CHAPTER 24

Influence of the magnesium in the ration on the excretion of magnesium in the urine

It was seen in the preceding chapter that aldosterone, the hormone secreted by the adrenal cortex, altered the excretion of potassium and sodium in the urine. How aldosterone injections caused the muscular cells to lose magnesium had previously been studied. It is only in the course of the last few years that the considerable influence exerted by aldosterone on the excretion of magnesium in the urine and, more generally, on magnesium metabolism has come to be discovered.
Some research workers have found that an excess of aldosterone in the organism, resulting from an injection of the hormone or from a tumour of the adrenal glands causes:

	negative magnesium balance;
	diminution in the content of magnesium in the blood serum;
	increased excretion of magnesium in the urine and faeces.

There is a fair amount of agreement between the results obtained by the various workers regarding the negative magnesium balance and the lower magnesium content in the blood serum; with regard to the excretion of magnesium in the urine, however, the results are more variable and even contradictory.

In the case of a diet deficient in sodium, which we know to give rise to increased production of aldosterone by the adrenal glands, it has been observed that the lower sodium content of the urine may be accompanied either by no change in the magnesium content of the urine or by a considerable diminution (40%) in that content. HILLS, who made the latter observation, thinks that there is a link between the excretion of magnesium and that of sodium ¹ by the kidneys; he thinks it probable that the greater activity of the adrenal cortex (or more correctly, of the zona glomerulosa of the cortex), resulting from the deficiency of sodium, gives rise simultaneously to diminished excretion of sodium and magnesium in the urine (owing to the greater tubular reabsorption of sodium and magnesium).
If this last result were confirmed, a fact of great importance for grass tetany would be established: namely, that the production of aldosterone by the adrenal glands, resulting from the very low content of sodium in the herbage, may help to reduce the magnesium content of the blood serum and at the same time the excretion of magnesium in the urine, which, as will be seen later in the present chapter, is very similar to what actually happens with tetanigenic herbage. There are many points, however, that are still not clear.

CARE'S experiments, although in their initial stages, appear to confirm this hypothesis. The British worker has used:

	(a) normal sheep;
	(b) sheep previously deprived of sodium over a period;
	(c) sheep previously deprived of sodium over a certain period and then fed a supplement of sodium bicarbonate.

He fed them ² herbage that had received large quantities of potassium fertilizers and studied how they were affected by injections of aldosterone.

Consideration having been given to the possible relationship of sodium and aldosterone with grass tetany as well as with the excretion of magnesium in the urine, attention will now be paid to the enormous role played by the urinary excretion of magnesium ³ in regulating the metabolism of magnesium. In cows suffering from hypomagnesaemia the excretion of magnesium in the urine is subject to considerable variations, which, from the practical point of view:

	(a) improve one's understanding of the phenomena accompanying or causing grass tetany;
	(b) assist the research worker in following the reactions of the animal to buccal or parenteral treatment with magnesium.

Right at the beginning of the experimental work concerned with magnesium deficiency it was observed that, in young female dogs receiving a very low-magnesium diet, the daily excretion of magnesium fell rapidly from 39 to 20 Mg.,⁴ or by about half.⁵ All the subsequent findings were to confirm these initial results, whether obtained with rats, dogs or ruminants. Fig. 11, for example, taken from FIELD of the Moredun Research Institute, Edinburgh, shows the highly significant positive correlation between the quantity of magnesium ingested by sheep and that excreted in the urine. It may be seen, moreover, that the quantities of magnesium excreted in the urine can reach very high levels when the quantities of magnesium in the ration become very large and greater than the requirements. This figure also illustrates the individual character of magnesium metabolism in an animal. For the same quantity of magnesium ingested, the amounts excreted in the urine are not identical.⁶ In other words, animals do not all utilize magnesium in the ration with equal efficiency.

Variations in urinary magnesium as part of the adaptation syndrome

The excretion of magnesium in the urine, or more exactly the renal mechanism of magnesium excretion, thus represents a remarkable regulatory system for the organism's magnesium metabolism.
In the case of magnesium excess administered bucally or parenterally there is a large increase in the magnesium excreted in the urine to obviate the toxic effects of this increase.

FIGURE 12: Relationship between the magnesium excreted in the urine and the magnesium content of the blood serum of cows

In the case of magnesium deficiency the organism tries to retain the very small quantities of magnesium available to it; it lowers, even to nothing, the amounts of magnesium it loses in the urine, with the result that the effects of the deficiency are reduced.
These very considerable variations in the magnesium content of the urine represent one of the mechanisms of the "syndrome of adaptation" to magnesium excess or deficiency. This syndrome becomes even more obvious on study of the correlation between the magnesium contents of urine and blood serum. It has been observed, in effect, that from a magnesium content below a certain limit (approximately ⁷ 1-80 mg. per 100 c.c. in the case of cows) there is a rapid drop in the quantity of magnesium excreted in the urine (Fig. 12). Below a magnesium level of about 0-7 mg. per 100 c.c. in the blood serum, magnesium excreted in the urine may even become non-existent. This means that, when the magnesium content of the blood serum reaches a certain critical and dangerous limit, the organism very rapidly reduces, or even stops completely, the excretion of magnesium in the urine. In this way it attempts to keep as much as possible of this magnesium that is dangerously lacking. The same almost total reduction of sodium excretion in the urine has been seen (Table 17) in the case of the sodium-deficient cow.
Conversely, when the normal level of magnesium in the blood serum is reached, the amount excreted in the urine will rise considerably where the supply of magnesium in the ration is in excess of the requirement.
The practical consequences of these two phenomena will now be examined.

A buccal supplement of magnesium can act rapidly on the magnesium in the urine and in the blood serum

It should be borne in mind that the animal organism has no capacity for rapidly stocking quantities, small though they may be, of mobilizable magnesium. As a result, buccal administration of magnesium:

1.	Acts very rapidly and obviously on the magnesium content of the urine.
2.	Re-establishes equally rapidly (although the effect is often less rapid than in the urine) the magnesium content of the blood serum if hypomagnesaemia has been present.

If the magnesium content of the blood serum is normal, the magnesium in excess of requirements resorbed in the digestive tract passes almost entirely into the urine; only a minute fraction is retained to regarnish the very low stocks of mobilizable magnesium in the organism (should the occasion arise and even then very much in part).⁸
This is illustrated clearly by an experiment undertaken in Norway by ENDER. He administered a daily supplement of 50 gm. magnesium bicarbonate buccally to cows suffering from hypomagnesaemia, the magnesium content of whose blood serum was very low (0-70 mg./100 c.c.) while the quantity of magnesium excreted in their urine was more or less nil (0-04 gm. per day). Fig. 13 shows with what speed the buccal administration of the magnesium supplement increased the amount of magnesium excreted in the urine and how the magnesium content of the blood serum regained its normal level, although a very little less rapidly. After the latter content had returned to normal, continued magnesium supplementation produced a further rise in the excretion of magnesium in the urine, which then remained steady at approximately 4 gm. per day, a figure almost 100 times greater than that in existence before supplementation.

FIGURE 13: Immediate effect of the buccal administration of magnesium bicarbonate on the excretion of magnesium in the urine and on the level of magnesium in the blood serum

The administration of magnesium supplements will be discussed again below, but a fundamental practical conclusion arising from these experiments should be stressed from the outset: namely, that a supplement of magnesium in the ration offers protection against tetany only during the period in which it is administered.

All the magnesium injected is very rapidly excreted in the urine

If intravenous injections of magnesium are given to dogs and sheep, almost all this magnesium is recovered in the urine.⁹ In other words, all the magnesium supplied parenterally is very rapidly excreted. Moreover, 48 hours after an intravenous injection of magnesium salt the magnesium content of the urine is more or less back to normal.¹⁰
It should be emphasized that rapid though the elimination of the magnesium excess via the urine may be, it is not, however, instantaneous. This explains the casualties (paralysis) that may result if a parenteral, and particularly an intravenous, injection of magnesium salt is given too rapidly. The injection must be sufficiently slow to allow urinary elimination to play its protective role.

Effectiveness of magnesium salt injections

The consequence of this rapid excretion of magnesium in the urine is that the injected element can only remain for a short time in the organism. During this short period there is a sudden rise in the magnesium content of the blood serum, which may or may not be maintained, depending on the circumstances.
1. If the hypomagnesaemia is caused by under-nourishment,¹¹ which has slowly exhausted the few meagre mobilizable reserves of magnesium, the temporary increase in the magnesium level of the serum resulting from the injection is of too short duration for the mobilizable magnesium reserves to be built up again.¹² Moreover, it generally happens in this case that, 24 hours after the injection, the magnesium content of the blood serum has fallen again to the previous level.
2. If the hypomagnesaeamia is the result of a temporary diminution in the magnesium resorption level (see Chapter 35), with a sudden upset of the endocrine mechanisms keeping the level of the element in the blood serum constant (as in the case of spring grass tetany ¹³), parenteral injection of magnesium may allow the shock resulting from these conditions to be overcome, and the magnesium content may then return more or less to normal, provided the disturbed endocrine mechanisms are able to function normally again.
But between these two extreme and well-defined instances are all the intermediate cases brought about by under-nourishment and disturbance of the endocrine system together,¹⁴ with the result that injections are only partly effective.¹⁵ This also happens if certain organs have begun to suffer irreversible biochemical lesions.

TABLE 19: Influence of the maturation of herbage on the excretion of magnesium in the urine of the cow

The magnesium in the urine reflects the different effects of mature and very young grass on the metabolism of magnesium

The question of magnesium in the urine cannot be left without examining how this content reveals the decline in the tetany-producing character of herbage as it matures: a question of fundamental practical importance.
Cows that were being stall-fed in winter were suddenly fed either very young or very mature grass. It is seen in Table 19 that, in the case where young grass was fed exclusively (20 % dry matter), the excretion of magnesium fell to very low, and sometimes even non-existent, levels. The mean daily excretion over 5 cows was 0-07 gm. On the other hand, when the grass was more mature (28% dry matter), the fall in magnesium excretion in the urine was much less marked, the mean for 6 cows being 0 - 59 gm. per day or 8 times the figure for the very young grass. It is obvious, therefore, that sudden feeding with more mature herbage causes only a very moderate upset in the magnesium metabolism of the animal: which is not the case with young herbage.

FIGURE 14: Variations in the magnesium content of the blood serum and urine on a sudden change-over to feeding with mature or young grass

Figure 14, concerning the same experiment, allows the simultaneous developments of urine and blood-serum magnesium to be foIlowed for two cows fed on young and mature herbage respectively. In the case of the cow Dorritt 29 (top of figure) fed on very young herbage, the magnesium content of the urine falls to zero.¹⁶ Despite this absolute "restraint" of urinary magnesium losses, the magnesium content of the blood serum continues to fall to the very low and dangerous level of 0-60 mg./100 c.c. With Winsome 33 (bottom of figure) that was fed mature grass, the magnesium content of the urine falls steeply, but without reaching zero levels. This reduction of the magnesium losses in the urine is quite sufficient, moreover, for there is only a moderate drop in the magnesium content of the blood serum, which, at its lowest, reaches the almost normal level of 1-70 mg./100 c.c. In addition, from the second day of this diet, the magnesium content of the blood serum rises again and very quickly becomes normal.
Thanks to this "barometer" of magnesium metabolism as represented by the magnesium in the urine, all the danger of a diet of very young grass is clearly obvious. The importance of the "indication" given by urinary magnesium will be even better understood when the serious digestive disorders caused by very young herbage and how these are reduced when the grass is allowed to mature are now studied.

1. It is not impossible that there may be an antagonism between magnesium and sodium at certain metabolic stages; but many points are obscure and contradictory. *

2. The change in diet was sudden. *

3. Until very recently urinary excretion of magnesium via the kidneys received hardly any attention and, in 1958, one of the most complete and notable publications on the kidney made no mention of the problem of magnesium excretion, nor even indicated the content of the element in the urine. No mention was made either of the nephro-calcinosis caused by the disturbance of the magnesium metabolism. *

4. Urinary excretion of calcium remains more or less unchanged, but, as in similar experiments, it is found that there is an abnormally high retention of calcium by the organism during an initial period, followed by a second one during which calcium is excreted in gradually increasing quantities. *

5. A simultaneous reduction in the excretion of magnesium in the faeces has been established. *

6. For the individual character of magnesium metabolism in the animal, see Chapter 33. *

7. The figure depends on various internal and external factors. *

8. These mechanisms will be understood to function only if the organs, the kidney and adrenal cortex, in particular, have not been adversely affected by previous deficiencies. *

9. This intravenous injection of magnesium salt not only brings about a considerable increase in the excretion of magnesium in the urine but, at the same time, it also increases the calcium content and diminishes the potassium content of the urine. *

10. In the case of subcutaneous injections the magnesium is excreted a little less rapidly in the urine, but the general picture presented by the phenomena is the same. *

11. Sometimes called seasonal hypomagnesaemia (see Chapter 35).*

12. These reserves build up again as slowly as they become exhausted. *

13. Often described as rapidly developing hypomagnesaemia. *

14. Noting that under-nourishment also affects the functioning of the endocrine system. *

15. For some of the practical details concerning magnesium injections, see Chapter 40. *

16. As long ago as 1930 SJOLLEMA noted that, in cows suffering from tetany, the magnesium content of the urine was extremely low, generally less than 1 mg./100 c.c. *