Grass Tetany by André Voisin

CHAPTER 20

Substances sensitizing the neuro-muscular system to the excitatory action of potassium

SUMMARY
Potassium is an excitant of the neuro-muscular system, the effect of which is enhanced by certain substances, known as "sensitizers" of the neuro-muscular system, to the excitatory action of potassium.
One of these sensitizers is thiocyanate (or sulpho-cyanate), the content of which in the blood may be considerably increased by the animal's consumption of some of the new strains of white clover.
Another sensitizer to potassium is histamine, which appears to be present in larger quantity in the blood of animals consuming very young grass. Anti-histamines are sometimes used to treat grass tetany.

Potassium increases the excitability of the neuro-muscular system

The brief study that has just been made of the mechanisms of neuro-muscular transmission reveals that potassium increases neuro-muscular excitability.1 This finds expression in the so-called LOEB formula, which indicates that clinical states of hypopotassaeamia and hyperpotassaemia 2 depend not only on the concentration of potassium in the blood serum but also on the other ions present.
Toxic effects of absorbing excessive quantities of potassium

It is interesting from the point of view of grass tetany to know what effect an excess of dietary potassium could have on the neuro-muscular system, the herbage that causes tetany being known to be particularly rich in potassium. Historically it is interesting to recall that in 1840 LIEBIG prepared a meat extract that caused the death of the animals consuming it. It was subsequently established that the high potassium content of this extract was the cause of the poisoning. As REINBERG states: "This misfortune that overtook the great German chemist shows that massive absorption of potassium, even through the digestive tract, can be dangerous."
Nevertheless, the results that have been obtained concerning the toxic effects of a potassium supplement are very variable. It was said prevously, in studying the resorption of magnesium in the digestive tract, that the effects of administering a potassium supplement on hypomagnesaemia and on tetany may be very different, depending on:
- the absolute magnesium content of the ration;
- accustoming the animal to a ration rich in potassium;
- the state of certain organs in the animal that enable it to get rid of the excess of potassium in the ration (defence reaction or adaptation syndrome).

It will now be seen how different organic substances present in the organism in variable quantities can reinforce the toxic effect of the potassium ion.

Sensitizers to the tetany effect of potassium

Certain organic compounds which are very numerous,3 can accentuate the effect of potassium on neuro-muscular sensitivity. Such compounds are known as "sensitizers to potassium", that is to say, they are substances that sensitize the neuro-muscular system to the excitatory effect of potassium. Another description sometimes used is that they are "factors responsible for triggering off attacks of tetany".
How the effect of potassium is accentuated by these "sensitizers - in the case of hypocalcaemic tetany has been particularly studied. It has been possible, for example, to produce attacks of hypocalcaemic tetany by administering guanidine 4 to animals whose parathyroid glands had been removed. The presence or absence of such sensitizers 5 to the tetany-producing action of potassium help to explain the contradictory results that have been obtained concerning the influence of potassium on the different forms of tetany. The Belgian research worker GOFFART, who has devoted an enormous amount of effort towards the study of this problem, writes:
"Anyone scanning this clinical literature, human as well as veterinary, has the feeling that an important factor must have been overlooked. We believe that this factor is represented by the sensitizers to potassium. Taken separately these substances are too diffuse to be effective; these sensitizers can become effective, however, when the relative content of potassium ions is increased: the attack of tetany brought on by the potassium ion that is inadequately antagonised (by, calcium and/or magnesium) will develop more or less rapidly, depending on whether the content of sensitizers is high or low."

The action of only two "sensitizers to potassium" will be examined here: namely, thiocyanate and histamine.
Thiocyanate, white clover and grass tetany

As has just been said, thiocyanate (or sulphocyanate) is one of the sensitizers of the neuro-muscular system to the action 6 of potassium. There is justification for assuming that the sensitization of the neuro-muscular system by thiocyanate may play a part in grass tetany. It is known, in fact,7 that certain strains of white clover, such as S.100 or Ladino, lead to the presence in the blood of hydrocyanic acid, which is transformed in the organism to thiocyanate.8 Sheep grazing these white clovers had a thiocyanate content in the blood serum of 8-3 mg./100 c.c., compared with 2-8 mg./100 c.c. when grazing indigenous white clovers. In other words, the presence of these few strains of white clover can multiply three-fold the thiocyanate content of the blood. It is possible, therefore, that new pedigree strains of white clover, by increasing the thiocyanate content of the blood serum, may sensitize the animals to the excess potassium in the herbage.
The presence of white clover in a sward will be seen to lower the ratio  
which, under certain conditions, may reduce the risk of tetany. It may be wondered, however, whether this effect of white clover is not frequently cancelled out, or even reversed, when new strains of white clover are involved that sensitize the organism to the tetany-producing action of potassium by increasing the thiocyanate content of the blood serum.

Potassium, histamine and anti-histamines

Another sensitizer of the neuro-muscular system to the action of potassium is histamine.9
In addition, histamine gives rise to the release of adrenaline by the adrenal medulla and it will be seen later that adrenaline can assume the role of a factor triggering tetany.
Hypomagnesaemia, that is, the low content of magnesium in the blood serum, causes the release of histamine 10 by certain cells called mastocytes.11 Although magnesium deficiency thus facilitates the release of histamine, it should be noted that magnesium can play the part of an anti-histamine,12 like calcium, and inhibit 13 in part the constriction of the pulmonary artery caused by histamine.
Besides these two mineral anti-histamines, calcium and magnesium, a considerable number of synthetic, organic anti-histamines are known today that cancel out 14 the effects of histamine by de-sensitizing the muscles with regard to the potassium ion.

Histamine and grass tetany

From the point of view of grass tetany it will be seen that, when very young grass is fed, the blood of cows suffering from grass tetany has been found to be richer in histamine (although the differences may not always be very marked) than that of normal cows. This is perhaps due to excessive histamine production in the rumen, the fermentations of which are upset because of the presence of too much ammonia; an effect accentuated by the application to the herbage of large quantities of nitrogenous fertilizer (see Table 20).
It is not impossible, therefore, that this very young grass saturated with nitrogen, by increasing indirectly the histamine content of the blood serum, is capable of sensitizing the organism to the excitatory action of potassium.15
FOWLER found histamine present in grasses and clovers, and writes:
"Diets hiqh in potassium lead to greater susceptibility to histamine when administered intravenously to mice....
"It seems desirable, therefore, to widen the scope of investigations in grass tetany from the field of magnesium availability alone to the manner in which magnesium deficiency, either alone or with other factors, causes tetany. In this wider investigation the relationship of magnesium deficiency to histamine metabolism may play an important part and deserves closer examination."

This hypothesis regarding the possible role of histamine in grass tetany appears to be confirmed by the fact that it is sometimes used successfully in the treatment of grass tetany with anti-histamine products such as soventol 16 in Germany 17 and phenergan (or Atosil, an ethlene diamine derivative) in France.18

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Notes



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  1. 

       
It must be added that this is only correct within the most common limits 
of the physiological
       concentration of potassium. Very low, like very high, potassium 
concentrations reduce or even inhibit
       excitability. There is a concentration at which potassium produces 
optimum excitability in the nerves
       and muscles, this concentration being a function of the organ and of 
various factors, ionic balances, the
       oxygen content of the environment, temperature, pH, etc., in 
particular. * 
    


    

    
 

  2. 
       
The normal potassium content of the blood serum of animals varies between 
17 and 26 mg./lOO c.c.. It is wise, therefore, to speak of hypopotassaemia 
only when this content falls below 17
       mg., and of hyperpotassaemia when it exceeds 26 mg., it being 
understood that these figures are only
       indicative and may vary as a function of many factors. * 
    
       

    

    
 

  3. 

Veratrine, guanidine, adenosine, uracil, thiouracil, urea, thiourea, 
caffeine, theobromine,
       D.D.T., thiocyanate, histamine, etc. Under certain conditions the 
para-thyroid hormone appears to be able to exercise such an effect of 
sensitization to the convulsive effects of potassium.
         It will be seen in later sections that the thyroid hormone also 
sensitizes to the excitatory action of
       potassium. * 
    

    

    
 

  4. 
       
Conversely, the action of guanidine as a sensitizer to potassium is 
antagonized by calcium.
       Note that the guanidine content of the blood and urine of animals 
with no parathyroids is higher. * 
    
       

    

    
 

  5. 

Many hypotheses have been put forward in explanation of this sensitization 
of the neuromuscular
      system to potassium. Almost all the various workers tend to believe 
that these sensitizers interfere with
       the process of repolarization. With regard to the nature of this 
interference, however, hypotheses are
       legion. * 
    

    

    
 

  6. 

This effect is antagonized by calcium. Although the author knows of no 
work published on this
       problem, it is probable that magnesium will have the same effect. It 
will be seen in later sections that
       calcium and magnesium exercise the same antagonistic effect with 
regard to another sensitizer to
       potassium, histamine. * 
    

    

    
 

  7. 
       
See Soil, Grass and Cancer. This is due to the presence in these 
clovers of a       
      cyanogenetic glucoside. * 
    


    

    
 

  8. 
       
The enzyme system responsible for this transformation is present in many 
organs and cells, but the liver
       is far and away the principal organ for the "manufacture" of 
thiocyanate. * 
    
 

    

    
 

  9. 
      
Amine of the imidazole family. It can be produced in the organism by 
decarboxylation of the amino-acid
       histidine.
           Histamine is an excitant of the smooth muscles and is the cause, 
for example, of contraction of the
       uterus. It contracts certain arteries and dilates the capillaries, 
which become more permeable. * 
    
       

    

    
 

  10. 

Cf. p. 68. It has been thought that this released histamine is the cause 
of the hyperaemia observed in
       magnesium deficiency. * 
    


    

    
 

  11. 
       
The mastocytes, or mast cells, are cells with small nuclei; they contain 
in their cytoplasm large and
       numerous metachromatic granules. Mastocytes are particularly 
numerous in the connective tissues. * 
    


    

    
 

  12. 
       
Calcium and magnesium perhaps act as anti-histamines by antagonizing 
potassium which cannot
       achieve as much effect on the neuro-muscular system sensitized by 
histamine. This is only a hypothesis. * 
    
 

    

    
 

  13. 
      
Histamine by itself can produce contractions. It has been established 
that, within certain
       limits of concentration, copper antagonizes the action of histamine 
(by the formation of a chelate). It is not impossible, therefore, that 
copper deficiency may facilitate the direct or indirect effects of
       histamine on tetany. * 
    

    

    
 

  14. 
       
Except for its effect on glandular secretion (production of gastric juice).
 * 
    

    

    
 

  15. 
       
See Chapter 21 for how these effects combine to finally increase the 
secretion of adrenaline, the hormone
       of excitability and the emotions. * 
    


    

    
 

  16. 
       
 N-phenyl-N-benzyl-4,amino-l-methyl-piperidine. * 
    
 

    

    
 

  17. 
      
In Schleswig-Holstein, the German province so seriously affected by 
grass tetany, soventol is in common use, quite often, apparently, with 
success. * 
    


    

    
 

  18. 
       
Note that these anti-histamines have sometimes also proved effective 
against bloat caused by the consumption of very young grass.
    
       See also the use of anti-histamines in the treatment of rye-grass 
tetany. *