CHAPTER 19

Magnesium and neuro-muscular transmission

	- deficiency of magnesium ions and excess of calcium ions increase the release of acetyl-choline which excites the muscle;
	- deficiency of magnesium or calcium ions prolongs the effect of acetyl-choline in exciting the muscle.

The different forms of tetany are simply the external manifestation of increased neuro-muscular excitability. This excitability is a function of qualitative and quantitative variations in the humoral environment: in particular, balances between mineral elements (total and ionized), acid base balances, organic elements, etc., present in the blood serum. These different factors can affect either the central nervous system, nervous transmission, neuro-muscular transmission or the stability of the motor endplate of the muscle.
Mineral elements are effective mainly in their ionized form, which is the biologically active form from the neuro-muscular point of view. This ionization ¹ is dependent on many factors, among them the blood's total content of these elements as well as the many vegetative endocrine influences.
As far back as fifty years ago LOEB had studied the effect exercised by the potassium (K⁺), sodium (Na⁺), calcium (Ca⁺⁺) and magnesium (Mg⁺⁺) mineral ions on the neuro-muscular junctions. He had expressed the effect of this ionic balance by the formula

Neuro-muscular excitability =	(K+)   (Na+)
	(Ca++) (Mg++)

This was LOEB's way of expressing the fact that the elements of the numerator increase while those of the denominator diminish neuro-muscular excitability. It was subsequently to become evident that this balance holds good only under certain conditions and may even be reversed in certain cases. In addition, account must be taken not only of the antagonism of all the elements in the numerator with regard to all the elements in the denominator but also of the antagonism existing between the constituent elements ² of both numerator and denominator.³

The concern of this book is hypomagnesaemic tetany. An attempt will therefore be made to establish how, in the light of the most recent scientific findings, the balance of the magnesium relative to the other ions affects neuro-muscular excitability. In other words, the reason will be sought as to why impoverishment of the fluid bathing the neuro-muscular junctions is the cause of tetany.⁴
If the few data presently available on this topic are to be better understood, it would be necessary to give a fairly detailed description of the physiological and biochemical mechanisms of the neuro-muscular system, which is largely outside the scope of the present work. The indications given here will certainly be too sketchy for the physiologist or biochemist who are referred to the specialist books and papers cited in this chapter. Only those phenomena essential to the understanding of certain aspects of therapeutic and protective medicine in the field of grass tetany will be discussed here, and in simplified terms.

The so-called motor nerve fibres proceeding to the muscle to order its contraction terminate in the synaptic knob.⁹

The latter is separated from the muscle end-plate by the synaptic cleft.¹⁰ When a presynaptic impulse reaches the extremity of a nerve, that is, the synaptic knob, depolarization ¹¹ of the terminal portion of the nerve takes place, with the following three subsequent developments:

1. Discharge ¹² of acetyl-choline ¹³ in the synaptic cleft.
   The acetyl-choline discharged will excite the muscle. This discharge is:
   (a) increased by -
   a deficiency of magnesium ions,
   an excess of calcium ions;
   (b) reduced by -
   an excess of magnesium ions,
   a deficiency of calcium ions.
   
   At this stage in neuro-muscular transmission, therefore, there is antagonism between the calcium and magnesium ions. The higher the Ca : Mg ratio, the more acetyl-choline is discharged.¹⁴ This explains why a calcium injection suppresses the paralysis caused by too rapid and too large an injection of magnesium salt: the discharge of acetyl-choline, inhibited ¹⁵ by this excess of magnesium, can now proceed again normally. ¹⁶
   Other mineral balances likewise influence the discharge of acetyl-choline. In effect, the latter is favoured by an increase ¹⁷ in the potassium content of the external environment.¹⁸ This action is antagonized by the magnesium ions, which means, as has just been said, that a shortage of magnesium ions or too high a ratio of K : Mg, exactly like too high a ratio of K : Ca, will have a tendency to release increased, if not excessive, quantities of acetyl-choline, thus creating a state of hyper-excitability.
   
2. Creation in the muscle end-plate of an action potential which produces excitation in the muscle.
   The acetyl-choline discharged by the synaptic knob combines with a receiving protein in the muscle end-plate. The result is depolarization of this plate, leading to a wave of current which excites the muscle.
   The potassium and sodium ions ¹⁹ control in the muscle the production of the depolarization wave (action potential), that is to say, the wave of excitation.
3. Destruction of acetyl-choline by the enzyme cholinesterase:
   The combination of acetyl-choline with the receiving protein of the muscle end-plate is very short-lived due to the fact that, at this point, acetyl-choline is very rapidly broken down ²⁰ by an enzyme known as cholinesterase.²¹ Any retardation of this breakdown will prolong and accentuate the depolarization of the muscle end-plate, thus giving rise to abnormal muscular excitation.
   Such a retardation is produced by a reduction in cholinesterase activity.²² This takes place when there is:
   a deficiency of magnesium ions;
   a deficiency of calcium ions.²³
   At this stage in neuro-muscular transmission, therefore, the action of the calcium and magnesium ions is analogous; on the contrary they are antagonistic in their effect on the discharge of acetyl-choline. The result is that a deficiency of magnesium or of a reduction of calcium causes stability in the muscle end-plate by, prolonging the depolarization ²⁴ of the latter, which leads to muscular disturbances. On this basis the analogy of some symptoms of hypocalcaemic milk fever and hypomagnesaemic grass tetany ²⁵ are better understood.

This description of the neuro-muscular mechanism is greatly simplified ²⁶ and leaves out many aspects, such as those covered by KUGELBERG'S theory, who is of the opinion that the phenomena associated with tetany originate in the proximal section of the peripheral nerve.²⁷
It does, however, aid one's understanding of how the imbalance of magnesium ions relative to the other cations can trigger off:

	either convulsions (magnesium deficiency);
	or paralysis (magnesium excess).

To end this chapter a practical question, fundamental from the point of view of preventing grass tetanv, will now be discussed in the light of these very condensed explanations.

1. Note that in practice it is almost always the total mineral elements of the blood serum that are determined, and the quantity ionized is not necessarily correlated with the total quantity. It should also be borne in mind that it is generally the mineral element content of the blood serum, i.e. of the extra-cellular fluid that is determined, but this content does not give a true picture of the mineral element (particularly the ionized mineral element) composition of the interstitial and intra-cellular fluids. *

2. In other words, neuro-muscular excitability is not a function of a cation or of the balance of some cations, but of the balance of each cation with all the other cations, bearing in mind that all the elements can affect the ionization (anions, etc.) of the different elements in balance. *

3. Attention was drawn above, for example, to the physiological antagonism of calcium and magnesium, the two elements in the denominator. The physiological antagonism of potassium and sodium, the elements of the numerator, will be discussed in later chapters. *

4. The question may also be asked in a positive form, namely: "Why is a constant level of ionized magnesium essential to the normal and satisfactory functioning of the nerves and muscles?" *

5. It should be noted that this paralysing effect of an excess of magnesium has been studied much more, from the physiological point of view, than the convulsive effect of an insufficiency of magnesium. *

6. Even in 1916 PECK and MELTZER came to the conclusion that magnesium excess caused narcosis by its action on the central nervous system and then paralysis by blocking the neuro-muscular junction.
   Old-established experimental work has shown that excitation of the motor nerve of animals injected with a magnesium salt does not cause the muscle to contract, whereas direct stimulation continues to cause muscular contraction. Magnesium excess, therefore, does exercise its effect in blocking neuro-muscular transmission (synapsis). It may be thought, moreover, that, taken on the whole, the effects of an excess of magnesium are analogous to those of curare; this is known as the curarizing effect of magnesium. In addition, curare and magnesium excess reduce the sensitivity of the motor end-plate of the muscle to the action of acetyl-choline. They differ, however, in their effect with regard to potassium: magnesium antagonizes the effect both of potassium and acetyl-choline on the sympathetic ganglion; curare does not alter the effects of potassium. Conversely, an injection of potassium reduces the muscular and respiratory paralysis produced in the animal by the injection of a large quantity of magnesium. *

7. This calcium effect can be cancelled by potassium. A cat is paralysed by the injection of sufficient quantities of magnesium chloride. It is then injected with calcium chloride in a quantity that has previously been proved to be adequate to inhibit the paralysing effect of magnesium; at the same time, however, equi-molecular quantities of potassium chloride are injected. No improvement is then observed in the paralytic condition of the cat. The antagonistic effect of potassium with regard to calcium has neutralized the effect of the latter with regard to magnesium.
   This is another example of the complicated nature of ionic balances. *

8. A mixture of magnesium and calcium salts is generally used. *

9. The region where two neurons join is called the synapse; this is the point where the impulse from one nerve cell is transmitted to a neighbouring cell. The synapse represents the contiguity of the plasmatic membranes rather than continuity of the protoplasms. In other words, there is close contact, but not continuity between two neurons. *

10. The synaptic knob of the neuro-muscular synapse measures approximately 1 micron in diameter. It contains a few isolated mitochondria and numerous synaptic vesicles. *

11. An excitable element, nerve or muscle, possesses a polarized membrane: that is to say, the inside of this membrane is negative in relation to the external surface. If this membrane is subjected to an impulse of more than a certain limiting value and with sufficient rapidity there is a sudden inward movement of positive ions. The result is depolarization. The impulse thus circulates in the form of an electric wave due to the depolarization of adjacent sectors of the nerve or muscle. This wave of electricity that develops is generally described as "action potential". *

12. This discharge is effected by the vesicles of the synaptic knob. *

13. Choline acetic ester. Plays a fundamental part in the transmission of both motor and para-sympathetic (cholinergic) nerve impulses. Acetyl-choline occurs in the synaptic vesicles in the form of an "acetyl-choline precursor" and is released from there. *

14. Within certain limits. *

15. It has likewise been observed that an excess of magnesium ions blocks the transmission of nerve impulses across the upper cervical ganglion, exactly as in neuro-muscular transmission. In addition, magnesium inhibits the stimulating effect of acetyl-choline and of the potassium ion on the ganglion. The depressing effect of magnesium excess on the motor nerves is much less marked than on neuro-muscular transmission. *

16. More or less. *

17. Within certain limits. In effect, the production of excitation in the nervous system can be arrested by too high or too low concentrations of potassium. *

18. If the addition of potassium ions is followed by the appearance of acetyl-choline, then, conversely, the addition of acetyl-choline may be accompanied by an increase in potassium ions. *

19. When there is excitation of the membrane of a cell of the muscular (or nerve) fibre the permeability of the membrane of that cell with regard to sodium ions is altered, with a consequent inward movement of the sodium ions (Na+). This sudden afflux of positive ions depolarizes the cell, with the result that, at the moment when the action potential becomes effective, the inside of the cell becomes positive in relation to the outside. When the maximum is reached, potassium ions (K+) begin to leave the cell. Then, when the fall in potential becomes more pronounced, the cell forces out the sodium ions that have invaded it and recovers the potassium ions it had lost (many points in this process are still far from clear). Depolarization is thus followed by repolarization. *

20. To acetic acid and choline, the latter becoming available for the synthesis of acetylcholine. *

21. More correctly, acetyl cholinesterase. *

22. Certain substances known as anti-cholinesterases likewise reduce this activity. *

23. It will be understood that this deficiency of calcium ions, causing the end-plate to forfeit its stability, is absolute as well as relative. Among others, the balance of potassium and calcium ions plays an important part. It has been shown in humans that a low content of potassium in the blood serum prevents the occurrence of hypocalcaemic tetany, while the administration of potassium to a hypocalcaemic patient triggers off this tetany. It was seen above that potassium cancels the antagonizing effect of calcium with regard to magnesium. The balance of potassium and magnesium outside and inside the cell probably also plays an important part in the stimulation of hypomagnesaemic tetany. *

24. Magnesium deficiency thus causes two analogous disturbances: it not only leads to the release of excessive quantities of acetyl-choline but it also reduces the breakdown of this excess acetyl-choline. The two effects are cumulative, which is not the case with calcium, deficiency of which reduces both the discharge and the breakdown of acetyl-choline. *

25. These effects, whether antagonistic or analogous, of calcium and magnesium on the neuro-muscular junction help one to understand better all the variable symptoms that can exist between those of "pure" hypomagnesaemia and "pure" hypocalcaemia. *

26. It must be stressed that many of the explanations offered are far from being either definite or final. In addition, these observations are only valid under certain conditions, but these are the conditions present in the majority of cases. *

27. These experiments were undertaken mainly on humans. *

28. Remembering that in this case it is wise to have at hand an ampoule of calcium salt, to be injected immediately the onset of paralysis is manifested in respiratory difficulties. *

29. CROOKSHANK. This author found that in green corn tetany the injection of a magnesium salt alone increases the calcium and phosphorus content of the blood serum for a period of about 6 hours. Conversely, the injection of a calcium salt alone causes an increase in the magnesium content of the blood serum. CROOKSHANK believes that this reciprocal action of calcium and magnesium might explain the greater effectiveness of a simultaneous injection of the salts of these two elements in the treatment of green corn tetany. *

30. In effect, it would be necessary to know, in the different cases, what stage in the neuro-muscular transmission is most affected by ionic imbalance. *