Arthritis and Potassium

ARTHRITIS as a CHRONIC POTASSIUM DEFICIENCY, chapter I

This site introduces a discussion of potassium nutrition and physiology especially as pertaining to rheumatoid arthritis.

OTHER CONTENTS II. Arthritis Research -- III. Arthritis and Potassium -- IV. Roles of Potassium in the Body -- V. Electrolyte regulation (sodium and potassium) -- VI. Purpose of cortisol -- VII. Copper nutrition and physiology -- VIII. Nutritional Requirements -- IX. Potassium in Foods -- X. Processing Losses -- X,cont. Losses in the kitchen -- XI. Supplementation -- Side Effects and Heart Disease

It is my contention that potassium deficiency is either causing, or greatly making worse, rheumatoid arthritis which I will shorten to "arthritis" in this article. In assessing the possibility of this hypothesis people have little to go on. Virtually any textbook in the past would devote no more than a paragraph to potassium which would state that potassium is never deficient in the diet, or give one exception to the dozen or more known, or in some only under clinical conditions.

The reason for this careless treatment of potassium is probably because potassium is present in almost all foods as grown in large quantities. Professionals think about it as if it were air or water. However even air and water can be deficient and if voluminous texts are not written on their deficiencies, it is because both deficiencies can be detected by our senses. Extremely powerful emotions and instincts impel people to correct these deficiencies immediately and at any cost. Potassium is odorless, colorless, and, in the usual concentrations, tasteless. There is no way to detect a deficiency and cell content can not even easily be assessed in the body by modern analytical procedures. Whole body cell content is virtually "invisible".

There is not any indication in the literature that potassium has ever been tried by scientists as an arthritis corrective. A rather exhaustive search of the medical literature has failed to disclose an experiment. This includes Exerpta Medica 1947 to 1974, and a computer search by the Central Library of the American Medical Association from 1965 back.

I will discuss potassium physiology and nutrition and what can be done to remove an actual deficiency and thus heal any tissue which has not actually been destroyed. If you do not know the meaning of a word in this article, for a definition click on http://www.m-w.com (Mirriam-Webster).

Please keep in mind, though, that potassium ramifies through every cell and process in the body, has no storage, and has a dangerous dependence on its precise control by nerve impulse transmission. This makes it a mineral to be cautious about. In particular I recommend getting as much as possible from food. Even food requires some care because it has a wide range of concentrations. You must take responsibility for your own intake and I assume no liability for the correctness of advice in this article. You use this information at your own risk.

Getting potassium from food is reasonably safe for normal people with reasonably sound kidneys. Even if you doubt my thesis of a connection between arthritis and potassium, you have nothing to lose by getting all the potassium that was originally in your food. It will even taste better. It will, in addition, help protect you from potassium's known link to heart disease. As the 12th century physician Maimonides expressed it: "A doctor should begin with simple treatments, trying to cure by diet before he administers drugs. No illness that can be treated by diet should be treated by any other means."

Anything a doctor can learn, you can also. There will be a list of definitions eventually which will make the difficult words much easier eventually. In the mean time one of the online technical dictionaries may do.

INTRODUCTION

Arthritis is the number one crippler in America. The estimate for rheumatoid arthritis is 43 million men, women and children and at least 65 billion dollars lost each year currently. Two thirds of the victims are women, most of them over 45 [Rodman]. The terrible pains associated with arthritis, reminiscent of and similar to the medieval torture racks must surely be among the top causes of contemporary misery. These pains along with the actual physical disability, weak joints, and loss of energy which accompany them, cause an enormous loss of productivity, estimated to be over six billion dollars in 1978 [Arthritis Foundation]. Arthritis may be a considerable part of the cause of increasing welfare roles. Even industrial accidents are related to this monstrous and onerous burden that society carries. Small jolts and falls which should do little more than bring out some colorful language results in loss of hours and even months. It is more than just the loss of time itself. It is also the super caution that blocks even fairly healthy people from making fast, risky moves when they see some of the debacles their friends get into.

Nor is arthritis confined to North America. Countries at such extremes of latitude as Finland and Jamaica have even higher rates than we do [Kellgren]. The simple life is not any guarantee against misery either. The Masai tribesmen of Africa have high rates [Best p768]. Political or economic ideologies are not barriers. Arthritis crosses the iron curtain, is also present in nomadic hunters, and cave men, cave bears, and ancient Egyptians are thought to have had it [Bach][Crain]. It shows no obvious clear association with any culture even though it is very variable, with low rates in tribes near the Masai and Laplanders near the Finns in Finland, as well as insane people in Massachusetts {Allander p260].

Most of the people who have pains in the joints have them because of arthritis. The pains usually strike first in the outer joints like fingers or joints with a history of injury. Load bearing joints are also vulnerable. The pain is most likely in the early morning. It is often accompanied by stiffness. It is not to be assumed that the disease is localized because the pain is, Arthritis is present throughout the body and can affect kidneys, pericardium of the heart, and connecting tissue [Strukov][Ropes]. It is a disease largely associated with humans [LaMont-Havers], probably partly because animals can not talk, but I suspect primarily because animals usually do not have access to refined food. Arthritis has few externally observable symptoms, especially in early stages. There are no known consistent biochemical changes in arthritis (which word in this article will be equated with "rheumatoid arthritis") except a much lower cellular potassium content than normal [LaCelle], and a higher copper content along with a protein which binds the copper in the serum [Schubert]. There has been an effort to use changes in some of the body's other proteins in diagnosis, but with limited success so far, although some of the other rheumatic diseases can be almost diagnosed from blood proteins alone [Waller]. As nearly as I can tell this seemed to be the consensus for arthritis at the 1982 Pan American Conference on Arthritis. There are significant correlations between IgM RF and IgA immune proteins and a higher disease activity [Chen] but the correlations are not perfect. C3 and C4 compliment are said to be the best of the other discriminators.[Sari, et al]. Arthritis sometimes has fatigue associated with it.

In the past arthritis was associated with old age in people's minds and there was a tendency to suffer it stoically as inevitable. While the medical profession has intellectually abandoned an assumption that only people in old age are affected, many laymen still assume this is the case. The concept that this is "old age" is pervasive, even creeping into common cultural media as modern as "Star Trek". This is not to indicate that the victims did not often attempt to do something. Arthritis has a long history of quack nostrums and screwball procedures. These quack remedies were assisted by the numerous spontaneous remissions that occur with arthritis or by pain deadening chemicals. It was not necessary to cure everyone, since those who were "cured" were very grateful and those who were not were fatalistic, since their doctors could do nothing either.

It is my contention that arthritis is either a potassium deficiency or is strongly affected by one. I suspect that some poison or some infections or decline in kidney function with age degrades our ability to concentrate potassium and thus makes it impossible to eat the food from which almost every processing procedure removes potassium these days. Arthritics characteristically have poor nourishment {Morgan et al]. One such poison which I suspect is the very poisonous bromine gas, since it probably affected me that way 50 years ago.

One technique which seemed to have some success was the use of spas. At least their popularity would seem to indicate some success. That king sized spa, the ocean, has been given credit for anti-arthritic tendencies also. This is plausible because the ocean contains potassium in about the same concentration as blood fluid. The spa at Bath, England, has a potassium content less than one tenth that of ocean water [Riley]. If it is typical of spas, then unless they were drinking the water, it is hard to see how it could have helped.

There have been closer associations with potassium. At one time sulfurated potash was used to combat arthritis [Osol p1092]. It is not surprising that it fell into disfavor associated with such a poisonous anion. An anion is a negatively charged substance which neutralizes the positive charge of an ion like potassium. The first person to definitively link potassium to arthritis in no uncertain terms was DeCoti-Marsh in a book published in England in 1957 [deCoti-Marsh]. He claimed numerous case histories. He recommended a whole pot-pouri of anions to go with the potassium, some of them not nutritional, and some even poisonous. He attributed magical properties to these anions. His approach was reminiscent of the writings of ancient alchemists.

A more successful technique was the raw vegetable diet described by Holbrook in Europe during the forties [Holbrook]. This diet became quite popular, even though most people must have found it fairly unpalatable. Eppinger hinted that the success of this diet may have been due to its high potassium content [Eppinger]. It might have become more popular if a recommendation to use fried vegetables, soup, or to drink the boil water had been made, which would have permitted the same potassium intake. There have been experiments with vegetarian diets in recent years but they have been changed merely by removing meat from the diet which is probably why only moderate success has been attained.

At the present time there are several books relating diet to arthritis. Jarvis stresses honey and vinegar in his book [Jarvis]. Since honey is extremely low in potassium, it would be counter productive. The vinegar could be very beneficial if well fed people are failing to metabolize all of the acetate ion because the acid hydrogen ion interferes with potassium at the excretion site as will be developed later. I know of no tests reported in the literature testing this concept. Jarvis hints at other dietary changes also, which if followed, would increase potassium intake inadvertently.

Dong and Banks prescribe a diet free of chemicals, milk, meat and sugar, and low in fat [Dong]. If his diet were followed it would definitely increase potassium intake, especially since he stresses unprocessed vegetables. However, he attributes its success to freedom from allergens and chemicals, so that philosophically he tends to be in the same general physiological category as the autoimmune hypothesis is in, to be discussed later. I am fairly certain that those who have success with his diet do so because of the lucky quirk that potassium increases at the same time. I think a good case could be made for keeping chemicals out of food. Some, like sulfite which destroys vitamin B-1 are known to be harmful, some like dyes and nitrites are fraudulent and\or harmful. I doubt if removing them would have more than a small affect on arthritis though. Alexander recommends vitamin D against arthritis. However like Dong he also speaks of low sugar and raw vegetables [Alexander]. I doubt if the vitamin D had much affect on arthritis, although those using his diet must have had less trouble with tooth decay, tuberculosis, and rickets.

Allergy has been proposed as a possible cause but stressing allergens naturally present in food. It is quite conceivable that allergens damage the kidneys' ability to retain potassium. However, no one has established this yet. There is good evidence, though, of beneficial results from defeating allergy in specific cases.

Evidence from individual case histories and the known characteristics of potassium physiology supports the proposal that arthritis is either a potassium deficiency or that a deficiency is its most important symptom. The replete body contains about 75 times as much potassium or more as is usually in the processed diet, so if it is increased, it will still take quite awhile to come up to normal. However there should be satisfying initial results in a month or two or even less.

I have been almost alone in proposing potassium as being central to rheumatoid arthritis (but see Dr. Jan de Vries' article). . However there is no substitute for an experiment, which has never been done. While you are waiting for such an experiment there is nothing stopping you from eating nutritious food and making sure you do not lose any of the potassium by your own preparations. I wish you good health.

CONTENTS of other chapters Back to INTRODUCTION chapter -- II. Arthritis Research -- III. Arthritis and Potassium -- IV. Roles of Potassium in the Body -- V. Electrolyte regulation (sodium and potassium) -- VI. Purpose of cortisol -- VII. Copper nutrition and physiology -- VIII. Nutritional Requirements -- IX. Potassium in Foods -- X. Processing Losses -- X,cont. Losses in the kitchen -- XI. Supplementation -- Side Effects and Heart Disease

For years arthritis was the poor relation of medical research. Its victims did not do something dramatic like die, as they often did with pneumonia, or go insane as they did with syphilis, or bring tears to the eyes as with childhood diphtheria, or have nice bright , easily recognizable symptoms as with measles. Arthritis tended to be a disability of old folks with vague, sometimes disbelieved symptoms. That has changed and extensive , well funded research is being done now. Forming the backdrop of this research are several hypotheses, some borrowed from research into other diseases, and some with a novel twist of their own.

One of the oldest of these is the stress hormone hypothesis championed by Selye [Selye 1949 & 1950 p197- 198]. Roughly his contention was that hormones released by the body, especially those released by the jacket of the adrenal glands, cause an adverse reaction to the joint tissues when they are released in too large amounts or the wrong ratios under conditions of environmental stress or psychic stress. His concept was generalized, and only mentioned arthritis as an unlikely possibility. The theory had some plausibility since arthritis can be produced by injecting deoxycorticosterone into a person who has been suffering from Addisons's disease or into animals [Selye et al 1944][Turner]. Some support is given to this approach in that repressed hostility is probably correlated with rheumatoid arthritis [Cobb]. The dramatic affect that cortisone has on arthritis, removing all symptoms in a short time, would give encouragement to a scientist trying to approach this matter from Selye's viewpoint. This hypothesis has never been refuted although it has fallen into disfavor recently. This is probably because some rather severe side effects materialized eventually when medical people used cortisone for a long time. As one author put it "It is remarkable how cortisone can get a seemingly hopeless patient on his feet again. Sometimes it is so effective that he can walk all the way to the autopsy table." Cortisone changes to cortisol which reduces resistance to infection, suppresses fever, causes polyarteritis nodosa (a blood vessel disease), and suppresses collagen synthesis. Stress theories did not always emphasize steroid hormones. Histamine was suggested as possibly being involved [Eyring].

A group called "Arthritis Medical Information Society" had revived this concept. They claim cures using a "balanced" regime of injected hormones, hormones which include the steroid testerone, a sex hormone. They claimed a preponderance of anabolic hormones prevent side effects. They also recommend better nutrition which I suspect was having the major effect.

McCord has proposed that arthritis may be caused by insufficient amounts of superoxide dismutase, an enzyme catalyzed by copper [McCord]. Copper supplements either as pharmaceuticals [Sorenson 1980] or as copper bracelets have been proposed with encouraging results

Because of the dramatic successes that scientists had in their battle against bacteria and virus, it is not surprising that these men should turn their attention to finding an organism which was responsible for arthritis . The fact that some infections could trigger an attack of arthritis must have given them encouragement. Also it is possible for joints to become directly infected, but the symptoms of this fairly rare condition are not exactly the same as arthritis. It causes skin rash, large lymph nodes, fever, and often affects the kidneys and heart * However an exhaustive search has not disclosed any microbe consistently present in inflamed tissue* although some investigators believe that an amoebic infection is involved.

The most popular current hypothesis is the auto immune hypothesis. This hypothesis proposes that the body's mechanism for killing disease organisms gets out of order, and starts killing connective tissue cells or perhaps dissolving the connecting tissue itself. Moderately high statistical associations between arthritis and physiological circumstances which are closely related to the immune system have given investigators all over the world encouragement. Many do not even regard the concept as a hypothesis, but as a proven theory. A much higher association of antigen HIA-B27, which is a known immunity factor, with diseases in the arthritic group such as Reiter's syndrome and ankylosing spondilitis [Mikkelsen] has tended to reinforce this feeling that they are on the right track. Investigations into the auto immune hypothesis are well funded.

It would seem strange that mesenchyme tissue (tissue derived from the middle layer of the embryo) is primarily affected, that it would take so long to be destroyed, or that there would be spontaneous remissions if the auto immune hypothesis were valid. At the very least some auxiliary hypotheses would be necessary.. Millman has proposed that some of the cell wall off of bacterial invaders become incorporated into the collagen [Millman]. Effects of steroid treatment may be due to inhibition of arachidonic metabolic cascade (the prostaglandin hormones) especially to leucotrienes, which are thought to activate macro white cells [Nalbandian]. The number of white cells can rise extremely high in arthritis [Meyer]. The hypothesis seems plausible but attempts to adapt it to diagnostic techniques have been unsuccessful. There have been medicines proposed which dampen the immune system, but most of them cause the joint damage to get worse in the long run.

There is a hypothesis that the enzymes inside the lysosome sacs inside the white cells are released because of weakness. This may be happening when sodium urate crystals are ingested by the white cells in gouty arthritis* but evidence for it in rheumatoid arthritis is inconclusive.

The hypothesis that arthritis is an allergy is in the same general category as the auto immune hypothesis. Such a hypothesis has the advantage not shared by the auto immune hypothesis directly of advancing an environmental factor which is almost certainly involved. The wide geographical variations already mentioned in chapter I virtually ensure this. Turnbull has had impressive percentages (50%) of arthritics improved by removing certain foods from the diet [Turnbull]. Others claim success by removing environmental poisons such as cooking gas [Randolph]. Anderson has been successful in removing a bad case of allergy by removing lustidine and sodium from his diet. However he removed sodium by adding potassium [Anderson]. Medical people do not pay much attention to this hypothesis even as a diagnostic approach. The references on allergy often mention this, and it appears to be true of most of the literature. Zussman, who improved four arthritics this way, could not believe he was dealing with arthritis or was afraid of ridicule, and so entitled his article "Food hypersensitivity simulating rheumatoid arthritis" [Zussman]. Allergens in food is Dong's hypothesis as mentioned in Chapter I [Dong], but he has no controlled experiments to verify his contention other than the general population being a control.

Allergy is without a doubt part of the arthritis picture since arthritics have two to three times as much allergy as average [Zeller]. White cells respond to human nuclei challenge with 3.5 times as much histamine production in arthritics as normal people [Permin]. At one time a hornet's sting caused me to break out in a rash and swell up tremendously. More recently numerous stings from wasps, yellow jackets, and a hornet caused nothing but a sharp moderate pain and irritation for a day or two resembling a mosquito bite. A genetic defect making me incompatible with hornets would surely still be with me. I put bicarbonate of soda (baking soda) on the sting immediately now, but it does not seem possible that this alkalinity would have an effect on an allergic response remote from the wound. This allergic attack preceded my bout with what was probably arthritis.

Similar in practical application to the food allergic hypothesis, but probably physiologically different, is a hypothesis put forward by Childers. He maintains that poisons in the solenaceous family are causing arthritis [Childers]. This is the night shade family and includes tomatoes, potatoes, pepper, egg plant, and tobacco. He suspects a chemical similar to vitamin D in its structure, or possibly one of the solenine alkaloids. If this hypothesis proves valid, it is possible that a substance similar to deoxycorticosterone (DOC) contained in these plants will be found to be responsible [Childers]. A poison which interferes with copper metabolism is another possibility. Smoking is known to cause emphysema, which is in turn known to be caused by a copper deficiency. Childers has had 70% of his volunteers report improvement by deleting these vegetables. However only 30% responded to his survey [Childers, private communication]so these figures could be as low as 25% and 10% respectively. Unless arthritis has more than one cause or is misdiagnosed, even 70% is too low to establish anything as a primary cause. While the causal evidence is not excellent, the evidence is good enough to persuade one to remove these vegetables from one's diet while symptoms of arthritis are present. There are plenty of other vegetables. Also never eat green or sprouting potatoes raw. Green potatoes have a very virulent poison, virulent enough to kill some people. The poison is destroyed by frying and baking but not by boiling. Also useful to know is that most of the solenines are close to the skin and possibly the other poisons as well [Childers, inside addenda].

Not surprisingly infections have been searched for as causal to arthritis. I know of no infection which has been proven to chronically inhabit the joints. Infections are known to trigger arthritis, however., and tooth abscesses can cause shoulder bursitis.

These hypotheses are not necessarily mutually exclusive. Potassium is an element which is essential to every cell in the body. It and sodium are controlled by at least five steroid hormones, several peptide hormones, and some molecular hormones. It would not be surprising that more than one disease syndrome could arise from a deficiency considering that in addition to that, the twenty five or more essential nutrients are often either deficient or wildly oversupplied in our society as well. Considering the last statement it would not be surprising either if fuzzy, inconclusive results are obtained with both nutritional experiments and medication. With such a complicated physiological situation as potassium you must surely see why I will always recommend that nutritional solutions be attempted by eating unprocessed food rather than supplements whenever possible. Thus imbalances tend to be avoided as well as other deficiencies.

I will attempt to explain potassium physiology especially as it pertains to arthritis and heart disease, how it can be changed in the diet, how it may be interacting with copper, how it can be supplemented, and dangers associated with its use in succeeding chapters. I am convinced that a perceptable improvement can be had in a few weeks even with food alone and potassium can be brought to normal in a few months for most people.

I am alone in championing the potassium hypothesis among scientists at present. You hardly have to wait until the last word in research has been unraveled in order to take steps to at least get all the potassium that was originally present in your food. There could be endless debate in scientific circles as to which fang the poison came out of in snake bite, or its exact chemical composition, or its mode of action. However this should not prevent one from staying away from the head end of a snake, even a non poisonous one , until such time as the matter were resolved in detail.

Most of the recent research has centered around the autoimmune hypothesis or in developing medicines which deaden pain. Unfortunately many of these medicines have had bad effects from the medicines.

ARTHRITIS AND POTASSIUM Chapt. III

It is proposed that the low cell potassium (whole body potassssium) always present in rheumatoid arthritis should be relieved.

CONTENTS of other chapters Back to INTRODUCTION chapter -- II. Arthritis Research -- III. Arthritis and Potassium -- IV. Roles of Potassium in the Body -- V. Electrolyte regulation (sodium and potassium) -- VI. Purpose of cortisol -- VII. Copper nutrition and physiology -- VIII. Nutritional Requirements -- IX. Potassium in Foods -- X. Processing Losses -- X,cont. Losses in the kitchen -- XI. Supplementation -- Side Effects and Heart Disease

The author, Charles Weber, has a degree in chemistry and a masters degree in soil science at Rutgers University. He has researched potassium for over 40 years, primarily a library research. He has cured his own early onset arthritis.

isoptera@angelfire.com

It has been determined by LaCelle that the whole body potassium is significantly lower in older arthritics. The body can sink to almost half of normal in some cases [LaCelle]. These determinations were made using a whole body scintillation counter. A scintillation counter is an extremely expensive machine which can count the number of x-rays emerging from the body as a result of the radioactive decay of one of the potassium isotopes, K-40. These machines cost well over $100,000 each. Potassium in the body cells is not often determined for patients because of the enormous cost of the equipment. Other methods for determining cell potassium involve biopsies, balance studies which must be conducted for long periods to get valid results [Lambie], isotope dilution studies which are almost as cumbersome [Jasani] and have difficulties with unreliable erratic diffusion to body components. Welt claims to be able to predict cell potassium from serum potassium if a formula is used which uses other ions, especially hydrogen ions (acid) [Welt 1958]. I am skeptical that it is always reliable. It is the case, though, that if for some reason the serum is more acid than normal, even small drops in serum potassium indicate significant lowering of cell potassium [Surawicz][Ono]. However in most cases when cell potassium is low the serum potassium is usually low also [Nickel]. A method has been developed which promises to be accurate and not too cumbersome. This involves the separation of white blood cells out and their subsequent analysis [Patrick]. So far as I know it is not used much. The upshot is that potassium is largely invisible to doctors.

LaCelle's finding is very significant. Even if one assumed that the arthritis caused the potassium content , rather than the other way around, it would seem good common sense to bring such an important mineral up to normal. It is strange that this finding has not created more interest, as a diagnostic clue if nothing else. Even if scientists are not interested, there is nothing stopping you from at least getting all the potassium that was originally in your food.

One can not draw sure conclusions from low potassium serum of the blood content alone and is dependant on the status of hydrogen ion and chloride. The reason is that plasma can have wide swings in content. However, 80% of people with rheumatic heart disease have low blood plasma content [Sokolov]. Even cell content is not certain proof all by itself. What is needed is a controlled experiment in which only potassium is varied. There never has been such an experiment for arthritis. However there has been an experiment performed by Schick on one of the arthritic diseases of the arteries called polyarteritis nodosa which was indicative. Unfortunately cortisone was administrated at the same time so the experiment was flawed. However, everyone given 1.5 to 3 grams of potassium supplements per day had a complete healing of all arteries [Schick]. There is also a single case history in which a subject was injected with various steroids to determine their effect. The only consistent thing that happened during the course of the experiment was that his daily intake of potassium was raised. His arthritic symptoms showed a consistent improvement throughout the course of the experiment [Clark]. Now an as yet unpublished experiment has been performed by Rudin in which potassium supplements showed favorable results on eight patients.[private communication]. In an experiment unrelated to arthritis, serum potassium was not improved with 1 gram of potassium per day unless magnesium was supplemented also. Perhaps an experiment supplementig both would be in order in the future for arthritis in order to get crisper correlations.

One of the arthritic diseases is known as gouty arthritis in which sodium urate crystals are deposited in cartilege, especially in the feet. Gonzalex has statistical evidence linking gout to lead poisoning. The lead poisoning makes the aldosterone system insensitive to potassium concentration and increases the potassium content of the blood plasma [Gonzalex]. I have no information in the medical literature on any direct link between gout and a potassium deficiency. I have a strong suspicion that there is a link however. I have heard of a doctor who gave his patients potassium losing diuretics and thus triggered an attack of gout. By adding a potassium supplement he was able to remove the gout. William Ellis has used potassium supplements for years for gout [private communication]. Gout can be triggered by the same agents which cause potassium losses such as fasting, surgery, and potassium losing diuretics [Rodman]. A potassium deficiency can increase urate levels in the blood [Davis][Halla] so there is a circumstantial connection. The initiating factor is probably usually lead poisoning though [Wright]. There is an association in peoples minds between gout and rich foods and lifestyle probably because people with gout have trouble excreting nitrogen, which is high in meat, in a soluble form and perhaps also because wine bottles and plumbing used to contain lead. Until such time as the matter is elucidated it would be a good idea to stop eating lead, eat less proteins, and not allow any potassium to be lost from one's food. There is a discussion of current treatment for gout online.

Osteoarthritis can not be corrected by potassium, or at least by potassium alone [Jones].

You must be thinking that surely scientists must have created deficiencies of potassium and observed their effects. This is indeed true, at least with animals. Experiments with humans are extremely dangerous since permanent damage can be inflicted on the heart and kidneys [Rubini 1961]. I know of no long term experiments on people. Arthritis is difficult to diagnose in animals since they have no way of describing pain, and since there are no sure laboratory tests for arthritis other than potassium, which we already know is going to be low in a deficiency. Also the most common experimental animals, rodents, do not use cortisol, as will be discussed in later chapters.

Acute symptoms can be detected by laboratory methods. Acute symptoms can begin to materialize when as little as 15 grams (10%) out of the approximately 150 grams of potassium normally present in an adult male are missing. Numerous animal experiments have revealed the following symptoms:

The fluid (serum) of the blood becomes lower in potassium, chloride, and acidity [Luke][Gardner 1950]. The serum potassium declines along a curve which becomes asymptotic cell content axis at about 50% loss of cell content and a little over 1 mEq per liter [Scribner (with a graph)]. Scribner and Burnell use 40%, but their designation of normal is too low for humans at about 4 mEq per liter which should be 4.8. Average in our society may be near 4.0 but 4.8 is optimum. At this -50% point much further reductions will result in death. His graph assumes normal renal function, insulin, and pH (hydrogen ion). Aldosterone decreases about six fold at low sodium intake [Baumann]. The blood volume, pulse, pressure, and body weight often decline [Gann]. Low serum potassium results in a lower T wave which are rounded and prolonged, as well as slightly prolonged Q-T interval, depression of S-T segment, and possible inversion of P waves.[American Medical Association p 455]. The plasma carbon dioxide, cholesterol triglycerides, urate levels [Davis], and renin [Abbrecht 1970][Sealey], which last is a hormone related to blood pressure, often rises. The loss of pulse pressure is probably a function of potassium inside the cell, rather than serum potassium [Abbrecht 1973]. A glucose intolerance develops exclusively associated with lower insulin secretion rather than cellular response to insulin [Rowe][Gardner 1952]. It could be an adaptation to avoid low plasma potassium resulting from the potassium entering into the cell in order to associate with glycogen which would otherwise occur. Low cell potassium can inhibit the insulin response independently of serum potassium [Spergel]. Apparently the glycogen in the liver increases though nevertheless [Marcus]

The gastric secretion decreases in acidity and in potassium content, and increases in sodium content [Welt 1960 (this is an extensive review)]

The urine usually shows a reduced excretion of the organic negative ions such as citrate [Evans]. Since this excretion may be a mechanism for helping to conserve chloride, this may explain the reason for some of chloride reduction mentioned above. It may be an adaptation to avoid too much acidity when a strong base forming ion like potassium is lost. Chloride wasting starts when 20 grams of potassium out of 150 are gone [Garella]. Most of the chloride reabsorption is said to occur in the ascending limb of the Henle tubule via the sodium-potassium-2chloide cotransporter and most of the chloride reabsorption in the distal tubule is by thiazide sensitive sodium - chloride cotransporter [Amlal]. These transporters are inhibited during a deficiency [there are diagrams in Amlal's reference]. Something like this would be necessary in order to prevent the chloride from making the plasma acidic when sodium entered the body's cells to take the place of potassium.

There are several enzyme systems in the kidneys which are affected by a deficiency. The enzyme which reduces the amino acid glutamine to ammonia is one of them and its activity is increased [Wohl p832][Rector][Brown][Tannen]. The ammonium ion has a positive charge and is about the same size as potassium. Therefore this may be a mechanism for helping to prevent potassium loss by substituting ammonium. The ammonium is said to be synthesized in the mitochondria of the proximal tubule cells, excreted in part by the sodium/hydrogen ion exchanger (NHE-3), then reabsorbed by the sodium- potassium-chloride cotransporter, and then brought to the collecting duct and excreted [Amlal]. I have not been able to find out which hormones regulate chloride excretion, if any. Fortunately getting enough potassium in food is not nearly as complicated as what happens to it after it arrives in the body.

Active excretion of potassium virtually ceases in the kidney tubules after two days on a low potassium diet*. A small part of the potassium which originally entered the kidneys through the glomerulus continues to be excreted, and potassium loss can not be completely cut off. The ability of the kidneys to conserve sodium is impaired.

Urinary excretion of calcium, magnesium and phosphate is higher during a potassium deficiency in Dahl rats. It is thought that the reduction of magnesium is what causes the association of potassium with hypertension by virtue of the affect of magnesium on the power of the potassium-sodium pumps [Potassium depletion and salt sensitive hypertension in Dahl rats: effect on calcium, magnesium, and phosphate excretions.] Six months are required of magnesiumm supplements before complete normalization of pumps [Potassium and sodium, and potassium pumps in the skeletal muscle]

The fluid inside the cells shows a decrease in potassium, alkalinity, and phosphate [Gardner 1953]. Part of the lost potassium inside the cells is replaced by sodium [Rubini 1972]. Arginine [Iacobellis] and lysine [Eckel], which are amino acids having a positive charge, show a marked rise in the fluid of some cells in some animals, going from almost zero to 8% of the positive ions. Adequate potassium has been shown to be necessary for protein synthesis [Cannon 1951]. There is considerably less protein metabolized in deficient chicks [Rinehart]. The positive ions calcium and magnesium increase inside the cells [Gardner 1950]. If these are adaptations to solve a potassium deficiency, such elaborate mechanisms are an indication that potassium is much more of a problem in nature than medical people think, let alone in our potassium starved society. DNA synthesis inside the muscle cell is decreased during a deficiency [Truong].

An abnormal thirst is also thought to be frequently present in a deficiency. Increased water intake rises to a peak in dogs in 3 to 7 weeks, then declines to normal [Smith]

Perhaps it would be a good idea to determine as many of these circumstances as is possible without a biopsy while people are healthy so that when they become sick the potassium status can be easily estimated without expensive machinery or long time delays.

I can not be certain that all the phenomena above are caused by an acute deficiency in humans, but most are quickly and easily reversible. Most of the data which do not require analysis of internal organs have been confirmed in humans. Effects which are not easily reversible or involve structural changes in the body's cells are as follows:

The part of the adrenal gland (zona glomerulosa) which synthesizes aldosterone atrophies [Cope p432]. Fat is deposited in the vascular system. This deposition is probably reversible [Davis][Strauss]. More serious is lesions of the kidneys in hypertensive salt loaded rats and permanent scarring of the kidneys which is probably irreversible [Holman]. Welt believes that the consensus is that kidney damage is reversible, however, and is largely in the tubules [Welt 1960]. Small particles in the cell called ribosomes have the internal structure lastingly altered. Mitochondria of the collecting tubules swell and disrupt [Kark]. Certain cells in the kidneys which have a darker color than the others increase in numbers. There is also abnormalities in the structure of other kidney cells [Rhodin][Naslund][Strauss]. Cells in the lining of the tubules are most affected in dogs [Tate]. The above is based on animal experiments. Man rarely has kidney destruction which appears the same as the rat's or dog's. Localized death of heart cells is usually found in the species observed [Rowinski][Folis][Molnar] but is not always obseved in every individual [Tate]. Heart lesions from a potassium deficiency are well established. They depend on an adequate sodium intake [Cannon 1953]]. However since sodium is almost always accompanied by chloride, I am not sure that this relationship is accurately known yet since it could be the chloride which is giving part of the problem. Heart disease will be discussed at more length in a subsequent chapter.

There is a striking, consistent alteration of the kidneys' ability to concentrate fluids in humans. This impairment reverses in one and a half to four years after relieving a deficiency, but not always [Hollander p933]. I suspect that this is to maintain urine flow by excreting water so as to reduce potassium loss which would otherwise obtain if the urine had a potassium concentration the same as serum.

Potassium is thought to be essential to defense against pathologic bacteria on the basis of increased liability to infection of deficient kidneys which have suffered no change otherwise.

Muscular strength is directly related to potassium intake [Judge]. Paralytic blockage of the lower intestines, which sometimes attends surgery, is probably contributed to by low potassium [Lowman]. Rats have symptoms during a deficiency which includes abdominal distention, lethargy, sagging organs, and loss of tone, and sometimes decreased movement of the intestines [Schrader]. A potassium deficiency seems to be most destructive to the tissues which derive from the middle layer of the embryo [Seekles]. These tissues include all the connecting tissues, the heart, the blood vessels, the kidneys and the white blood cells.

In addition to the above phenomena, most of which have either been established beyond any doubt or have fairly substantial experience behind them. (although usually based on animal experiments), it is my contention that rheumatoid arthritis is essentially a chronic potassium deficiency. It may be that some genetic difference like sexual hormones, or differences in secretion of other hormones such as the glucosteroid response modifying factors, or some other imbalance with other nutrients such as copper affect who and when arthritis strikes. Obviously any disease or poison which interferes with retention of potassium would increase the chance of a deficiency developing.. Considering that some of the symptoms of a deficiency take a long time to heal, it seems as if a deficiency should be avoided with almost the same urgency as a water deficiency (dehydration). Also, a deficiency of, say, 40 or 50 grams would take a fairly long time to be corrected by food. It would probably be measured in weeks at least.

If "rheumatoid arthritis" are not words describing a potassium deficiency then what is the word equivalent to "beri-beri" which describes a chronic potassium deficiency? Hypokalemia or hypopotassemia are not such words. They simply are words describing a low plasma content, with symptoms of lower T wave on the electrocardiogram, drowsiness, nausea, muscular weakness, low blood pressure, and reduced digestive ability [Robinson] (but for some reason hypokalemia induced by testosterone does not affect the electrocardiogram [Goldberger p113]). It would seem strange to have no word which describes a chronic potassium deficiency. I would suggest that we find one soon.

ROLES OF POTASSIUM IN THE BODY

Body changes when potassium is deficient are described.

CONTENTS of other chapters Back to INTRODUCTION chapter -- II. Arthritis Research -- III. Arthritis and Potassium -- IV. Roles of Potassium in the Body -- V. Electrolyte regulation (sodium and potassium) -- VI. Purpose of cortisol -- VII. Copper nutrition and physiology -- VIII. Nutritional Requirements -- IX. Potassium in Foods -- X. Processing Losses -- X,cont. Losses in the kitchen -- XI. Supplementation -- Side Effects and Heart Disease

The author, Charles Weber, has a degree in chemistry and a masters degree in soil science at Rutgers University. He has researched potassium for over 40 years, primarily a library research. He has cured his own early onset arthritis.

isoptera@angelfire.com

Potassium makes up 70% of the positive ions in the cells [Harper (with graphs)]. The cell is essentially a little bag of potassium salts. The remaining positive ions are sodium, magnesium, calcium, argenine and other miscellaneous ions, primarily charges on the amino acids of the proteins. A lean 70 kg man will have a total potassium content of about 175 grams when replete [Shohl] (there is some disagreement in the literature as to the exact amount, and a man high in fat would have a lower amount than others per weight). About 2.5 grams are in the blood serum. Virtually all the potassium is disassociated [Lev]. This last implies very little storage of potassium beyond its concentration tolerance.

MOVEMENT OF POTASSIUM ACROSS CELL MEMBRANES

The potassium probably enters the cells of higher animals by passive diffusion [Bennett][Solomon], and the active exclusion of sodium by a one way pumping mechanism has the effect of setting up a true Donnan equilibrium [Albers]. The sodium is excluded by constantly being pumped out of the cell using metabolic energy [Hendricks] through a hollow enzyme buried in the cell wall. The pumping mechanism has been shown to be powered by adenosine triphosphate (ATP) by virtue of similar inhibitors and other parameters being similar [Post]. Lactic acid metabolism as regulated by insulin appears to be also part of the energy system [Kernan p109]. Thiamine [Sharp] and possibly magnesium [Schoner] are also involved. There is more than one pump mechanism, and it has been suggested that sodium concentration inside the cell regulates one of them [Robinson]. The sodium pumps utilize 10% of the body's resting energy [Potts p274].

Inositol may also be involved, but probably only affects the diffusion of potassium [Charalampous]. The apparent passive diffusion is really an active simultaneous inward pumping of both potassium and sodium There is some evidence that such a pump exists on the mitochondria walls [Ulrich]. It is believed that the sodium pump acts by pumping three sodium ions out while simultaneously pumping two potassium ions out. However there is considerable variation in different animals so there must be more than one mechanism present in varying ratios of action.

The net pump virtually fails to operate at temperatures below 4 degrees C [Hendricks]. The rise in serum potassium that this implies is undoubtedly the reason why we feel such pain when our extremities become too cold.

There is very little chance that potassium is transported actively by an exclusive pump independently of sodium, however. Such a valuable mechanism would surely have ramified throughout the body by this time. It would, for instance, be priceless in the absorption mechanism during a deficiency. Since it is not transported actively independently of sodium, it follows then that all the movement of potassium in the body must actually or in effect be by passive diffusion as a counter current to sodium. This is not a simple ion exchange. Since it is powered by metabolic energy, a considerable number of interactions are theoretically possible, depending on the organ, direction of motion, and which facing wall the various pumps are on.

This dependence on sodium is probably the reason why electrolyte steroid hormones such as aldosterone affect the status of both sodium and potassium. It is also probably the reason why these two elements affect each other's excretion. It is also undoubtedly the reason why the excretion of potassium can not be cut off [Tarail]. It is thought that potassium in the urine can decline to almost half the amount in the serum [Fourman]. It must be done by excretion of water after the potassium has been reabsorbed. Sodium can be concentrated against a concentration gradient of 10,000 to 1 (by the toad's bladder, for instance) [Ulrich]. There is nothing even remotely resembling such an efficiency for potassium.

OSMOTIC PRESSURE

Since sodium and Potassium are the primary soluble positive ions in the body, they must be the primary regulators of osmotic pressure. Precisely how all the mechanisms interact is not known yet with perfect clarity. The cell must be kept in perfect balance with the blood plasma, or it would either shrivel up or swell and burst. If one system fails, the others tend to take up the slack, and attempt to keep the situation at a reasonably normal level [Davis]. The various ions have various affects on each other, but ultimately excretion of each has to be independent of the others, since intake is very variable.

BLOOD PRESSURE

Part of the regulatory system involves blood pressure. The sodium pump in the toad's bladder probably operates at two different sites, one affected by aldosterone, the other by vasopressin (a protein peptide hormone), and using a different energy system [Sharp]. Since the effort of the regulators of the various systems to counteract a failure or overload of one of the other regulators could involve disadvantageous compromises, it would seem wise to put no strain on them which could have been avoided by proper diet. For instance high blood pressure is thought to be caused by at least three different causes (maybe even 4 or 5). One of them may be involved with a potassium deficiency and at least that should not be allowed to contribute to the difficulty. Hypertension will be discussed a little further in a subsequent chapter.

ACID - BASE REGULATION

Since potassium makes up so large a part of the cell's osmotic pressure` it is indirectly involved with regulation of the acid - base balance. During a potassium deficiency, potassium migrates out of the cell and causes the cell fluid to become acidic (lower pH) [Davis][Halla]. This is probably related to the circumstance that sodium does not take up the full slack [Rubini], coupled with a rise in weak base forming anions such as positively charged amino acids [Eckel] (which should really be called amino bases in this case). The buffering action of the negatively charged ions of weak acid forming anions such as phosphate is the chief innate regulator of the acid - base balance. however, some of the above alterations would tend to overwhelm it. Since enzyme systems are often sensitive to acidity, this drift toward acidity could easily be the cause of some of the symptoms from a potassium deficiency, and therefore also of arthritis.

The kidneys have an enzyme which makes ammonium ion, using glutamine as a precursor. This enables the kidneys to excrete more acid [Harper p217] and to do so at a site which interferes with potassium excretion. The above enzyme becomes more active when the cell's fluid becomes more acidic [Rector]. Glutamine itself is an essential amino "acid", at least in the sense that it must ultimately be present. This may be an adaptation primarily for the purpose of conserving potassium even though ammonium excretion itself may be directly related to hydrogen ion (acid) and not to potassium concentration [Tannen]. The ammonium ion and potassium are the same charge and size, and they are handled at the same site in the kidneys. Berliner, Kennedy, and Orloff believe that hydrogen ion and potassium compete at the same site in the kidney's distal tubules [Berliner]. In any case potassium excretion is quite sensitive to hydrogen ion concentration (acidity). Injecting sodium bicarbonate or even hyperventilating (breathing rapidly beyond need) can triple potassium excretion [Kilburn]. The diurnal rhythm for potassium and hydrogen ion excretion show a rather close inverse relationship [Mills], which gives additional circumstantial support to the supposition that they compete at a common site.

It is obvious that a potassium deficiency puts an increased drain on glutamine, and would presumably be disadvantageous to someone not getting enough protein. It also seems likely that eating baked goods which have been risen with sodium bicarbonate, or stomach antacids would worsen a deficiency. There is a possibility that fruits which contain acids which acids can be absorbed but not metabolized would have a conserving effect on potassium. I am aware of no investigation which would substantiate this. However there is a report of cherries having a beneficial effect on arthritis*.

NERVE TRANSMISSION

One of the most important roles for potassium in animals having a nerve net work is as a counter flow for sodium's function in nerve transmission. When a neuron decides to fire, the cell wall suddenly becomes permeable to sodium ions, and sodium ions near the cell wall suddenly move into the cell, followed a microsecond later by a flow of potassium ions in the opposite direction [Fuhrman]. This change in permeability shoots down the nerve fiber as a wave at about 100 meters per second powered by 1/10 of a volt of concentration differential [Baker]. This is approximately the speed of a thrown baseball.

Half the metabolic energy supplied to nerve cells is required to move the sodium back out of the cell [Potts p37] in order to recharge it. For this system to work the potassium in the plasma has to be kept as close as possible to 187 milligrams per liter (4.8 milliequivalents per liter) [Lans (complete with graph)]. If it rises above 400 or falls below about 80 death is almost certain from failure of the nerves leading to vital organs to fire. Rising above 400 is the greatest risk because excessive loading of plasma is quite possible from supplements, metabolic shock, and various hormone failures. On the other hand , it is quite unlikely that excessive potassium could be suddenly lost from the plasma, but even if it were lost, replete cells provide an enormous reservoir of potassium to replenish the plasma's potassium in case the lower limit were approached. A sudden rise in potassium, then, ranks high among the most dangerous physiological events which can happen to a person. Some of the implications of this will be elaborated further in the supplements chapter.

ENZYME ACTIVATION

Potassium is known to be the activator for several enzyme systems [Suelter]. Since only minute amounts are needed for most of them, there could never be a deficiency which would inactivate the majority of them. The amount needed for activation is usually about 40 milligrams per liter [Kernan p127], and no cell could ever get this low and live. One exception is transport of d-amino isobutyric acid which is permanently disrupted at a cellular level which is still well under the amount needed to live. [Charalampous]. It is safe to say that no enzymes are inactivated directly by a low potassium whole body count.

COLLAGEN I suspect that a large part of the weakened connective tissue is manifesting itself by virtue of the indirect effect a continuing potassium deficiency is having on the the copper metabolism especially as it pertains to the copper catalyzed lysyl oxidase enzyme.

Healthy collagen ranks with steel in strength of individual fibers*. Healthy bone, which is essentially an ossified connective tissue, has a strength which approaches that of cast iron [45]. Such theoretical strengths are above the strengths which are observed in most people, and would be very advantageous in solving everyday problems. Such strengths would give people considerably less apprehension about injuries. There should be no reason why these strengths can not be obtained. It is my belief that the strength of connecting tissue and its ability to regenerate are of considerable importance, not only in clear cut cases of arthritis, but also very likely in a large number of degenerative diseases which affect modern society such as susceptibility to sprains and shaving cuts, aneurysms of blood vessels, ruptures, weak bones, varicose veins, sagging organs, slipped discs, and bleeding while breast feeding. I further believe that one of the common threads running through many of these difficulties is potassium deficiency, and that the carelessness of modern processing is causing far more problems in ruined lives, inexplicable accidents, marginal loss of efficiency, and needless fear than the raw statistics of arthritis, strokes, and other mesoderm tissue [Lamont-Havers] disasters would indicate. It would be a good idea to get all the potassium originally present in your food. If someone succeeded in defrauding you of 30% of your after taxes paycheck, you would probably scream in anguish. Perhaps it is time to scream about losses in nutrition of this much or more.

REGULATION OF ELECTROLYTES, POTASSIUM AND SODIUM

ABSTRACT

Sodium and potassium (Chapter I) 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, 11 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 [Potts p261]. Thus 580 grams of sodium and 36 grams of potassium are filtered each day. All but the 1-10 grams of sodium and the 1-3 grams of potassium likely to be in the diet must be reabsorbed. Sodium must be reabsorbed in such a way 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 [Lans] (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 fifty times as large, the situation is not so critical for potassium. Since potassium is moved passively [Bennett] [Solomon] in counter flow to sodium in response to a Donnan equilibrium [Kernan p48] 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. [Wright] 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/1 in about one week, [Squires] and can never be cut off completely. Because it cannot 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 probably through one of the pumps which also pumps sodium. Even so, the net apparent effect is active in the tubules. In addition to the kidneys, the gastric glands, salivary glands, colon, perspiration glands, and maybe the red cells are target organs for the mineralocorticoids. [Turner]

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 [O'Malley]. When potassium in the serum is higher than 4.8 mEq/1, the zona glomerulosa [Brown] of the adrenal jacket secretes more aldosterone [Lans] and potassium is excreted into the end of the tubules and the collecting ducts [Peterson]. Aldosterone also reverses potassium inflow in the last part of the colon and increases sodium absorption throughout the colon [Dolman]. The amount of aldosterone secreted is a function of the serum potassium [Bauer & Gauntner] [Linas]as probably determined by sensors in the carotid artery [Gann , Cruz & Casper], pressure in the carotid artery [Gann, Mills, & Bartter], the inverse of the sodium intake as sensed via osmotic pressure*, anxiety [Vening], and of the angiotensin II formation [Brown][Dluhy][Williams & Dluhy], which last is a peptide hormone for increasing blood pressure by constricting the arteries just ahead of the capillary bed [Haddy]. Angiotensin II is regulated by the rennin (a peptide hormone) from the kidneys. Depletion of either potassium [Albrecht] or sodium activates secretion of rennin, but in potassium depletion aldosterone is suppressed [Sealed]. If blood pressure has to be increased by constricting capillaries, which is what angiotensin II does [Encyclopedia], it is an indication that the body needs more sodium in order to expand blood volume or more potassium to strengthen the heart beat. That is undoubtedly the reason why angiotensin is involved in regulating aldosterone and is the core regulation [Williams & Dluhy]. A portion of the regulation resulting from angiotensin II must take place from decreased blood flow through the liver due to constriction of capillaries ['Messerli]. 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 to aldosterone is virtually inoperative when no angiotensin is present [Pratt][Williams & Dluhy]. 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 at serum contents of potassium [Haddy] above 4.8 mEq/liter of potassium, 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 [Brown]. I suspect that this is an adaptation to inversely help protect the body during diarrhea assuming that the primary purpose of ACTH is to inversely mobilize the body's defenses against intestinal disease [Weber 1999]. Aldosterone is increased by blood loss [Ruch p1099], pregnancy [Farrell], and possibly by other circumstances such as physical exertion, endotoxin shock,, and burns [Glas & Vecsei p209]. The aldosterone production is also affected to one extent or another by nervous control which integrates the inverse of carotid artery pressure [Gann, Mills, & Bartter], pain, posture [Farrell], and probably emotion (anxiety, fear, and hostility) [Venning 1956, 1957](including surgical stress) [Davson p715] to produce an unknown messenger hormone which stimulates aldosterone secretion.* 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 [Sharp]. 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 [Rechcigl]. Anxiety's effect can be discordant. People with an anxiety neurosis can have as high as four times the secretion as normal and people with schizophrenia have a low secretion [Lamson].

This system has been well studied and its major features are not subject to much doubt. Potassium feedback is the main regulation of aldosterone in normal diet and health, and the other features of aldosterone's regulation are for the purpose of fine tuning and forestalling future circumstances.

The slope of the response of aldosterone to serum potassium is almost independent of sodium intake [Dluhy]. Aldosterone is much increased at low sodium intakes, but the rate of increase of plasma aldosterone as potassium rises in the serum is not much lower at high sodium intakes than it is at low. Feedback by aldosterone concentration itself of a nonmorphological character (changes in of the cells' number or structure) is poor so the electrolyte feedbacks predominate short term [Glaz & Vecsei]. 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 secretes potassium into the distal loop of the tubules [Stanbury], 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 [Peterson]. That aldosterone makes available the sodium in the bones which contain nearly half the body's sodium is circumstantial evidence that the body depends considerably on aldosterone to keep the serum sodium retained and normal [Davson p717].

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 stimulates the collecting tubules (the tubules which branch together to feed the bladder) [O'Neil] to continue to excrete potassium in much the same way that aldosterone did but not like aldosterone in the end of the looped tubules (distal) [Peterson & Wright]. At the same time it is not nearly so rigorous at retaining sodium as aldosterone [Ellinghaus], more than 20 tmes less [Brommer]. In addition to its inherent lack of vigor there is an escape mechanism controlled by an unknown non steroid hormone [Pearce] which overrides DOC's conserving power after a few days just as aldosterone is overridden also [Schacht]. This hormone may be the peptide hormone kallikrein which is augmented by DOC and suppressed by aldosterone [Bonner]. If sodium becomes very high, DOC also increases urine flow [O'Neil]. DOC has about 1/20 of the sodium retaining power of aldosterone [Oddie] and is said to be as little as one per cent of aldosterone at high water intakes [Desaulles]. Since DOC has about 1/5 the potassium excreting power of aldosterone [Oddie] it probably must have aldosterone's help if the serum potassium content becomes too high. DOC's injections do not cause much additional potassium excretion when sodium intake is low [Bauer & Gauntner]. This is probably because aldosterone is already stimulating potassium outflow. When sodium is low DOC probably would not have to be present, but when sodium rises aldosterone declines considerably, and DOC probably tends to take over.

DOC has a similar feedback with respect to potassium as aldosterone. A rise in serum potassium causes a rise in DOC secretion [Brown], which is the correct response for this thesis. However, sodium has little effect [Schambelan & Biglieri], and what effect it does have is direct [Oddie}. Angiotensin (the blood pressure hormone) has little effect on DOC [Brown], but DOC causes a rapid fall in rennin, and therefore angiotensin I, the precursor of angiotensin II. [Grekin]. Therefore, DOC must be indirectly inhibiting aldosterone since aldosterone depends on angiotensin II. 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 cannot be resolved by transferring sodium to the intracellular (inside the cell) 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 [Grekin] in rabbits since DOC injections lowered serum potassium but did not alter excretion [Law]. 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 [Rubini]. Thus, it is desirable to resolve the blood pressure problem as much as possible by the fall in rennin above, therefore avoiding loss of sodium which was usually in very short supply on the African savannas where humans probably evolved.

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, [Helman & O'Neil] would tend to support the above view. The above attributes are consistent with a hormone which is relied upon to unload both sodium and potassium.

DOC's action is augmenting kallikrein, the peptide hormone thought to be the sodium "escape hormone," and aldosterone's action in suppressing [Bonner][Wright & Davis] it is also supportive of the above concept

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[Weber 1999] since during dehydration, aldosterone virtually disappears any way even though rennin and angiotensin rise high [Gyton WB]. DOC's primary purpose is to regulate electrolytes. It has other effects on copper enzymes, proteins and connective tissue which I believe is used by the body to survive during potassium wasting intestinal diseases. Most of the DOC is secreted by the zona fasciculata of the adrenal cortex which also secretes cortisol, and a small amount by the zona glomerulosa which secretes aldosterone.

The greater efficiency of DOC in permitting sodium excretion (or perhaps it should be expressed as inefficiency at retention) must be partly through morphological 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*

CASE #3: Sodium Intake Is Low; Potassium Intake Is Low.

Someone living on the Savanna, profusely perspiring and confined to eating nuts, or worse yet 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. [Bauer & Gauntner]. The large decline in aldosterone secretion [Bauer & Gauntner] 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. Under low sodium intake 18 OH DOC is increased in serum [Williams, Brale & Underwood] . I have not seen anything to indicate directly behavior with potassium yet. However there is a marked increase in serum 18 OH DOC after injection of insulin [Sparano] [Hiatt] and this may be due to the hypokalemic (low serum potassium) tendency after a rise in insulin [Flatman]. Insulin is used by the body to counter high serum potassium only at low potassium intakes. At high intakes insulin stays normal [Knochel].

It is possible that the 18OH DOC does not act directly on electrolytes, but through a synergistic or blocking action on other hormones. I suspect that 18 OH DOC acts primarily by blocking aldosterone's effect on potassium, and must have aldosterone to assist it. 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 [Nichols]. This implies a considerable sparing of potassium by 18 OH-DOC. If the original aldosterone could have been removed from the serum first, it is possible that the difference would have been greater yet.

Angiotensin II has very little effect on 18 OH-DOC and is ambiguous nor does serum potassium above 4.8 mEq/litter (187 mg) [Biglieri & Lopez].- This last is not surprising since 18 OH DOC would not be used at high serum potassium. Under low sodium intake, 18 OH-DOC rises in the serum [Williams], which is the correct response for the proposed purpose. ACTH causes a marked increase in 18 OH-DOC [Moore] up twenty fold [Melby, Dale & Wilson], probably by a generalized affect on the zona fasciculata of the adrenal cortex where 18 OH-DOC is synthesized . I believe that the decline in 18 OH-DOC when ACTH declines implied by this is part of the defense against diarrhea already mentioned because of the dehydration that ensues then and the need to preserve osmotic pressure by unloading sodium. When ACTH drops to zero, 18 OH-DOC does also.* I have not seen evidence so far that cholera enterotoxin, or any other aspect of digestive disease except dehydration [[Aguilera] directly affects ACTH yet. If this hypothesis is correct, some aspect of diarrhea should affect ACTH

More important to know would be the effect of 18 OH-DOC has on angiotensin II because at low serum potassium situations, the intracellular (inside the cells) potassium is usually decreased and this depresses heart contraction. I suspect that 18 OH-DOC will be found to stimulate angiotensin II rather than the reverse because the intracellular potassium is much more important than serum potassium on the strength of heart contractions [Libretti][Biglieri & Lopez]. 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 rennin and therefore angiotensin II at low potassium intake than at any other electrolyte status. [Douglas] .

.

CASE #4: Sodium Is High; Potassium Is Low.

Any of our progenitors who managed to find a salt lick, nothing but nuts 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 in urine slightly when injected into rats. This slight increase takes place even when small amounts of aldosterone are injected at the same time. That amount of aldosterone injected alone lowered the ratio slightly. [Fuller]. 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. [Donowitz]. Also, their ascending colon increases water absorption under c-AMP stimulation, opposite the effect in the descending colon and in other animals.[Hornyck]. Thus, the enterotoxin of diarrhea undoubtedly has much less effect on them. DOH-DOC combined with aldosterone is more retentive of sodium than either alone. [[Melby & Dale 1976]. DOH-DOC does not displace aldosterone in general. [Fuller]. DOH-DOC must act in conjunction with aldosterone. If both are secreted together, sodium would be drastically conserved. 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 in the tubules. 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 [Linas].

It may yet be found that angiotensin II or rennin do not increase DOH-DOC, but that DOH-DOC decreases angiotensin II in the vicinity of 4.8 mEq/l and then considerably increases it if the intracellular (cell interior) potassium becomes low. If the mechanism is such that both trends are not possible, then only the second should obtain, for in matters of regulation it is the extreme circumstances which should prevail if a compromise becomes necessary, those circumstances when an animal is fighting for its life.

When DOC is injected into people, it creates malaise, headache, loss of appetite, insomnia and muscle cramps. [Relman & Schwartz]. 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 from excessive action during diarrhea. Some of the damaging effects of DOC injections on the heart may arise this way also [Melby, et al 1972]. The loss of appetite, if it exists, would be especially valuable 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 ACTH has no effect. I know of no information on this.

CONCLUSIONS

By secreting various ratios of the above steroids in conjunction with rennin, the angiotensins, ADH water retaining hormone, thirst and unknown supporting hormones, 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*.

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. Such a diet is low in sodium and fairly high in potassium [Abernethy]. If so, and I am right about the 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* and it is possible that tends to increase the thickness of artery walls [Coz}and decrease their elasticity. The much greater tendency to grow excess connective tissue when foreign bodies such as silica are imbedded in the skin during DOC injections [Desaulles] [Pospisilova] would give circumstantial support to such an explanation.

Case #3 is probably furnishing some of the symptoms of rheumatoid arthritis (ChapterI, Arthritis) since there is a consistently low whole body potassium content in this disease [LaCelle] aldosterone is low in arthritics [Cope & Llaurado] [Gonall], and personal experience is supportive[Weber 1974]. Indicative is that arthritis has been produced by DOC injections [Selye]. I have no information on the status of 18 OH DOC in arthritis. Anyway, it is probable that the bulk of the symptoms manifest themselves through cortisol (Chapter VI) status and its response modifying factors because this hormone is reduced in its secretion by the effect of low potassium on the zona fasciculata [Mikosha] 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 [Clark], assuming his sodium intake was normal. Black people receive 1.5 grams/day and white people 2.0 grams/day in Georgia *. There is also circumstantial evidence from nutritional experiments using vegetables [Eppinger][Kjeldsen-Kraw]. An unpublished experiment performed on eight subjects has revealed beneficial results from potassium supplements [Rudin MV, private communication]

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 as one possibility, for instance. Childers has proposed poisons in tomatoes, potatoes, egg plant, and peppers [Childers]. 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 rennin hypertension, since there is increased secretion of DOH-DOC in all cases of that last disease [Melby & Dale 1976]. 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 [Parker 1980] and have a markedly higher secretion before the onset of menstruation [Parker 1981]. It may be that the larger secretion of progesterone which takes place at these times [Parker 1981] makes necessary the enhanced secretion of DOC by virtue of progesterone's interference with DOC's primary purpose [Gornall]. 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. Past nutritional texts reflect this view both in the amount of space devoted to potassium and its content, which content will usually list only one cause of a deficiency [Robinson]. 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 for diarrhea)", or similar terms. A deficiency is further defined out of existence by defining the blood serum content is normal at a 4.2 mEq/liter when the actual figure is 4.8.

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% [Darrow]. Numerous experiments have shown that potassium supplements are very important for recovery from heart disease [Kadaner]. It is not possible to produce heart disease in animals with any known poison unless potassium is also deficient [Prioreschi]. It is important to know whether the heart disease is caused by potassium deficiency or vitamin B-1 deficiency because heart disease cannot materialize in rats if both are deficient [Folis]. 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. This may be one reason why results with potassium against heart disease have been statistically fuzzy in the past.

Psychic stress stimulation of aldosterone, profuse perspiration, excessive vomiting, eating sodium carbonate or bicarbonate (because hydrogen ion is excreted at the same site as potassium), laxatives, diuretics, licorice, hyperventilating, enemas, shock from burns or injury, hostile or fearful emotions, and very high or low sodium intakes 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 cannot 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, even 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 DOC may not prove logical for all cases. Excess potassium is the main problem in shock [Fox], yet previous texts about shock did not even so much as mention potassium. 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 cannot 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 quasi religious conviction or instinct that foods our parents taught us to eat or taste good could not possibly be harmful. This is not necessarily 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 conviction (or instinct) is so strong that most people will not eat nutritious food if tastier, less nutritious food is available. Their instincts toward sweet, salty, and parent's instructions override their intellect not only in their eating habits, but in their scientific efforts. These scientific efforts are further thwarted from pursuing nutritional investigations because medical science stresses pharmaceuticals, glamour theories [Forman], and patentable procedures.

THE PURPOSE OF CORTISOL

ABSTRACT

It is proposed that the primary purpose of the glucocorticoids, including cortisol, is to mobilize the body to resist infection. They do so by normally altering processes which increase pathogens' growth or their adverse effects and then declining when under attack. Cortisol is for intestinal disease and corticosterone serum disease. Glucocorticoid mobilization for fight or flight is an adjunct, made possible because most processes which resist infection impair fight or flight. A different hormone controls those which do not.

Potassium loss is the most serious aspect of intestinal diseases, so the electrolyte capabilities of cortisol, but not corticosterone, are oriented toward conserving potassium. Low cell potassium reduces adrenal synthesis of cortisol, but not corticosterone. Sodium, water, glucose, amino acids, chloride, hydrogen ion, copper , and numerous others are controlled by cortisol such as to survive during intestinal disease.

Some gram negative bacteria have an endotoxin which subverts this strategy by forcing the secretion of huge amounts of ACTH, which is the chief mediator of cortisol. A glucocorticoid response modifying factor and interleukin-1, raises the effective set point of cortisol. The immune cells thus take over their own regulation, using interleukin-1 to mediate production of cortisol via ACTH.

Scroll down to INTRODUCTION below.

CONTENTS of other chapters Back to INTRODUCTION chapter -- II. Arthritis Research -- III. Arthritis and Potassium -- IV. Roles of Potassium in the Body -- V. Electrolyte regulation (sodium and potassium) -- VI. Purpose of cortisol -- VII. Copper nutrition and physiology -- VIII. Nutritional Requirements -- IX. Potassium in Foods -- X. Processing Losses -- X,cont. Losses in the kitchen -- XI. Supplementation -- Side Effects and Heart Disease

INTRODUCTION

This paper will propose that the primary purpose of cortisol and corticosterone in mammals is to mobilize the body's physiological processes against infection and its adverse effects, cortisol against potassium wasting intestinal disease and corticosterone against serum disease. These steroids control a large number of enzymes, hormones, and processes, most of which could enhance growth of pathogens or make the adverse symptoms worse. The few which do not, do not affect immunity either, and are probably opportunistic adaptations of these hormones to peripheral functions. Extinction of juvenile play traits is an example.

Glucocorticoids mobilize immunity by declining their serum concentration. This inverse style is highly desirable, otherwise a pathogen could easily overwhelm the immunity defenses simply by evolving an enzyme which could degrade steroids. Some circumstances controlled inversely enhance an animal's survival from the adverse effects of bacterial poisons or the animal's own defenses. Such a defense would be control of blood pressure. This control, I suspect, is largely to protect infection damaged and copper starved blood vessels from hemorrhage.

Please keep in mind as you read this, that cortisol's functions to inhibit or stimulate become the reverse, to stimulate or inhibit, upon decline respectively. This concept will be handled by use of the phrases "inversely stimulates" or "inversely inhibits" respectively as cortisol declines.

Cortisol is controlled by the pituitary peptide ACTH.¹ ACTH is in turn controlled by the hypothalamic peptide, corticotropin releasing factor [CRF],² under nervous control. CRF is synergistic with arginine vasopressin, angiotensin II, and epinephrine.² Therefore ACTH and CRF cannot be overwhelmed by bacterial degradation either. ACTH probably controls cortisol by controlling movement of calcium into the cortisol secreting target cells.¹

Cortisol prevents proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1(IL-1), and unable to produce the T-cell growth factor.⁴ That cortisol often increases during infection does not make this hypothesis invalid because when activated macrophages start to secrete IL-1, which synergistically with CRF increase ACTH,⁵ T-cells also secrete glucosteroid response modifying factor [GRMF] as well as IL-1, both of which increase the amount of cortisol required to inhibit almost all the immune cells.⁶ Thus immune cells take over their own regulation, but at a higher set point. Even so, the rise of cortisol in diarrheic calves is minimal over healthy calves and drops below with time.⁷ The cells do not lose all of the fight or flight override because of interleukin- 1's synergism with CRF. Cortisol even has a negative feedback effect on interleukin-1 ⁵ which must be especially useful against those diseases which gain an advantage by forcing the hypothalamus to secrete CRF, such as the endotoxin bacteria to be discussed later.

The suppressor cells are not affected by GRMFs,⁶ so that the effective set point for the immune cells may be higher than the set point for physiological processes. It may be that the GRMFs have a different spectrum of effects for each of the physiological processes in order to fine tune the immune response in order to optimize the attack against different organisms.

It seems to me that resources diverted to immunity or denied to non-viral pathogens usually diminish an animals performance when fighting or fleeing. Therefore, the cortisol system can be overridden by perceived danger. This is no doubt made desirable because it takes several hours or more for pathogens to rise to dangerous levels, but only a few seconds for a predator to kill an animal. Anxiety is also factored in because, I suggest, cortisol operates by changing the nucleus commands to send RNA for production of enzymes, etc. in almost every case and the various diffusion steps take an hour or more to complete. Therefore, an anticipation of danger would be desirable.

The desirability of inhibiting activity during infection is no doubt the reason why cortisol creates euphoria,^{8, p.736} as does aldosterone,⁹ and presumedly the reverse upon declining. The desirability of not disturbing tissues weakened by infection or of not cutting off their blood supply could explain the inverse stimulation of pain widely observed for cortisol. These neural mechanisms as geared to stress have been emphasized in concepts concerning glucocorticoids as pioneered by Selye up to now. Nevertheless, when a process must move in the same direction for both immunity and fight or flight, a different hormone system controls it for stress. An example is release of ceruloplasmin by the liver which is controlled for purposes of stress by epinephrine and by an unknown hormone for immunity to be discussed later.

The most dangerous digestive diseases produce a protein poison which stimulates cyclic adenosine monophosphate [c-AMP] hormone in such a way that the intestines cannot remove water from their contents¹⁰ and thus cause diarrhea. Since potassium in food and the 2.5 grams or so secreted with digestive fluids can only move into the blood stream passively,¹¹ this causes a large loss of potassium. Judging by the reduction of the death rate in babies with virulent diarrhea from 34% to 6% by potassium supplements¹² in spite of the danger of hyperkalemia (high serum potassium) during dehydration, the loss of potassium implied is the most serious consequence of diarrhea. When this poison first evolved, it must have been catastrophic to terrestrial vertebrates. Even today, after probably a major evolutionary transformation of cortisol, the diarrheas are one of the most important causes of mortality in the tropics. It must have been imperative to evolve mechanisms to surmount those pathogens. In most mammals, a wide range of processes are stimulated by cortisol, each of which would make an animal less able to resist potassium and water wasting intestinal disease. Rodents have very little cortisol which may be related to a marked inhibition of the effect of cholera toxin by rodents' intestinal contents.¹³ Also, c-AMP increases water absorption in their ascending colon, opposite to the effect in their descending colon.¹⁴ This makes rodents dubious for experiments on the hypothalamic-adrenal axis and perhaps for any experiments.

DISCUSSION

POTASSIUM

The greatest urgency during diarrhea is to prevent loss of potassium, since there is no storage of potassium in any cell. In cells, 88% of the potassium is in free solution.¹¹ Indeed, one of cortisol's functions conserves potassium. It has been suggested that cortisol tends to move potassium inversely into the cells [cortisone].¹⁵ If this is the case, potassium is inversely conserved by lower secretion of cortisol (dexamethasone).¹⁶ In order for potassium to move into the cell, cortisol inversely moves out an equal number of sodium ions.¹⁵ It can be seen that this should make pH regulation much easier, unlike the normal potassium deficiency situation in which about 2 sodium ions move in for each 3 potassium ions that move out^{17, p.445} which is closer to the DOC effect.¹⁵ This is probably the reason why the cell becomes acid during a deficiency caused by low potassium intake.¹⁸ Nevertheless, cortisol consistently causes alkalosis of the serum [inversely acidosis] while in a deficiency pH does not change. I suspect that this is for the purpose of bringing serum pH to a value most optimum for some of the immune enzymes.

Potassium is also inversely inhibited from loss in the kidneys somewhat by cortisol [9 alpha fluorohydrocortisone].¹⁹ Potassium is primarily blocked from loss in the kidneys by a drastic decline of aldosterone during dehydration.²⁰ Aldosterone acts on the last part of the kidney tubules and the lower colon.²¹ In the colon, aldosterone reverses the normal inward flow of potassium, or at least stops its reabsorption²² and so inversely conserves potassium there. Aldosterone is directly controlled by potassium and inversely by osmotic pressure²⁰ while angiotensin II is required. Thus as osmotic pressure rises during dehydration, aldosterone undergoes a drastic decline. Aldosterone also backs up cortisol by possibly inversely moving potassium into muscle cells somewhat.²²

To be useful in combating a potassium wasting disease, it would be necessary for cortisol to decline at such a time. A high potassium media which stimulates aldosterone secretion in vitro also stimulates cortisol secretion from the fasciculata zone of dog adrenals.²³ Therefore, low potassium should decrease cortisol secretion by the adrenals in vitro in dogs. At the same time, potassium has no effect on corticosterone secreted by the adrenal fasciculata.²⁴ Since the fasciculata accounts for 5/8 of the corticosterone secreted, the net effect is very little decline in corticosterone secretion. This is evidence that the body does not rely on corticosterone against diarrhea. Potassium chloride supplements do not affect cortisol or corticosterone plasma concentrations in humans in vivo when the cell content is adequate.²⁵ I know of no experiment which would establish the effect of potassium, cholera toxin or detection of intestinal pathogen microbes on ACTH. ACTH has its greatest effect on cortisol.

SODIUM

Cortisol is used to stimulate sodium inward for fresh water fish and outward for salt water fish.²⁶ The necessity of conserving potassium while still unloading electrolytes to maintain osmotic pressure may explain cortisol's inverse sodium losing power in the small intestine in mammals.²⁷ By using the intestine to excrete sodium, less water is needed for kidney processes, which is crucial during diarrhea. Sodium depletion does not affect cortisol,²⁸ so cortisol is not used to regulate serum sodium. It is known that the sodium retaining hormone, 18-hydroxy 11- deoxycorticosterone [18OH DOC] acting on the kidneys is strongly dependent on ACTH. When ACTH sinks to zero, 18OH DOC also does.²⁹ Therefore, it also is inversely involved in unloading sodium in what little water is excreted from the kidneys. The need for sodium chloride by diarrhea bacteria in order to grow rapidly³⁰ may be the main reason why cholera enterotoxin is so successful for this bacterium and of course increased water undoubtedly assists it also.

If my contention that 16-alpha 18-dihydroxy 11-deoxycorticosterone [DOH- DOC] is relied on to excrete excess sodium and to conserve potassium¹⁷ is valid, it should follow that ACTH and/or cortisol either have no effect on DOH-DOC or, possibly more usefully, to inversely stimulate it. It should also be desirable for DOH-DOC to exert its effect in the intestines because in nature it is almost always during diarrhea that the body experiences a potassium deficiency and sodium glut. I have no direct evidence for either phenomenon. However, it is known that DOH-DOC has very little affect on the kidneys.^{17, p.446} The malaise, headache, loss of appetite, insomnia, and muscle cramps created by DOC injections³¹ may be due to the loss of potassium and retention of sodium, resulting from increased DOC, causing DOH-DOC to rise, since none of these symptoms appear from a high sodium and potassium diet which stimulates DOC.¹⁷ Some of those attributes would be useful during diarrhea, but I have no evidence for DOH-DOC's role. 11-deoxycorticosterone [DOC] is the only steroid left of the four I proposed for electrolyte regulation.¹⁷ Sodium retention must never completely disappear. This may be why, as possibly the only renal sodium retainer left, DOC has acquired its auxiliary powers with respect to amino acids and copper to be discussed later and why a fall in leucocyte potassium of over 10% is observed from DOC³² and a decline in muscle potassium,³³ thus joining cortisol in inversely conserving potassium. It also probably explains why it is mediated partly by ACTH since ACTH must surely largely be an immune hormone with stress as an adjunct.^17,p.445

WATER

Cortisol also acts as a water diuretic hormone. Half the intestinal diuresis is so controlled.²⁷ Kidney diuresis is also controlled by cortisol in dogs.³⁴ The decline in water excretion upon decline of cortisol [dexamethasone] in dogs is probably due to inverse stimulation of antidiuretic hormone [ADH or arginine vasopressin] the inverse stimulation of which is not overridden by water loading.³⁴ Humans also use this mechanism³⁵ and other different animal mechanisms operate in the same direction.

Since loss of water is the circumstance which produces the worst adverse effects of diarrhea, it would seem to be logical to use dehydration as a signal to decrease cortisol. ACTH production is inhibited by water deprivation at the pituitary level. Basel secretion of ACTH is not affected, but high plasma ACTH resulting from immobilization stress is almost cut in half. Base corticosterone is increased in plasma from dehydration, but the much higher corticosterone from immobilization stress is not affected by water status.³⁶ The above is additional evidence that corticosterone is used by the body to fight serum disease and cortisol is used to fight intestinal disease.

GLUCOSE

Reinforcing the concept that cortisol is relied on more for intestinal disease control and corticosterone for serum disease is the circumstance that corticosterone at physiological levels shows a marked inhibition of insulin and enhancement of glucagon in vitro.³⁷ Cortisol shows a small inhibition of glucagon which reverses in a short time and has no affect on insulin.³⁸ Insulin is used to help prevent hyperkalemia [high serum potassium] by the body. As glucose moves into the cell, it takes potassium with it. This mechanism is only used at low potassium intakes. At an intake of 8 grams per day, insulin stays normal.³⁹ This is logical since there is no need to conserve potassium at high intakes and aldosterone is relied on to lower serum potassium. Cortisone greatly inhibits insulin secretion.³⁸ The cortisone-cortisol equilibrium may explain why in vivo experiments contradict the above.⁴⁰ This equilibrium may permit the body to change cortisol glucose responses for particular kinds of situations.

The inversed stimulation of insulin by corticosterone would lower serum glucose and thus deny glucose to pathogens. Such an aptitude in cortisol would be of little value if my thesis is correct, and could even endanger an animal from hypokalemia [low serum potassium] during diarrhea. A sudden withdrawal of glucose by insulin in a potassium deficiency can lower serum potassium enough to be lethal. However, apparently there is an advantage in locking up the potassium that does enter the cell in a more orderly manner with glycogen, because DOC inversely stimulates glycogen formation.⁴¹ Cortisol does inversely cause serum glucose to fall, but this is probably an indirect effect caused by inverse inhibition of amino acid degradation.

Theintestinal brush border disaccharide enzymes are inversely inhibited by cortisone.⁴² If it is cortisol that is actually involved, this could be a mechanism to deny energy to bacteria incapable of using sucrose. However, present day cholera can ferment sucrose^{43, p.557} so it would have to be an attribute against diarrheas which evolved before cholera It is also possible that it helps prevent the hypokalemia above.

AMINO ACIDS

Glucocorticoids have the attribute of inversely lowering amino acids in the serum.^{44, p.273} They do this by inversely stimulating collagen formation, increasing amino acid uptake by muscle, and stimulating protein synthesis.^{44, p.273} Cortisol also inversely inhibits protein degradation.^{45, p.207} Such an attribute would help deny amino acids to bacteria. An additional advantage is that collagen can be very useful in repair of infected tissue. An indication of this last is that loss of collagen from skin by cortisol is ten times greater than from all other tissue in the rat.⁴⁵ Thus the skin can be a reasonably safe source of energy during stress and be rapidly repaired during damage preliminary to or caused by infection. Lowering serum amino acid or even tissue damage repair during intestinal disease should be not nearly so advantageous. An indication that it is not is that DOC acts in the opposite direction for collagen [mice]⁴⁶ and thus tends to cancel cortisol's effect if the same thing happens in other animals.

It can be seen that denying amino acids to bacteria above could be very advantageous in a serum infection. However, the inverse generalized stimulation of protein synthesis^{44, p.273} [I'm not certain how generalized it is] could have additional survival rationale against digestive disease. 40% of the protein synthesis is in the intestines of the rat, much of it for synthesis of IgA.⁴⁷ IgA acts as an inert, nonlethal coating on bacteria to prevent adhesion to intestinal walls⁴⁷ and is the predominant immunoglobulin in the human intestine.^{43, p.597} Cortisol probably inversely stimulates IgA precursor cells in the intestines of calves [opticortinol].⁴⁸ Cortisol also inversely stimulates IgA in serum, as it does IgM, but not IgE.⁴⁹ I cannot account for the effects on IgM and IgE.

Cortisol has an opposite effect on liver than it has on muscle, but I cannot tie this for sure into the immune concept now. I suspect that it may be to provide a small amount of maintenance amino acids when the muscles are withdrawing them from the blood and possibly also to provide liver amino acids for IgA. The same inability is true of its inverse activation of luteinizing hormone.

HYDROGEN ION

Sodium, potassium, and chloride make strong bases and acid so that any unilateral movement by any of them has considerable implications in hydrogen ion control. Cortisol inversely inhibits gastric acid secretion.⁵⁰ Since hydrogen ion interferes with potassium excretion at the kidneys,^{51, p.215} this could be having a potassium conserving effect, especially since gastric secretion carries 0.6 grams of potassium per day into the stomach as well. Corticosterone has a much greater effect on gastric acid secretion than cortisol.⁵⁰ I cannot explain why it should have any affect at all unless there is some advantage to keeping the serum at a lower pH during infection for enzyme enhancement as already mentioned. Some leucocyte enzymes have a pH optimum lower than serum. If so, 18hydroxycorticosterone, which reduces bicarbonate and stimulates hydrogen ion excretion at the kidneys,⁵² operates in the same direction, since it also declines with ACTH half again more than cortisol.⁵³ Cortisol's only direct effect on the hydrogen ion excretion of the kidneys is to inversely inhibit excretion of ammonium ion by inactivation of renal glutaminase.⁵⁴ Glutaminase splits ammonia off of the amino acid glutamic acid, and this provides ammonium ion to take the place of potassium for excretion. However, cortisol's presence is necessary for the other hydrogen ion excretion regulator to operate.⁵⁴ There would have to be some restraint on hydrogen ion loss because when potassium is deficient, the kidneys fail to resorb chloride and the serum tends toward alkalosis.⁵⁵ Perhaps cortisol's inverse inhibition of gastric secretion being lower than corticosterone's is a compromise made necessary by the advantage in keeping the stomach reasonably acid, below a pH of 6, in order to help prevent reinfection by cholera bacteria.^{43, p.556} The acidosis of serum that attends cholera^{43, p.601} may become too high, so this lower inhibition may also be a compromise to help solve such a situation. The net effect of glucocorticoids is to inversely acidify the serum.

CHLORIDE

Chloride is intimately involved with potassium loss because when the cell loses potassium to take the place of serum losses and sodium migrates in, chloride must also be excreted as the only ion which has a chance of maintaining serum pH. In a potassium deficiency chloride is lost.⁵⁵ This is a serious circumstance in nature because chloride is not bound very well by soils. It is a seriously limiting element inland where vegetation is devoid of it as a rule. Some indication of its importance is that it is the only essential nutrient we can detect and be attracted to other than water [the salty taste].

Net chloride secretion in the intestines is inversely decreased by cortisol in vitro [methylprednisolone].⁵⁶ Cholera toxin forces chloride secretion to reverse from flow inward to larger flow outward.⁵⁷ Thus cortisol tends to inversely neutralize cholera's effect. There is no net movement of chloride by cholera toxin in vivo.⁵⁸ It is possible that movement of sodium and/or chloride into the intestines is the chief advantage that diarrhea bacteria attempts to gain from their water losing toxin.

COPPER

The immune system is very sensitive to copper availability. Spleen of copper deficient animals show little growth during infections.^{59, p.334} Even a mild deficiency causes spleen derived immune cells to be significantly less competent as stimulators in general and also to be stimulated by endotoxin, pokeweed, or concanavalin A.⁶⁰ Resistance to infection is reduced somewhat by a deficiency.^{59, p.334} A reduction in neutrophils is the first symptom of a deficiency in children.^{59, p.336}

It is therefore probable that increasing copper for immune purposes is the reason why many copper enzymes are inversely inhibited to an extent which is often 50% of their total potential by cortisol.^{59, p.337} This includes lysyl oxidase, an enzyme which is used to cross link collagen and elastin.^{59, p.334} DOC acts in the same direction as cortisol for lysyl oxidase.^{59, p.337} Particularly valuable for immunity is the inverse shutdown of superoxide dismutase by cortisol⁶¹ since this copper enzyme is almost certainly used by the body to inversely permit superoxide to poison bacteria. Superoxide is lethal to cholera.⁶² Indication that superoxide dismutase is involved in immunity is that phagocytic activity is reduced by free radical scavengers.⁶³

The safest way to transport copper to the immune system would be by the transport protein,^{59, p.335} ceruloplasmin. This avoids copper toxicity when copper availability is increased, since ceruloplasmin copper is not in equilibrium with the serum.^{59, p.335} The concept that ceruloplasmin is used by the immune cells as a source of copper is supported by the fact that ceruloplasmin quadruples in replete chickens during infection⁶⁴ and several antigens raise plasma ceruloplasmin in mammals^{64, p.557} by an unknown hormone, which has been tentatively proposed to be leucocyte endogenous mediator, at low ACTH levels.^{65, p.557} Cortisol is not used to inversely stimulate ceruloplasmin. I suspect the reason why cortisol is not used is that stress requires extra copper, also, and at high ACTH levels epinephrine is used for this purpose.^{65, p.556} Transporting copper as the ion is not so important for denying copper to pathogens during digestive disease, which is probably why DOC inversely loses copper from the liver and inhibits liver uptake somewhat thus providing the immune cells with free copper to supplement the ceruloplasmin source.⁶⁶ Some might argue that it is not likely that the immune cells depend on ceruloplasmin since people with Wilson's disease, in whom ceruloplasmin cannot be synthesized, are not prone to infection. However, such people cannot transport copper to the bile excretory proteins either, so their cells are already loaded and even overloaded with copper.

Cortisol causes an inverse four or five