The Relationship of the Ion Content of the Cell to Symptoms of Disease With Special Reference to Calcium and Its Therapeutic Application

Cell Life

If only Virchow and his followers in anatomic pathology could have had physiologic pathologists working side by side with them, we should have a much saner conception of diseases than we today possess. Our interest is no greater in the pathologic anatomic than it is in the pathologic physiologic cellular changes, but knowledge of their anatomic characteristics was developed first; and so it is difficult to secure adequate interest in their physiologic aspects. Even though nearly every symptom of disease represents an alteration in function of cells and many symptoms are not even accompanied by detectable disturbance in anatomic relationship, still the anatomic concept holds first place in interest among medical men. 

Much of the failure on the part of clinicians to appreciate the importance of the study of physiology, normal and pathologic, is due to an inability to visualize what is occurring in the body when a disease process is established. To understand disease we must understand how the cells react both normally and in its presence. We now know that this reaction varies with the ionic content of the cell. Cellular action, stated in a crude and simple way, means a continuous struggle to maintain a physical and chemical equilibrium between the body cells (which are composed of colloids holding crystalloids in physical or chemical union) on the one hand and the substances which are brought in contact with them on the other hand. The changes which are continually produced as a result of this struggle follow the laws of physical and chemical forces. 

From this it may be seen that the processes during the course of a disease may be very different from those during health because there are alterations in the cells themselves and also in the substances which react with them. The reactions which occur take place between the colloids of the cells on the one hand and the oxygen brought in during respiration; the normal and pathologic substances formed during metabolism; the crystalloids which are formed from the colloidal foodstuffs which are eaten; and the inorganic salts on the other hand.

The colloids possess the power of combining with some of these substances under every condition of alkalinity and acidity which is compatible with life, acting as acid salts when the pH of the solution is below the isoelectric point and as bases when above (Loeb¹). 

Action of the cell may be carried on independently of the correlating and integrating forces of these two great systems of body regulators, the nerves and the incretions; but full and purposeful activity requires a coordination of all regulatory forces. 

What a nerve action or what an action resulting from an incretion will be depends on the physical and chemical state of the cell upon which these act, and this is different in states of disease from what it is in conditions of health. For reaction to take place between electrolytes found in the bloodstream and the colloids of the body cells, they must first pass through the cell membrane and this depends on the relative osmotic pressure of the substances on the two sides of the membrane. When it has once entered the cell it then diffuses into the cell colloids and unites physically and chemically with them, following, in the latter case, the laws of valency and electric charge. This chemical union occurs by displacing other ions which are already combined. 

It can thus be seen that pathologic substances, or normal substances in pathologic quantities may alter the physical and chemical makeup of the cell and thus change its reaction capacity. 

As mentioned elsewhere in this paper, nerve reaction consists in changing the ionic content of the cell; therefore, when, through disease or a failure of nature to meet the requirements of normal cell life, the cell departs from the normal in its chemical and physical makeup there will take place as a result of nerve stimulation an abnormal reaction. If the departure from normal is sufficiently great to make a recognizable disturbance in physiologic equilibrium, it is recognized as a symptom of disease. 

With this physio-chemical conception of physiologic reaction we are in a position to realize the great importance of the inorganic salts which are introduced into the body along with food, and, to recognize that their metabolism is as important as that of protein, carbohydrates and fats. Recognizing that all foodstuffs must be changed from their colloidal into a crystalloidal form before they can pass the cell membrane and that their absorption and utilization depends upon the readiness with which they can be taken up by the proper chemical substance in the cell, again it will be seen how nutrition is harmed by conditions which alter this cell reactivity. 

The ionic cell content, therefore, becomes exceedingly important not only in its relationship to the reaction of the individual cell, but in its relationship to the remaining parts of the body through nerve and hormone correlation and integration. Just what the forces are which preserve the normal ionic balance in the body cells is but imperfectly understood at this time. The controlling factors are probably quite complex. Hormones, vitamines and general nutritional factors are all probably concerned. 

Common Ions Found in Tissues 

The inorganic salts contained in the cells of different tissues vary both as to variety and quantity. The fixed tissue cells also contain different salts from those found in the blood, and contain different quantities of those which are held in common. The same is true of the different constituents of the blood, as will be seen from the following analysis, adapted from Starling.²

Analysis Of Human Blood 

Contents of liter of human blood 

Corpuscles………………. 513.02 grams

Plasma………………… 486.98 grams

Corpuscles content per liter

Water…………………… 349.69 grams

Substances not vaporized at 120° 163.33 grams

Haematin………………… 7.70 grams

Blood casein……………… 151.89 grams

Inorganic salts……………. 3.74 grams

Inorganic salts per liter and in toto 

Chlorine…………. 0.898 per liter grams 2.592 In toto grams

Sulphuric acid……. 0.031 per liter grams 0.124 In toto grams

Phosphoric acid…… 0.695 per liter grams 2.780 In toto grams

Potassium……….. 1.586 per liter grams 6.344 In toto grams

Sodium…………. 0.241 per liter grams 0.964 In toto grams

Phosphate of calcium. 0.048 per liter grams 0.192 In toto grams

Phosphate of magnesia 0.031 per liter grams 0.124 In toto grams

Oxygen…………. 0.206 per liter grams 0.824 In toto grams

Plasma content per liter

Water…………………… 439.02 grams

Substances not vaporized at 120° 47.96 grams

Fibrin…………………… 3.93 grams

Albumin…………………. 39.98 grams

Inorganic substances……… 4.14 grams

Inorganic substances per liter and intoto 

Chlorine…………. 1.722 per liter grams 6.888 In toto grams

Sulphuric acid……. 0.063 per liter grams 0.252 In toto grams

Phosphoric acid…… 0.071 per liter grams 0.284 In toto grams

Potassium………… 0.153 per liter grams 0.612 In toto grams

Sodium…………. 1.661 per liter grams 6.644 In toto grams

Phosphate of calcium. 0.145 per liter grams 0.580 In toto grams

Phosphate of magnesia 0.106 per liter grams 0.424 In toto grams

Oxygen…………. 0.221 per liter grams 0.884 In toto grams

The constancy in relative proportions of the inorganic salts found in the blood in states of health, suggest that they are a vital part of the body structure. Their part in cellular activity is just beginning to dawn upon physiologists and clinicians. It is a fundamental fact that the function of cells is altered when the proportion of certain organic salts contained in them varies. 

Of the salts found in the blood, mentioned above, calcium, potassium, magnesium and soda have come in for considerable study. It is of special interest that certain of these salts are antagonistic to certain others. Calcium, for example, is antagonistic to potassium and sodium in certain viscera, such as the heart, intestinal tract and respiratory system. In the intestinal tract it is also antagonistic to magnesium. 

This antagonism assumes the same characteristics as the antagonism between the sympathetic and parasympathetic components of the vegetative nervous system in these structures, a fact of importance from a clinical standpoint. 

There is much evidence to show, as I have cited elsewhere,³ that not only does this relative proportion of organic salts in the cells determine to a certain degree their independent action, but it also determines how they will respond to nerve stimulation. Calcium is probably an element in the cell essential to response to sympathetic stimulation; and we are led to believe by the experiments of Ringer,^4,5,6 Howell,⁷ Howell and Duke,⁸ Zondek,⁹ and others, that potassium, at least as far as the heart is concerned, is necessary to parasympathetic stimulation. It is probably not sufficient for the calcium, potassium and other ions to be found in the circulating fluids of the body. They must be incorporated in the cell. We are warranted in assuming this from the experiment of Howell and Duke⁸ which showed that after the cardiac branches of the vagus were stimulated an increase in the amount of potassium in the perfusate was found, indicating that the vagus stimulation dislodged it, so to speak, from the heart cells. 

In order to make this conception of greatest value to medicine it is necessary to find out the many factors which control absorption and retention of calcium and other ions. 

What Controls Ion Content of Cells 

While cellular activity varies in different tissues and organs it is probable that in conditions of health, activity in the cells of a given organ always means, within narrow limits, the same physical and chemical process. This I assume means that the contents of the cell are always practically the same and that the stimulating physiologic factors are always practically the same. Interpreted, this means further, that there is a normal cellular metabolism which is maintained by physiologic forces and preserved in stable equilibrium. 

Could we know all the forces which tend to maintain this equilibrium in health and the agencies through which it is disturbed in disease we would have a key to the unlocking of many pathologic secrets. 

The two forces which control metabolism are the nervous system and the glands of internal secretion. Metabolism here must be taken in its broadest sense to include inorganic salts as well as organic substances. All anabolic and catabolic processes in the body are subject to these nervous and chemical controls. They are dependent upon them for their normal occurrence and they are subject to alteration as a result of abnormal stimuli arising in both. 

Of the inorganic salts which influence cellular activity, calcium seems with our present knowledge to be one of the most important. A study of calcium metabolism offers a rich field for investigation. It seems evident from the studies so far made that it is intimately bound up with the sympathetic nervous system. While this is not as apparent as is the case with adrenin which is secreted by the sympathetically derived chromaffin tissue of the adrenals; yet the presence of calcium in the perfusate in the heart experiments, and in intestinal strips and in other tissues when used clinically, stimulates activity in tissues which is similar to that produced by stimulating the sympathetic nerves going to those tissues. 

It is very suggestive that certain glands of internal secretion should be intimately connected with calcium metabolism. It seems particularly evident that the thyroid, pituitary and the parathyroids have to do with the retention of calcium in the body, while the gonads have an opposite effect. If the presence of calcium ions in the cells is essential to the action of the sympathetic nerves, is it not probable, if we wish to theorize, that calcium is a link between certain incretions and the sympathetic component of the vegetative nervous system and that as such it becomes an important link not only in the activity of the cell but in correlating and integrating action in various vegetative organs and in the body as a whole? 

Clinical Use of Calcium 

Calcium has long been used empirically in the treatment of many different diseases. For the most part it has been administered by the mouth, although under certain conditions it has also been employed intravenously. It is an important constituent of our food. With its intimate relationship to the sympathetic component of the vegetative system we are now able to place its employment upon a more or less scientific basis. 

From theoretical knowledge we know that it should increase that action which is brought about by stimulation of the sympathetic nerves. From clinical experience we find this true in many instances. For example, its action upon the heart is largely that which would be produced by stimulating the sympathetic nerves going to the heart. It strengthens the systole. In the respiratory tract it relaxes the musculature and reduces the secretion of the mucous glands, thus opposing the action of the vagus nerve, which produces the opposite effect. In the eye, calcium produces dilatation of the pupil. In diseases of the skin, accompanied by dryness and itching, calcium will relieve the symptoms. Thus it will be seen that calcium is indicated in a large group of diseases such as anaphylaxis, serum disease, hay fever, asthma, bronchitis, urticaria, angioneuroticedema diarrhea, intestinal colic, eczema, and other diseases of the skin accompanied by itching. It has been particularly valuable in tuberculous enteritis.

I have recently tested the synergism between calcium and sympathetic nerve stimulation in a variety of vagotonic syndromes. Such syndromes on the part of organs which have both sympathetic and parasympathetic innervation should be relieved could we directly depress the reacting mechanism of the parasympathetics sufficiently, or increase the reacting mechanism of the sympathetics to such a degree that it would equal or overbalance the action of the parasympathetics. This we have found to be the case in a sufficiently large number of conditions to give us hope for an improvement in therapy in many visceral syndromes. 

As one becomes familiar with vegetative neurology and accustomed to think of disturbed function in terms of sympathetic and parasympathetic action, he will see a gradual simplification of the symptomatology of disease. Instead of there being a large group of disconnected and incoordinated symptoms attached to each visceral disease there will be a logical grouping into those denoting either action or inhibition of action in one or the other component of the vegetative system. 

This classification being a physiologic one offers a basis for a more rational therapy, especially since certain drugs and physiologic remedies may also be classified according to whether their action is upon one or the other division of the vegetative system. Adrenin and calcium are among the substances which produce action in tissues similar to that caused by stimulation of the sympathetics; ergotoxine has the property of stimulating in small doses and paralyzing in large doses the activating sympathetic fibers without influencing the inhibiting fibers; and the phosphates in certain structures also fortify the action of calcium which seems to be necessary to sympathetic nerve action. On the other hand, pilocarpine produces stimulation and atropine inhibition of the parasympathetics; while potassium, magnesium and sodium all produce parasympathetic action in visceral structures. 

Based upon these facts we find a rational method of relieving many disturbing symptoms and syndromes met in disease, a few of which will be enumerated. Others will readily occur to the observing clinician. 

1. Anaphylaxis. Anaphylaxis is a condition which resolves itself into a more simple group of phenomena when analyzed from the standpoint of the neurocellular mechanism than when approached in any other manner. The phenomena appear primarily and predominantly as parasympathetic hyperirritability whether they affect the respiratory, the gastrointestinal or other systems of the body. The symptoms may be reduced in severity or even be prevented by inhibiting the action of the vagus through the previous administration of atropin; and, they may be ameliorated or relieved, when present, by adrenin and calcium. 
2. Serum disease. Serum reaction is a hypersensitive phenomenon and as such is a parasympathetic syndrome. It can be partially or wholly prevented by administering atropin prior to the injection of the serum and when established may be partially or wholly relieved by the same remedy, adrenin or calcium. I have seen symptoms disappear quickly following the hypodermic use of adrenin and the intravenous administration of calcium chloride. 
3. Urticaria. Urticaria is another hypersensitive phenomenon of parasympathetic nature and may be relieved by adrenin and calcium. 
4. Asthma. One of the most interesting and instructive subjects for investigation bearing out the facts cited in this chapter is asthma. From the standpoint of visceral neurology, the essential conditions in asthma are bronchial spasm and increased bronchial secretion, both of which are due to over-action of the bronchial branches of the vagus nerve. Action of the sympathetics is for the time being overcome and the normal equilibrium between them and the vagus is destroyed and hyperactivity of the vagus established. To be sure, there are other symptoms present such as rapid heart, heartstrain, dyspnoea, cyanosis and emphysema, but these are secondary and dependent upon the heightened vagus action.

There is much evidence, as I have discussed elsewhere,^10,3/span> that asthma is not primarily a condition of anaphylaxis to pollens, foods and other proteins, nor a primary vagus reflex from a stimulus arising in some other organ, nor a condition produced primarily by changes in weather or climate or dust or other inhaled irritants, but a condition incited by these various factors in a susceptible individual whose bronchial neurocellular mechanism is out of equilibrium and in whom vagus action predominates. The same seems to be true of many other parasympathetic, and the reverse of many sympathetic syndromes. 

In the treatment of asthma, aside from sedatives which relieve the irritability of nerves in general, we find that relief may come from any one of three methods of attack: (1) by direct inhibitory action on the vagus by atropin, or by stimulating the sympathetics so that they are able to overcome the hyperactivity of the vagus, as I have seen occur during the toxic period of acute infections such as tonsillitis, influenza, pneumonia and typhoid fever; (2) by increasing the relative calcium as compared with potassium content of the bronchial cells; and (3) by employing incretions, adrenin which produces the same action on the bronchial musculature as is produced by stimulating the sympathetics, and such other products as parathyroid, thyroid and pituitary, which are intimately connected with calcium metabolism. 

Asthma thus well illustrates and emphasizes the interdependence of the visceral nerves, the endocrine secretions and the ionic content of the body cells, and shows how necessary it is to take into consideration all parts of the neurocellular mechanism and all substances which may influence it if we would understand disturbances in function. 

5. Hay fever. Hay fever is a condition of hypersensitiveness closely related to asthma. Its relation to the parasympathetic neuromuscular mechanism is emphasized by the fact that it may be relieved or alleviated by either desensitization or by atropin, adrenin, and calcium. 
6. Bronchitis. The increase in bronchial secretion which accompanies asthma is reduced by atropin, adrenin and calcium. This should be expected because it is primarily due to increase in vagus action. These measures, while less valuable in the bronchitis which is due to chronic infections, will at times even in them effect a diminution in the secretion. 
7. Affections of the gastrointestinal tract. While there are many interesting syndromes in the gastrointestinal tract expressed on the part of both the sympathetic and parasympathetic systems, yet I shall refer to only a few. Any condition found, however, should be considered from the standpoint of action or inhibition of action and classed according to whether such activity belongs to the sympathetic or parasympathetic neurocellular mechanism.

It can be seen that all symptoms which represent increased muscular or secretory activity in the gut proper (excluding the sphincters which bear opposite innervation), or, those organs such as the liver, pancreas and body of the bladder which are derived from the gut and bear the same innervation, are due to a predominance of parasympathetic activity. Among such may be mentioned hypersecretion in the stomach (hyperchlorhydria) or intestinal tract; hypermotility in the same leading to such conditions as diarrhoea, mucos colitis, colicky pains and spastic conditions of the intestinal tract. Such conditions may be influenced through the inhibitory action of atropin upon the vagus, or through stimulation of the sympathetic neuromuscular mechanism by adrenin or by calcium which has a tendency to increase the action of the sympathetic so that they may the stronger oppose the heightened vagus action to such a point that equilibrium may be again restored. 

There are also certain sympathetic syndromes on the part of these structures which need to be considered, such as the hyposecretion and hypomotility represented by the slow digestion and constipation which accompany the acute toxic stage of infections. This is explained by the fact that the toxins act upon the sympathetics and overbalance the action of the parasympathetics represented by the vagus, destroying the nervous equilibrium and producing a predominant sympathetic effect. The same neurocellular condition exists in chronic hyposecretion and hypomotility and likewise results in relaxation of the bowel and constipation. 

These conditions may be improved, at least temporarily, by the administration of sodium or magnesium salts, particularly the sulphates, which stimulate the vagus mechanism and cause an increase in glandular secretion and an increase in muscular contraction. Such conditions may also be influenced at times by general stimulants for the parasympathetic system, such as pilocarpine. 

Spasm of the various sphincters as a rule is a condition of hyperactivity of the sympathetics, Carlson¹¹ believes cardiospasm may be due to either increased sympathetic or increased parasympathetic action. The relief for such conditions consists in general sedative measures, but should be aided by substances which are distinctly inhibitory to the sympathetics, such as ergotoxin in rather large doses, or substances which raise the action of the vagus to the point of restoring nerve equilibrium in the part affected. We must not forget pilocarpine and the salts of sodium and magnesium in this connection. 

Gall-bladder drainage as carried out by the Meltzer-Lyon¹² method is an instance of applying stimulation to one of the neuromuscular mechanisms which maintain equilibrium in the gall-bladder and gall ducts in such a way as to relieve these structures of undesirable and dangerous conditions. The sympathetics innervate the sphincter at the ampulla of Vater and probably the common duct and inhibit muscular action in the gall-bladder. The parasympathetics oppose this action and when stimulated dilate the sphincter and possibly contract the musculature of the gall-bladder, although the musculature is very weak and there is some doubt as to how much force could be exerted by its contraction.

They also activate the ducts in the liver and cause them to contract when stimulated. In the presence of infection and stasis it is desirable to empty the gall-bladder and drain it and the ducts of the liver. This has been successfully done by introducing magnesium sulphate into the duodenum where it exerts its influence upon the vagus neuromuscular mechanism stimulating it and producing conditions which favor the emptying of the gall-bladder and the liver ducts. Other parasympathicotropic drugs might act in the same way, but magnesium sulphate in 25 to 35 per cent solutions introduced through the duodenal tube has acted best. There are failures reported where this method is employed the same as there are in all procedures which are instituted for the relief of disturbed physiologic conditions in the human organism, but this does not change the fact that the procedure is based on sound physiologic principles. 

Eczema. One must not forget the importance of the sympathetic nerves in their relationship to all dermal and sub-dermal structures. As far as we know, there is no physiologic connection between dermal and sub-dermal structures and the parasympathetic system, therefore eczema and other affections of the skin accompanied by itching should be considered in their relationship to the sympathetic neurocellular mechanism. 

For a long time, itching of the skin has been treated empirically by calcium. We have recently tried its effect upon ichthyosis and very severe eczema. We have employed thyroid substance in connection with the calcium in both instances. In the patient suffering from eczema there was marked thickening of the skin over the hands, arms, thighs and face. The arms showed long deep scars where she had torn the flesh by her nails during sleep. The patient had tried so many things without relief that she was hopelessly pessimistic as to obtaining benefit. By the use of calcium and thyroid we have not only brought about a cessation of the itching but a satisfactory reduction in induration. The case of ichthyosis has been favorably influenced by the calcium. 

Discussion 

Calcium must not be put forward as a cure-all; otherwise its very important function will be lost sight of through disappointment. I have used it sufficiently in parasympathetic syndromes to demonstrate beyond question that we are able to influence practically all purely parasympathetic syndromes. This fact of itself is of utmost importance to clinical medicine. Its employment is surrounded by many difficulties which must yet be overcome. Its relationship to other ions must be more carefully worked out; so must its relationship to the sympathetic nerves and the various incretions. One must not expect it to bring about a cessation of all symptoms in these conditions mentioned. At present it must simply be looked upon as an aid. In the future we hope that we may understand the entire neurocellular mechanism sufficiently so that its action may be definitely understood.

When calcium therapy is indicated it is desirous that we bring about a maximum calcium retention, so the relationship of calcium to protein foods must always be borne in mind. Protein foods are broken down into certain acids which combine with calcium and cause its rapid elimination. The clinical observation that patients suffering from asthma and eczema and other diseases of this type do best on low protein diet is now furnished with a physiologic explanation. 

While I have published in previous papers the method of using calcium, it might be well to repeat it here. We usually employ a 5 per cent solution of calcium chloride, put up in sterilized ampoules. Of this we have used most commonly 5 cc. at an injection–sometimes 10 cc.–the same to be repeated at intervals of from one to two days or a week. The remedy must be injected very slowly. We usually take from five to ten minutes to inject 5 and 10 cc. During its administration the patient usually complains of a sensation of warmth or intense heat; constriction in the throat; sometimes nausea; sometimes burning in the rectum; but all of these symptoms are evanescent, passing away in a few minutes. 

One should never forget that the employment of intravenous therapy is a serious matter, and that it must be surrounded by every precaution: Personally, I feel that it is better that the patients be in bed, although we have treated quite a number as ambulatory patients.

References Cited:

1. Loeb, Jacques: Protein and the Theory of Colloidal Behavior. 1922, McGraw-Hill Book Co., New York.
2. Starling, E. H.: Principles of Human Physiology, 1915, Lea & Febiger, Philadelphia, p. 864. 
3. Pottenger, F. M.: “A discussion of the etiology of asthma in its relationship to the various systems composing the pulmonary neurocellular mechanism, with the physiologic basis for the employment of calcium in its treatment.” To be published in the Amer. Jour. Med. Sc.* [*Editor’s note: This article was published in the American Journal of the Medical Sciences, Vol. clxvii, No. 2, February 1924.]
4. Ringer, Sydney: “Concerning the influence exerted by each of the constituents of the blood on the contraction of the ventricle.” Jour. Physiol., iii, 380-393. 
5. Ringer, Sydney: “A further contribution regarding the influence of the different constituents of the blood on the contraction of the heart.” Jour. Physiol., iv, 29-42. 
6. Ringer, Sydney: “A third contribution regarding the influence of the inorganic constituents of the blood on the ventricular contraction.” Jour. Physiol., iv, 222-225.
7. Howell, W. H.: “The vagus inhibition of the heart in its relation to the inorganic salts of the blood.” Amer. Jour. Physiol., 1906, xv, 280-294. 
8. Howell, W. H., and Duke, W. W.: “The effects of vagus inhibition on the output of potassium from the heart.” Amer. Jour. Physiol., 1908, xxi, 51-63. 
9. Zondek, S. G.: “Untersuchungen uber das wesen der vagus and Sympathikusreizung.” Berl. Klin. Wchnschr., 1921, lviii, 1393; and Deutsche Med. Wchnschr. Leipz. u. Berl., 1921, xlvii, 1520-22; also p. 1541. 
10. Pottenger, F. M.: “The physiologic basis for the employment of calcium in the treatment of asthmatic paroxysms.” Calif. State Jour., 1923, ii, 293-294.
11. Carlson, H. J., Boyd, T. E., and Pearcy, J. F.: “Studies of the visceral sensory nervous system. XIV. The reflex control of the cardia and lower esophagus.” Arch. Int. Med., xxx, No. 4, October 1922.
12. Lyon, B. B. Vincent: Non-Surgical Drainage of the Gall Tract. Lea & Febiger, Philadelphia 1923.