in inhibiting the absorption of fluids from the intestine.
Loeb in studying the action of salts in the production of muscular twitchings in voluntary muscles, and of hypersensitiveness of the skin and nervous elements, recognized the fact that the salts which had these actions included those commonly known as saline purgatives. He says in this connection: “I will not deny the effect of these salts upon the phenomena of absorption of water from the intestine, but it is obvious from our experiments that the same salts must increase the irritability of the nerves and muscles of the intestine, and that this must facilitate the production of peristaltic motions, possibly through the mechanical or contact stimuli of the faeces upon the nerve endings or the muscular wall of the intestine.”[88]
My own experiments which I have described above support this suggestion of Loeb’s. In the first place it was found that the subcutaneous or intravenous injection of one of these salts, especially sodium citrate, caused muscular twitchings in the living rabbit. This had already been done by Loeb in the frog. In both cases the injection of calcium chloride inhibits the twitchings. As shown above, there are produced in a rabbit by such an injection of a purgative salt not only muscular twitchings, but also increased peristaltic movements, and an increased flow of fluid into the intestine. The subsequent injection of calcium chloride was shown to inhibit both the increased secretion and the increased movements of the intestine. There thus seems to be a very distinct analogy between the action of these salts in producing twitchings in voluntary muscles and the production of their purgative effect; and a similar analogy between the suppression of the former and the suppression of the latter by calcium chloride. One is tempted to suppose that these purgative salts act by removing calcium from the tissues, as suggested by Loeb, in the production of muscular twitchings, since they are all calcium precipitants. There is, however, no direct proof of this, and other saline purgatives such as BaCl2 and Hg2Cl2 certainly have an action which is independent of calcium.
There thus seems to be produced by saline purgatives a condition of increased irritability in the intestine analogous to the increased irritability produced in the voluntary muscles. As a result of this the two main activities of the intestine are increased, namely, the peristaltic activity and the secretory activity. The action of the saline purgative, then, as far as we know, consists of two main parts. The peristaltic movements are greatly increased in rapidity and force, and the faeces are carried rapidly from the upper to the lower parts of the intestine. They are thus passed through the large intestine in so short a time that the fluid they already contain has not time in which to be reabsorbed, a process which apparently takes place normally in the large intestine. At the same time there is a much larger quantity of fluid secreted into the lumen of the intestine than takes place in the normal animal. The faeces which are thus forced rapidly through the gut by the increased peristaltic movements are more fluid than normal. This together with the rapid passage of the faeces accounts for their fluid character when a saline purgative is given.
Whether or not the saline purgatives also inhibit the absorption of fluid from the intestine cannot be stated with certainty. The experiments of Wallace and Cushny leave out of account the increased secretion of fluid into the intestine caused by the purgative, a process which undoubtedly takes place. Thus in comparing the amount of NaCl, and the amount of a saline purgative absorbed in a given time from separate loops under the same conditions, it is not surprising that the amount of NaCl solution found in the loop after the experiment is less than the amount of purgative solution left. If the quantities of the two salts were equal in the beginning and an equal amount were absorbed, there would still be more fluid left in the loop containing the purgative on account of the secretion of fluid into the loop which was caused by the purgative, and not by the NaCl.
With regard to the mode in which the salt must be administered it is quite clear that it is not necessary to place it in the stomach or the lumen of the intestine. As shown above, the action is more rapid and more powerful when the solution is injected into the blood, or applied locally to the peritoneal surface of the intestine. Nor is the action due to its being secreted again into the lumen of the intestine, because the action is almost immediate when the solution is poured on the outside of the loops, and only takes place after several minutes when placed in the lumen. If injected into the blood the action is slower than when the solution is applied to the serous surfaces of the intestine. In the former case every opportunity would be afforded for its rapid excretion into the intestine if that were a factor. It is evident that the solution must be absorbed into the blood and bathe the tissues just as a solution surrounds a muscle which is immersed in it.
As to the tissues in the intestine which are primarily affected, it is impossible to make a definite statement. The muscle and glands cannot be at all separated from the complex nervous mechanism of the intestine, and it is necessary to take the whole as an organ made up of many tissues and affected in definite ways by certain solutions.
It is interesting in this connection to again note the effect of these salts on the secretion of urine. It is well known that practically all of them are diuretics, when introduced with a considerable amount of fluid. And even when the flow of urine has been greatly increased by the injection of m/6 NaCl solution, it can be still further augmented by the addition of, e.g., sodium citrate to the injection fluid. These salts constitute the well known class of saline diuretics. All salts do not, however, belong to this class, as is often stated. Calcium chloride, magnesium chloride, and to some extent strontium chloride exert exactly the opposite effect, inhibiting the action of the diuretics and diminishing the flow of urine. These salts might be termed antidiuretics. There is thus an entire analogy between the action of the saline diuretics on the kidney and that of the saline purgatives on the intestine, and also the action of calcium and magnesium is the same in both cases. And the analogy can be traced farther back to the production and inhibition of muscular twitchings in voluntary muscles, which was demonstrated by Loeb.
The actual mechanism of the secretion of fluid into the intestine is difficult to determine. It seems improbable that a change in blood pressure plays any very important rôle, if indeed it has an influence at all. There is much evidence to show that many glands consisting of cells resembling those of the intestine roughly, secrete their characteristic fluids quite independently of blood pressure. In Sida crystallina, a small fresh-water crustacean, it was found[89] that if a small quantity of one of the saline purgatives or of BaCl2 or pilocarpine be added to the water in which these crustaceans are lying, there is not only a rapid increase of intestinal movement and a rapid evacuation of faeces, but there is also an increased secretion of fluid into the intestine, so that the whole lumen becomes filled with a pale greenish fluid. It was pointed out further that in this organism there is no closed blood vascular system, the blood simply running in wide channels in more or less definite directions. There can therefore exist nothing here comparable with the blood pressure of higher animals, and yet secretion normally takes place without changes in blood pressure. Further, it can be greatly increased by chemicals without an increase in blood pressure being possible. A similar secretion without blood pressure as a causative factor is seen in the skin of the common slug (Ariolimax). Here the secretion of the skin may be markedly increased by the injection or local application of a solution of any of the saline purgatives. This takes place equally well when the heart of the animal is removed, and also in an isolated portion of the animal, or in a piece of the skin cut off with the scissors. In these latter cases there can be no possibility of blood pressure taking a part in the secretion.
It has been further shown[90] that loops of intestine entirely removed from the body may be caused to secrete a measurable quantity of fluid by immersing them in certain purgative solutions, especially those containing BaCl2. Other solutions such as pure m/6 NaCl do not cause this secretion, although active peristaltic movements go on in NaCl. In this case the secretion must be entirely independent of the blood pressure. Pilocarpine also in the salivary gland causes an enormous increase in the secretion, without raising the blood pressure in the carotid.
It is certain from these facts that in many glands secretion is quite independent of any change in blood pressure; and it seems probable that such changes must play a very subordinate part in the secretion of fluid from the intestine.
On the other hand, it is to be noted that in many instances muscular and secretory activities are controlled by the same conditions. There seems to be a common factor in the production of the two functions. Saline purgatives produce not only muscular activity, but also increased secretion; and calcium and magnesium are capable of inhibiting both. Atropin also quiets the movements of the intestine, and at the same time is conspicuous in suppressing the secretion. Section of the splanchnic nerves causes not only increased muscular movements, but an increased secretion of fluid in the intestine. These instances could be greatly increased in number. From them it seems that something exists in common in muscular movements and in glandular activity. What first suggests itself is that the gland cells themselves are made to contract rhythmically by the various conditions which cause rhythmical contractions in muscle. That the stimulus for this must be greater in the case of secretion is shown by the fact that in the intestine peristaltic movements may be maintained in a solution (m/6 NaCl) in which no secretion takes place. It seems not at all improbable that one factor in the production of secretory activity is dependent on a property of the gland cell closely related to muscular contractility.
A further factor is suggested by the action of certain diuretics. In the kidney the changes in the quantity of blood flowing through the organ and to some extent changes in blood pressure influence the flow of urine. The diuresis produced by such substances, however, as saponin, digitalin, potassium chlorate, etc., probably depends on an increase in permeability of the capsule of Bowman. As shown[91] recently, these substances produce haemolysis, and are also strong diuretics. Calcium chloride, which inhibits the flow of urine produced by them, inhibits also the haemolysis. Haemoglobinuria, which readily appears with small doses of saponin or digitalin, is inhibited by simultaneously injecting calcium chloride. There thus seems to be something in common between haemolysis and diuresis; and what suggests itself as most probable is that the permeability of the red blood corpuscle, as well as that of the kidney cell is increased, so that on the one hand haemoglobin escapes into the blood (is secreted into the blood), and the amount of urine on the other hand passing through the kidney cell is increased. Calcium, according to the same idea, would decrease the permeability in both cases.
In secretion we have therefore among other things two factors which probably play a rôle, namely, a property of the gland cell resembling that of muscular contractility and controlled in many cases by the same conditions, and a change in permeability of the cells which are secreting. In the kidney there is a third factor dependent on the flow of blood through the organ. A continuous supply of blood is of course necessary in all glands for a continued secretion.