CHAPTER 21

Adrenaline, factor triggering tetany

Before the problems directly concerning the neuro-muscular system are left and the role of some of the endocrine glands studied, the way in which a hormone, adrenaline, which is secreted by the adrenal medulla,¹ can help to trigger grass tetany will be examined.
This chapter will act, therefore, as a transition between questions concerned with the neuro-muscular system and the endocrine glands. This is all the more justified as the adrenal medulla is a prolongation of the nervous system,² although it is coupled ³ with the adrenal cortex, which is a true endocrine organ. Moreover, the mechanism for secreting the hormone adrenaline differs from that of the other internal secretory glands in that it is very much less controlled by the blood than by the nervous system.⁴

In the case of a psychical excitement,⁵ the suprarenal medulla discharges adrenaline, which acts on the neuro-muscular system as a whole. Any strong emotion that has suddenly triggered an adrenaline secretion of this kind is followed by palpitations of the heart, bristling of the hair, etc. The effect of adrenaline is transitory, the hormone being rapidly destroyed.⁶
This flow of adrenaline can trigger an attack of tetany in pre-disposed subjects who are in a state of "latent tetany" and have previously suffered from the disease. In such cases intra-arterial injection of very small doses ⁷ of adrenaline immediately produces tetany. This is solely a triggering action, because, in normal subjects, even larger doses of adrenaline never give rise to tetany attacks.⁸

Adrenaline is known to increase the muscular contractions of the body. This effect is exerted on the neuro-muscular junction, and is more marked, the higher the ratio of potassium to calcium ions.⁹ In other words, adrenaline adds to the effect of the imbalance existing between potassium and its antagonist, calcium. Although to the author's knowledge no experiments have been undertaken in which adrenaline has been injected into hypomagnesaemic patients or animals, it is probable that the effect of the adrenaline is the same. This generalization appears all the more justified as an intravenous injection of adrenaline ¹⁰ causes a temporary increase ¹¹ in the potassium content of the blood serum.
This hyperpotassaemia results from a rapid release ¹² of potassium from the liver ¹³ into the bloodstream, and will aggravate ¹⁴ the imbalance already existing between potassium and magnesium and/or calcium, the contents of which in the blood serum are already low in cases of hypomagnesaemia and/or hypocalcaemia.

At least as important as the sudden hyperpotassaemic effect of adrenaline is the action of potassium on adrenaline secretion.
As long ago as 1925 the future Nobel prize-winner, HOUS SAY, had observed what he called the adrenaline-secretory effect of potassium, that is to say, that potassium increased the secretion of adrenaline by the suprarenal medulla. In 1933 HAZARD confirmed that the vaso-constrictive and hypertensive effect resulting from the intravenous injection of potassium chloride into a dog is due to a discharge of adrenaline by the suprarenal medulla.¹⁵ The French worker was subsequently to observe an extremely important fact, namely, that magnesium ¹⁶ (or calcium) salts reduce the adrenaline-secreting effect of potassium. Injections of adequate doses of magnesium chloride are sufficient to cancel out the renal vaso-constrictive and hypertensive effect achieved by the injection of potassium chloride which triggers the secretion of adrenaline. This is another example of the physiological antagonism of magnesium (and calcium) to potassium, so far as the adrenaline-secreting effect of the latter element is concerned.

1.	The hyper-irritability caused by the herbage in the hypomagnesaemic animal is perhaps attributable to the fact that this herbage gives rise to increased adrenaline secretion by the suprarenal medulla, and for two reasons - (a) The very great wealth of rapidly decomposable nitrogenous substances in the herbage leads to the production of excessive quantities of ammonia in the rumen, and also to the presence in the blood serum of larger amounts of histamine, which stimulates the secretion of adrenaline. (b) The excess (absolute and relative) of potassium in the herbage may have an adrenaline-secreting effect. It seems possible, therefore, that- Nitrogenous fertilizers increase (see Table 20) the tendency of young grass to produce excessive quantities of ammonia in the rumen, and thus promote the production of histamine. Potassium fertilizers, by increasing the absolute and relative wealth of potassium in the herbage (see Table 4, among others), combine their effects to augment considerably the secretion of adrenaline by the suprarenal medulla of the grazing animal.
2.	Any emotion or fear, whether it is caused by a loud noise or a prick with a hypodermic needle, will trigger off the sudden and considerable secretion of adrenaline, which will then become superimposed on a secretion already rendered excessive by the feeding of young, tetanigenic herbage.

1. The adrenal glands comprise an external section, the cortex, and an internal section, the medulla. *

2. Note that excitement of the sympathetic, so-called adrenergic nerves is bound up with the release at the nerve ending of a substance comprising 80-90% nor-adrenaline and 10-20% adrenaline. The secretion of the medulla, on the other hand, contains much more adrenaline than nor-adrenaline.
   Adrenaline contains one methyl radical (CH₃) more than nor-adrenaline.
   In the present text the word adrenaline signifies a mixture of adrenaline and noradrenaline. *

3. This "coupling" appears to be due to a "chance" happening in the course of the evolution of the species, because in selachians (sharks, ray, etc.) there are two adrenal glands (corresponding with the medulla and cortex) which are entirely separate. *

4. It appears to be the hypothalamus that governs the secretion of adrenaline either directly through the medium of the sympathetic nerves or perhaps indirectly through the medium of the pituitary. Other nerve centres likewise affect the secretion. *

5. The emotions, however, are not the only factors triggering the secretion of adrenaline. In fact, it sometimes happens that the organism is on the defensive: for example, in the case of asphyxia, poisoning, sudden hypoglycaemia, etc. It was seen previously that histamine also favours adrenaline secretion. *

6. This destruction is due to the action of amino-oxidase, to methylations, etc. It can also be brought about, however, by spontaneous oxidation or under the influence of phenol and poly-phenol oxidases, reactions which are governed by the presence of copper. It is not impossible for copper deficiency in the animal to be able to prolong, and in the same way strengthen, the action of adrenaline as a "triggering factor" in tetany. *

7. One tenth of a milligramme in humans. *

8. This triggering of tetany attacks is independent of vaso-motor disturbances engendered by adrenaline. All that is known is that the point of attack of adrenaline is peripheral, because the tetany-producing effects of the hormone can be restricted to the extremity of a limb by administering an arterial injection below a venous tourniquet. *

9. In the solution in which the preparation was immersed. An innervated rat diaphragm was used, placed in a Krebs solution. It was supposed that the adrenaline is able to act on the neuro-muscular junction by reducing the content of ionized calcium in the surrounding fluid.
   Adrenaline also increases contractions to a large extent when the ratio of potassium to sodium ions is raised by reducing the sodium content of the solution. *

10. Chemically true adrenaline. In the case of nor-adrenaline the hyperpotassaemia is more persistent. *

11. Then this content falls, generally for a short period, below the initial value before regaining its normal level again. *

12. Excitation of the large splanchnic nerve has the same effect, moreover. There is an increase of 3-7 mg./100 c.c. in the potassium content of the serum. Excitation of the distal end of the hepatic nerves produces even more marked increases (9-16 mg./100 c.c.) in the potassium content of the serum. *

13. This loss of potassium from the liver is connected with the glycogenolysis (conversion of glycogen to glucose) brought about by adrenaline. The vascular effects of adrenaline may also enter into play.
    For the relationship between the metabolism of magnesium and that of the carbohydrates see JAVILLIER (who has done so much to advance our knowledge of the biological role of magnesium) and AIKAWA. *

14. Although it does not appear to alter the magnesium and calcium contents of the blood serum. *

15. After suprarenslectomy neither hypertension nor vaso-constriction is observed.
    The purely adrenalinogenic excitation provoked by potassium is peripheral in origin. It is observable after section of the splanchnic nerves. Further research was to show, however, that potassium also has a central effect. The strength depends on the dose and rapidity of potassium chloride injection.*

16. As well as such substances as cocaine, atropine, curare, etc. Other substances such as acetylcholine, eserine, veratrine, etc., accentuate the adrenaline-secreting effect of potassium. *