Mostafa Elbaba
Doha, Qatar

In humans, sodium controls the balance of fluids in the body and the absorption of nutrients in the alimentary tract. Sodium is also involved in nerve impulse transmission and cell membrane electrical activity. Significant changes in the sodium level prevent cells from carrying out those physiological functions, disrupting what is known as “homeostasis.” Claude Bernard (1813–1878), a French physiologist, first described this concept in what he called the “milieu intérieur.” Later, Walter Cannon (1871–1945) coined the term “homeostasis” by developing Bernard’s concept. Cannon popularized his theories, including the theory of homeostasis, in his book The Wisdom of the Body published in 1932.

The word “sodium” probably originated from an Arabic word “suda” meaning “headache,” because sodium was used in the past to cure headaches. “Suda” carried over into Latin to become “sodanum”, which also means “headache remedy.” Ancient Egyptians used sodium to dehydrate mummies; they called it “soda natron.” The Romans then used a similar name for the compound, “natrium,” which explains the chemical symbol used for sodium, “Na.” The ancient medical texts are full of recipes using sodium chloride or natrium. Current pharmacological knowledge does not fully explain its place in ancient medicine.

Because it is so active, sodium never occurs as a free element in nature. Instead, it binds to other elements to create compounds that are difficult to break apart. Naturally occurring sodium compounds have been known throughout human history but were not synthesized until the early nineteenth century. Moreover, at that time no distinction had been made between potassium and sodium. By the late 1700s, chemists were convinced that both potash and soda ash contained elements they had never seen. They tried to find a way to break these compounds down into their elements. In the 1780s, French chemist Nicolas Le Blanc (1742-1806) invented an inexpensive method for making soda ash. He used three common and inexpensive materials: salt (sodium chloride), limestone (calcium carbonate), and coal (pure carbon). The Le Blanc method of making soda ash is quick, easy, and cheap.

Sir Humphry Davy (1778–1829), a British chemist and inventor, found a way to extract sodium and other elements from compounds. Davy’s method is called electrochemistry; it involved melting a compound of the active element, then passing an electric current through the melted compound. At first, Davy tried to pass an electric current through a water solution of a compound, but no new element was formed. Later, in 1807, he melted potash and soda ash and passed an electric current directly through the melted substances. He observed that tiny liquid droplets of potassium and sodium metals formed in each case. In 1809, the German physicist and chemist Ludwig Wilhelm Gilbert (1769–1824) proposed the names “Natronium” for Davy’s “sodium” and “Kalium” for “potassium.” In 1810, chlorine was given its current name by Davy himself. The chemical abbreviation for sodium “Na” was first published in 1814 by Jöns Jakob Berzelius (1779–1848) in his system of atomic symbols.

In 1858, Claude Bernard found that a lesion in the brain produced chloride diuresis but not glucose in urine. Bernard thought this syndrome was due to renal denervation. Later, in 1913, by inducing lesions in the medulla of animal brains, Jungmann and Meyer from Germany observed polyuria and increased salt excretion, which continued despite water restriction. In 1936, McCance described patients with extrarenal salt losses and low urinary sodium, but the mechanisms behind these conditions were not fully understood.

Shortly after World War II, it became possible to determine serum sodium concentration. In 1945, Berry, Barnes, and Richardson measured sodium and potassium by means of a new device called a “flame photometer.” Yale was one of the first medical centers to have a flame photometer, and so published some of the first observations about hyponatremia.

Alan Hodgkin (1914–1998) from Britain and Bernard Katz (1911–2003) from Germany were Nobel prize-winning physiologists and biophysicists. Alan Hodgkin conducted his initial experiments on electrical activity in the sciatic nerve of frogs in July 1934. Bernard Katz described the properties of synapses and studied the biochemistry and action of acetylcholine. In 1949, both Hodgkin and Katz hypothesized that the cellular membrane might have different ion permeabilities. They correlated a mathematical model with discrete ion channels that could exist in different opening states.

Almost a century after Bernard’s work in animals, John P. Peters (1887–1955), an American chemist, in 1950 reported on three patients with cerebral pathologies associated with hyponatremia and severe dehydration. Urine sodium losses persisted despite hyponatremia and a high-salt diet, there was no evidence of extrarenal sodium loss, and the hyponatremia responded well to salt therapy. He suggested that an extrapituitary cerebral structure mediated normal sodium metabolism, but the mechanism of action was not well explained. A subsequent paper from the group at Yale incorrectly attributed such hyponatremia in neurologic disease to an SIADH-like syndrome. In 1952, Louis G. Welt found that a direct neural control of the renal proximal tubular reabsorption of sodium was disrupted, and that neither pituitary nor adrenal insufficiency was involved.

After 1950, the normal renal regulatory mechanisms for salt and water balance were better understood. The responsibility for the maintenance of a normal volume and tonicity of body fluids falls on the kidneys. This modern concept of renal physiology described the transformation of a large volume of glomerular filtrate to a much smaller volume of final altered urine. The proximal portion of renal tubule is responsible for decreasing filtrate volume, and to a lesser extent, for alterations in composition. However, the distal tubule is responsible for fine adjustments in the handling of water and sodium. Animal studies in the 1950s also suggested that renal denervation disrupts proximal tubular reabsorption, resulting in osmotic diuresis in the distal tubule.

Alexander Leaf (1920–2012) was an American physician born in Japan. His research on how sodium and potassium pass through cell walls contributed significantly to understanding the causes of heart disease. In 1953, Dr. Leaf demonstrated that exogenous administration of vasopressin resulted in hyponatremia. Moreover, natriuresis was dependent on water retention and weight gain as a physiologic response to an expanded intravascular volume, not a salt-wasting condition. Other studies at the time showed that vasopressin administration to healthy humans resulted in water retention and urinary loss of sodium. Following these publications, the term “CSW” vanished from the literature for over two decades, with hyponatremia in patients with cerebral pathology assumed to result from SIADH.

The sodium–potassium pump was identified in 1957 by the Danish biochemist Jens Christian Skou (1918–2018), who was awarded a Nobel Prize in 1997. While working as an assistant professor in physiology and studying the action of local anesthetics, he discovered that a substance’s anesthetic action was related to its ability to dissolve in a layer of the lipid part of the plasma membrane. He initially looked at ATPase in crab nerves and suggested the anesthetic molecules affected the opening of sodium channels, which he assumed to be protein. The properties of the sodium–potassium pump were thereafter gradually illuminated.

William Schwartz (1922–2009) attended Duke University after serving in the US Army in World War II. He observed that sulfanilamide increased excretion of sodium in patients with heart failure. This observation was the basis for the discovery and development of modern diuretic drugs. Frederic Bartter (1914–1983) worked on hormones affecting the kidney that led to the discovery of syndrome of inappropriate antidiuretic hormone (SIADH) in 1957 and Bartter syndrome in 1963. Schwartz-Bartter syndrome is named after these two scientists. The first reports of hyponatremia and renal sodium loss corrected by fluid restriction in patients with bronchogenic carcinoma were published by Bartter. At that time, no direct measurement of vasopressin was done.

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