REGULATION OF ELECTROLYTES Charles Weber weber@brinet.com Most of the references may be seen in J. Theor. Biol. 104; 443, 1983. For a discussion of potassium see; http://pages.prodigy.com/JTQJ41A/potassium.html ABSTRACT Sodium and potassium are proposed to be regulated by varying secretion of aldosterone, DOC, 18 OH-DOC, and 16 alpha 18 dihydroxy 11 deoxycorticosterone in response to the nutritional load. The first two steroids are for high potassium and the second two for low potassium intake. The first and third steroids are for low sodium intake. INTRODUCTION Examination of the results of past experiments on the mineralocorticoid hormones seems to say that they exert their control over kidneys for the purpose of keeping blood serum sodium and potassium content constant through at least three and possibly four or more steroid hormones. I believe that aldosterone's role is fairly clear, and well accepted. The others are largely speculations of mine. The three discussed here besides aldosterone are deoxycorticosterone (also called cortexone, desoxycorticosterone, DOCA, or DOC), 18 hydroxy 11 deoxycorticosterone (also designated 18 OH-DOC), and 16 alpha 18 dihydroxy 11 deoxycorticosterone which I will designate DOH-DOC. They all must conserve sodium in order to be called a mineralocorticoid. Sodium makes up most of the cations of blood plasma. Plasma is filtered through the glomerulus of the kidneys in enormous amounts, about 180 liters per day [1]. Thus 580 grams of sodium and 36 grams of potassium are filtered each day. All but the 1-10 grams of sodium and the 1-8 grams of potassium likely to be in the diet must be reabsorbed. Sodium must be reabsorbed in such a way such as to keep the blood volume exactly right and the osmotic pressure correct; potassium must be absorbed in such a way as to keep serum concentration as close to 4.8 mEq [2] ( about 190 mg ) per liter as possible. Therefore the sodium pumps must always operate to conserve sodium. Potassium must sometimes be conserved also but since the amount of potassium in the serum is very small and the pool of potassium in the cells is extremely large, the situation is not so critical for potassium. Since potassium is moved passively [3] in counter flow to sodium in response to a Donnan equilibrium the urine can never sink below the concentration of potassium in serum except sometimes by actively excreting water at the end of the processing. Potassium is secreted twice and reabsorbed three times before the urine reaches the collecting tubules [4]. At that point it usually has about the same concentration as plasma with respect to potassium. If potassium were removed from the diet, there would remain a minimum obligatory kidney excretion of about 200 mg per day when the serum declines to 3.0-3.5 mEq/l in about one week [5], and can never be cut off completely. because it can not be cut off completely, death will result when the whole body potassium declines to the vicinity of one half normal. At the end of the processing potassium is secreted one more time if the serum potassium is too high. The potassium moves passively through " gates " and through one of the pumps which also pumps sodium. Even so, the net apparent effect is active in the tubules. The gastric glands, salivary glands, colon, perspiration glands, and maybe the red cells are target organs for the mineralocorticoids. DISCUSSION I believe I now see how the regulation of sodium and potassium is organized by the mineralocorticoids. Case #1: sodium intake is low, potassium intake is high. Aldosterone has been shown to be the primary steroid used to control the force and direction of the pumps under this circumstance [6]. When potassium in the serum is higher than 4.8 mEq/l the zona glomerulosa of the adrenal jacket secretes more aldosterone [7] and potassium is secreted into the end of the tubules and the collecting ducts [8]. The amount of aldosterone secreted is a function of the serum potassium [9] as probably determined by sensors in the carotid artery [10], the inverse of the sodium intake as sensed via osmotic pressure [11], and of the angiotensin II formation [12], which last is a peptide hormone for increasing blood pressure. If blood pressure has to be increased by constricting capillaries, which is what angiotensin II does [13], it is an indication that the body needs more sodium in order to expand blood volume. That is undoubtedly the reason why angiotensin is involved in regulating aldosterone. A considerable portion of the regulation resulting from angiotensin II must take place from increased blood flow through the liver due to constriction of capillaries [14]. When the blood flow decreases so does the destruction of aldosterone by liver enzymes. However the primary regulation is acting directly on aldosterone production because angiotensin II acts synergistically with potassium, and the potassium feedback is virtually inoperative when no angiotensin is present [15]. Such an arrangement tends to be fail safe. If anything happens to send the blood pressure spiraling upward out of control, when angiotensin II drops out in order to correct the situation, it leaves behind a somewhat enhanced potassium serum concentration which also tends to reduce pressure [16], and causes sodium to start to decline by the same failure to stimulate aldosterone. ACTH, a pituitary peptide, also has some stimulating effect on aldosterone probably by stimulating DOC formation which is a precursor of aldosterone [17]. I suspect that this is an adaptation to help protect the body during diarrhea assuming that a primary purpose of ACTH is to inversely mobilize the body's defenses against intestinal disease [18]. The aldosterone production is also affected to one extent or another by nervous control which integrates carotid artery pressure [19], aldosterone concentration [20], pain [21], posture [22], hemorrhage [23], probably emotion [24], and possibly other circumstances [25] to produce an unknown messenger hormone which stimulates aldosterone secretion [26]. I suspect the main reason why emotion is factored in, especially anxiety, is that the aldosterone operates by diffusing to the nucleus to produce a messenger RNA and the various steps take about an hour to come completely on stream. Thus there is an advantage in an animal anticipating a future need from interaction with a predator since too high a serum content of potassium has very adverse effects on nervous transmission [27] and thus the animal's ability to avoid predation. This system has been well studied and its major features are not subject to too much doubt. Potassium feedback is the main regulation of aldosterone in normal diet and health, and the other features of its regulation are for the purpose of fine tuning and forestalling future circumstances. The slope of the response of aldosterone to serum potassium is independent of sodium intake [28]. Thus the potassium is strongly regulated at all sodium intakes by aldosterone when the supply of potassium is adequate, which it usually is in primitive diets. The known stimulation by aldosterone of the sodium pump which indirectly secretes potassium into the distal tubules [29] along with the nature of the potassium feedback already mentioned make aldosterone certainly a hormone for unloading potassium. As much as 26 grams of potassium can be unloaded per day by healthy people accustomed to a large intake [30]. The question is, what hormones are involved when a different diet or disease makes necessary a different excretion pattern ? I suggest that at least three other mineralocorticoids may be involved. Aldosterone is designated case #1. Case #2: Sodium intake is high, potassium intake is high. Such a case would obtain when well fed primitive humans have a clam bake or find a salt lick. It is still necessary to unload potassium, but sodium retention must be less strenuous. I suspect that DOC is used for this purpose. DOC has a similar feedback with respect to potassium as aldosterone. However sodium has little effect, and what effect it does have is direct [31]. Angiotensin has little effect on DOC [31], but DOC causes a rapid fall in renin, and therefore angiotensin I, the precursor of angiotensin II [32]. Therefore DOC must be indirectly inhibiting aldosterone. Sodium, and therefore blood volume, is difficult to regulate internally. That is, when a large dose of sodium threatens the body with high blood pressure, it can not be resolved by transferring sodium to the intracellular space. The red cells would be possible but that would not change the blood volume. Potassium, on the other hand, can be moved into the large intracellular space, and apparently it is by DOC [33]. Thus a problem in high blood potassium can be resolved somewhat without jettisoning too much of what is sometimes a dangerously scarce mineral. Movement of potassium into the cells would intensify the sodium problem somewhat because when potassium moves into the cell a somewhat smaller amount of sodium moves out [34]. Thus it is desirable to resolve the blood pressure problem as much as possible by the fall in renin above, therefore avoiding loss of sodium which was usually in very short supply on the African savannas where humans probably evolved. DOC stimulates the collecting tubules to excrete potassium , but with one fifth the power of aldosterone [35]. The collecting tubules are the tubules which branch together after the distal tubules to feed the bladder. At high water intake aldosterone is up to 100 times more effective than DOC at retaining sodium [36]. At low water intake aldosterone is still 20 times as effective. When potassium rises in the serum DOC secretion is increased [37]. The resemblance of the pattern of the electromotive forces produced by DOC in the kidney tubules to normal potassium intake, and the total dissimilarity of their shape as produced by potassium deficient tubules [38], would tend to support the above view. These attributes are consistent with a hormone which is relied upon to unload both sodium and potassium. When potassium intake is very high, I assume that DOC must have the assistance of aldosterone. DOC's action in augmenting kallikrien, the peptide hormone thought to be the sodium " escape hormone ", and aldosterone's action in suppressing it is supportive of the above concept [39]. ACTH has more effect on DOC than aldosterone. I suspect that this is to give the immune system control over the electrolyte regulation during diarrhea [40] since during dehydration aldosterone virtually disappears anyway [41]. Most of the DOC is secreted by the zona fasciculata of the adrenal cortex , a small amount by the zona glomerulosa. ACTH exerts its differing control over these two steroids by virtue of its different effect on the those two zonas. Therefore the zona fasciculata seems to have evolved in order to protect the body during diarhea. Zona fasciculata's role in producing cortisol [40] supports this concept. The greater efficiency of DOC in permitting sodium excretion (or perhaps it should be expressed as inefficiency at retention) must be partly through changes in the kidney cells because escape from DOC sodium retention takes several days to materialize , and when it does, these cells are much more efficient at unloading it if sodium is then added than cells accustomed to a prior low intake [42]. Case #3: Sodium intake is low, potassium intake is low. Someone living on the Savannah, profusely perspiring and confined to eating nuts, or worse nothing at all could find himself in this situation. When potassium becomes low, the first thing that happens is that excretion of potassium from the far end of the kidney tubules and collecting tubules declines. This happens within 24 hours, and virtually stops in 2 days [43]. The large decline in aldosterone secretion is undoubtedly a large part of it. However, it is still necessary to rigorously conserve sodium and I tentatively propose that this is the function of 18 OH-DOC. I have no direct evidence for this yet, but there is strongly suggestive circumstantial evidence. Nichols, et al, have been able to show that injection of 18 OH-DOC which raised blood levels of this hormone ten times were more retentive of sodium than a similar amount of aldosterone. At the same time the ratio of sodium to potassium declined very little for 18 OH-DOC, while for aldosterone the ratio fell to as little as 1/3 that of control men [44]. This implies a considerable sparing of potassium by 18 OH-DOC. If the original aldosterone could have been removed from the serum, it is possible that the difference would have been greater yet. Angiotensin II has very little effect on 18 OH-DOC nor does serum potassium above 4.8 mEq/liter [45]. More important to know would be the effect of 18 OH-DOC has on angiotensin II because at low extracellular potassium situations the intracellular potassium decreases. I suspect that 18 OH-DOC stimulates angiotensin II because the intracellular potassium is much more important than extracellular potassium on the strength of heart contractions [46]. So when heart contraction strength decreases from low potassium status it should be imperative to contract the capillaries in order to make sure that blood pressure does not drop. Whether the above stimulation has evolved or not I don't know since I know of no experimental data. If this hunch is correct the low sodium status in this case would reinforce its evolution because low serum sodium's effect on volume also decreases blood pressure. While direct evidence is not available to me, it has been demonstrated that there is more of a marked rise in renin and therefore angiotensin II at low potassium intake than at any other electrolyte status [47]. Under low sodium intake, 18 OH-DOC rises in the serum [48], which is the correct response for the proposed purpose. ACTH causes a marked increase in 18 OH-DOC [49], probably by a generalized effect on the zona fasciculata where the 18 OH DOC is synthesized [50]. When ACTH drops to zero, 18 OH-DOC does also [50]. I suspect that this is to avoid sodium retention when the immune system is fighting diarrhea and dehydration makes it imperative to unload sodium. I have not seen evidence so far that cholera enterotoxin, or any other aspect of digestive disease other than dehydration directly affects ACTH yet, however. If this hypothesis is correct some aspect of diarrhea should affect ACTH. Dehydration causes a drop in ACTH [51]. The surge in 18 OH-DOC which attends insulin injections [52] may be due to an attendant drop in serum potassium [53]. Case #4: Sodium is high, potassium is low. Any of our progenitors who managed to find a salt lick, but nothing but nuts, honey, or nothing at all, would find themselves in this circumstance. Modern man eating only starchy, salty refined food would also be there. Someone with diarrhea would probably also be because the dehydration creates a serum artificially high in sodium concentration and because when water can't be absorbed in the lower intestinal tract, potassium can't be either and is lost. For this situation I propose DOH-DOC. DOH-DOC increases the sodium to potassium ratio slightly when injected into rats. This slight increase takes place even when small amounts of aldosterone are injected at the same time. That mount of aldosterone injected alone lowered the ratio slightly [54]. Unfortunately rats are not good experimental animals for experiments on a hormone possibly used during diarrhea because rats have something in their digestive fluid which neutralizes cholera enterotoxin [55]. Also their ascending colon increases water absorption under c-AMP stimulation, opposite to the effect in the descending colon and in other animals [56]. Thus the enterotoxin undoubtedly has much less effect on them. DOH-DOC combined with aldosterone is more retentive of sodium than either alone [57]. DOH-DOC does not displace aldosterone [58]. DOH-DOC must act in conjunction with aldosterone. If both are secreted together sodium would be drastically conserved therefore. If aldosterone drops out there would be a precipitous loss of sodium retention, while at the same time, if my contention is correct, potassium would cease to be excreted. I suspect that DOH-DOC has its greatest effect on sodium in the colon because it is here where it would be most advantageous to unload sodium in order to keep water loss in the kidneys at a minimum. I know of no evidence for the colon effect. Its affect on potassium excretion would be most valuable in the kidneys and this may be why it interferes with DOC's potassium excretion stimulation in the kidneys [59]. When DOC is injected into people, it creates malaise, headache, loss of appetite, insomnia and muscle cramps. It is possible that some of these symptoms are actually arising from increased internal secretion of DOH-DOC which may be resulting from retention of sodium and loss of potassium implied in the use of DOC injections. It is unlikely that the DOC is causing these symptoms directly because they do not appear when a diet high in sodium and potassium raises DOC in the body. The body may be using DOH-DOC to create some of those symptoms and feelings in order to help to protect it during diarrhea. If DOH-DOC is important during diarrhea as I suspect, it could be that ACTH inhibits it, and thus stimulates it upon ACTH's decline, or at least has no effect. I know of no information on this. CONCLUSIONS By secreting various ratios of the above steroids in conjunction with renin, the angiotensins, ADH water retaining hormone, thirst and unknown supporting hormones, a fairly accurate fine tuning should be possible of sodium, potassium, serum volume, osmotic pressure, and blood pressure. The cell status is maintained largely by controlling the serum [60]. I suspect that the distant ancestors of man evolved primarily as fruit, nut and leaf eaters of broad leafed plants, using meat as a fortuitous supplement. The tooth design is almost conclusive evidence of a herbivore, the salivary gland which dissolves starch is strongly suggestive of nuts, and the present day eating preferences of most people is supportive of broad leafed (dicotyledon) plants. If so, and I am right above, we are organized around aldosterone. I suspect that when we depart from this possibly ideal state for any length of time, we lay ourselves open to the statistical chance of degenerative diseases because our other physiological processes are geared to this hormone balance. I suspect that case #2 may be associated with the form of hypertension which is hard to reverse. The reason I suspect this is that DOC is associated with increased synthesis of collagen [61] and it is possible that that tends to increase the thickness of artery walls and decrease their elasticity. Case #3 is probably furnishing some of the symptoms of rheumatoid arthritis since there is a consistently low whole body potassium content in this disease [62] and personal experience is supportive. However, it is probable that the bulk of the symptoms manifest themselves through cortisol status because this hormone is reduced in its secretion by the effect of low potassium on the zona fasciculata [63] and because cortisol removes many of the symptoms of arthritis. The amount of potassium to heal rheumatoid arthritis must usually be 3.5 grams/day or more because this is the amount which permitted slow improvement of a man across a three month time span [64], assuming his sodium intake was normal. Black people receive 1.5 grams/day and white people 2.0 grams/day in Georgia [65]. Vegetables are the richest source of potassium and vegetables have been used successfully to heal rheumatoid arthritis [66]. I suspect that most of the people who have rheumatoid arthritis, especially young onset, have had their kidneys damaged by poison or disease in such a way as to make them less efficient at retaining potassium or too efficient at excreting it. I suspect bromine gas, for instance. Childers has proposed poisons in tomatoes, potatoes, egg plant, and peppers [67]. Some infectious diseases may have a similar effect. Case #4 may prove to be associated with degeneration of heart and kidneys, but based primarily on nutritional statistics. It is also possible that it plays a role in suppressed renin hypertension, since there is increased secretion of DOH-DOC in all cases of that last disease [68]. There is no evidence I know of that the DOH-DOC itself causes the damage. Pregnant women increase their DOC secretion 10 times by the end of the pregnancy [69] and have a markedly higher secretion before the onset of menstruation [70]. It may be that the larger secretion of progesterone which takes place at these times [71] makes necessary the enhanced secretion of DOC by virtue of progesterone's interference with DOC's primary purpose. This erratic secretion may have something to do with the much larger rate of arthritis among women. It is not difficult to envision a problem if such large swings became even a little misregulated or had to handle odd electrolyte intakes of sodium and potassium. Modern nutritional professionals are all convinced that potassium is adequate in all diets and that a deficiency never materializes except occasionally clinically. Nutritional texts reflect this view both in the amount of space devoted to potassium and its content. When potassium supplements are prescribed they get around the discordance between their convictions and practice semantically by calling the supplements " salt substitutes ", " polarizing solutions ", " pharmaceutical effects ", " ORT salts ( oral rehydration therapy ) ", or similar terms. Nevertheless, there are numerous circumstances which can cause potassium to be ominously low in the diet or cause excessive excretion. I have already mentioned diarrhea, the most common and dangerous circumstance in nature. Potassium supplements to babies brought mortality from a virulent strain of diarrhea from 35% to 5% [72]. Numerous experiments have shown that potassium supplements are very important for recovery from heart disease [73]. It is not possible to produce heart disease in animals with any known poison unless potassium is also deficient [74]. It is important to know whether the heart disease is caused by potassium deficiency or vitamin B-1 deficiency because heart disease can not materialize in rats if both are deficient [75]. Therefore it is probable that potassium supplements or a high potassium diet to a patient with the" wet " heart disease of beri-beri would kill him. Psychic stress stimulation of aldosterone [76], stress stimulation of cortisol (an operation, for instance) [77], profuse perspiration [89], excessive vomiting [78], eating sodium carbonate or bicarbonate (because hydrogen ion is excreted at the same site as potassium) [79], laxatives [80], diuretics [81], licorice [82], hyperventilating [83], enemas [84], shock from burns or injury [85], hostile or fearful emotions [86], and very high or low sodium intakes [87] all increase potassium losses, some massively. All together would probably be lethal in a fairly short time. Reliance on grain (especially white flour) or fatty foods, boiling vegetables, use of chemicals (soft drinks for instance) instead of food, and use of most processed foods including frozen and canned permit considerable reduction of intakes. So does the reduced appetite associated with a sedentary life. To speak of potassium deficiency as an aberration when enormous numbers of people are affected by these circumstances is not logical. Even if a serious degenerative disease does not materialize, an adequate intake is desirable to forestall future disasters and to permit one to operate at optimum. Some of the manifestations of the placebo effect become understandable in light of the effect of emotions on hormones. However we can not always be assured of a placebo being available, certainly not on the firing line, but not even for that matter in the quiet of a hospital where even nurses can be testy at times. While understanding the hormonal basis for electrolyte control will not always have a practical nutritional application it is nevertheless important that it be well understood. Unless the medical establishment understands the physiological basis for nutritional strategy it will never accept programs with any ardor based on vague nutritional statistics alone. Also, if it did, some patients would slip through the cracks as we have seen in the potassium vs vitamin B-1 interaction. Also, sometimes clinical intervention is essential for genetic or cancer malfunctions of the hormonal systems or to help correct massive assaults of poison or injury. It is well to realize clearly what is happening. The abandonment of aldosterone for DOCA may not prove logical for all cases. For instance Potassium is the main problem in shock, yet texts about shock don't even so much as mention it. Our nutritional strategy and even our philosophy of life is entwined with understanding hormones. It is especially important that nutrition be established by experiment. Currently every one in the medical establishment is convinced that potassium deficiency can not be involved in rheumatoid arthritis, but this without an experiment ever having been performed. It simply is not possible to predict the outcome of an experiment without performing it. It would be desirable to determine the effect of every food common in commerce not only on arthritis but on all the degenerative diseases. Some foods known to be poisonous to animals or have poisonous related species in the wild have been used for thousands of years without ever having been tested. This is undoubtedly due to a universal quasireligious instinctive conviction that foods our parents taught us to eat or taste good could not possibly be harmful. This is not the case. Such experiments could have another advantage in that they might uncover foods which have a beneficial effect. Even small effects would be worth knowing about. The above instinctive conviction is so strong that most people will not eat nutritious food if tastier, less nutritious food is available. Their instincts override their intellect not only in their eating habits but in their scientific efforts. REFERENCES See J. Theoretical Biology 104; p443, 1983.
Charles Weber
Hendersonville, nc USA-Monday, December 15, 1997 at 08:13:09 (PST)