Physiological Ion Chloride Arafat Siddiqui East-West University Dhaka, Bangladesh

Chloride II Introduction Physiological ions or electrolytes are released through the dissociation of inorganic compounds; they are so named because they can conduct an electrical current in a solution. Electrolytes play a vital role in maintaining homeostasis within the body. They help to regulate myocardial and neurological function, fluid balance, oxygen delivery, acid-base balance and much more. Sodium, potassium, calcium, magnesium, chloride, phosphate and bicarbonate are major electrolytes. Our particular attention will be restricted for chloride ion. Chemistry of chloride ion The chloride ion is formed when the element chlorine picks up one electron to form an anion (negatively-charged ion) Cl−. Atomic molecular weight is 35 and radius is 0.12 nm. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. An example is table salt, which is sodium chloride with the chemical formula NaCl. In water, it dissolves into Na+ and Cl− ions. Chloride as a physiological ion in human body Chloride is the major extra cellular anion and is principally responsible for maintaining proper hydration, osmotic pressure, and normal cation- anion balance in the vascular and intestinal fluid compartments. The normal plasma concentration is 95-105 m Eq/L and interstitial fluid concentration is 115mEq/L. In the ICF, its usual concentration is 3mEq/L. Total amount in human body is 50mEq/kg. Best food sources include animal foods, table salt. Required daily allowance (RDA, 1968) for Cl− is 5-10 g as NaCl.

Figure 1: Electrolyte composition of human body fluids.

Chloride III Chloride balance in human body Each day, our body fluids gain electrolytes from the food and drink we consume and loss electrolytes in urine, sweat and feces. For each ion, daily gains must balance daily losses. For example, if we lose 500 mg of Clˉ in urine and insensible perspiration, we need to gain 500 mg of Clˉ from food and drink to remain in chloride balance. This balance is known as electrolyte balance. Electrolyte balance primarily involves balancing the rates of absorption across the digestive tract with rates of loss at the kidneys, although losses at sweat gland and other sites can play a secondary role. Chloride is almost completely absorbed from the intestinal tract. It is removed from the blood by glomerular filtration and is reabsorbed by the kidney tubules. Absorption of chloride from the intestinal tract: Cl- normally enters enterocytes from the interstitial fluid via Na+-K+-2Clcotransporters in their basolateral membranes (Figure 2), and the Cl- is then secreted into the intestinal lumen via channels that are regulated by various protein kinases. One of these is activated by protein kinase A and hence by cAMP. The cAMP concentration is increased in cholera. The cholera vibrio stays in the intestinal lumen, but it produces a toxin which binds to GM-1 ganglioside receptors, and this permits part of the A subunit (A1 peptide) of the toxin to enter the cell. The A 1 peptide binds adenosine diphosphate ribose to the α subunit of Gs, inhibiting its GTPase activity. Therefore, the constitutively activated G protein produces prolonged stimulation of adenylyl cyclase and a marked increase in the intracellular cAMP concentration. In addition to increased Cl - secretion, the function of the mucosal carrier for Na+ is reduced, thus reducing NaCl absorption. The resultant increase in electrolytes and water content of the intestinal contents causes the diarrhea. However, Na+-K+ ATPase and the Na+/glucose cotransporter are unaffected, so coupled reabsorption of glucose and Na+ bypasses the defect.

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Figure 2: Movement of ions across enterocytes in the small intestine. Cl- enters the cell via the Na+-K+-2Cl- cotransporter on its basolateral surface and is secreted into the intestinal lumen via Cl- channels, some of which are activated by cyclic AMP. K+ recycles to the interstitial fluid (IF) via basolateral K+ channels. Reabsorbtion of Chloride by the kidney tubules: Chloride is a chemical the human body needs for metabolism (the process of turning food into energy). It also helps keep the body's acid-base balance. The amount of serum chloride is carefully controlled by the kidneys. Renal reabsorption of chloride (Cl-) is a part of renal physiology, in order not to lose too much chloride in the urine. Several carrier protien along the renal tubules reabsorbs Cl- with Na+ . Chloride reabsorbtion mainly occurs in nephron loop and distal convoluted tubule. In the nephron loop this reabsorbtion follows countercurrent multiplication. The thin descending limb is permeabke to water but relatively impermeable to solutes.

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Table1: Clˉ reabsorption in kidney (PCT= proximal convoluted tubule, DCT= distal convoluted tubule) Chracterstics: Concentration (mM) Electrical Driving Force (mv) Electrochemical Driving Force (mv) Apical transport Protein Passively Clˉ-formate exchanger, Clˉ-oxalate exchanger, Clˉ-bicarbonate exchanger, Clˉ-OHˉ exchanger, Basolateral Transport Protein Clˉ channel, Clˉ-K cotransporter Clˉ channel Clˉ channel Na+-K+-Clˉ Na+-Clˉ cotransporter cotransporter paracellularly β-intercalated exchanger, Clˉ-HCOˉ exchanger Positive -3 +3 +15 +5 to -5 -40 PCT(S1) PCT(S3) 115 135 Loop of Henle DCT Collecting Duct

Chloride VI The thick ascending limb, which is relatively impermeable to both water and solutes, contains active transport mechanism that pump sodium and chloride ions from the tubular fluid into the peritubular fluid of the medula.

Figure3: Countercurrent multiplication. The countercurrent multiplication is described below: • • • Sodium and chloride are pumped out of the thick ascending limb and into the peritubular fluid. This pumping action elevates the osmotic concentration in the peritubular fluid around the thin descending limb. The result is an osmotic flow of water out of the thin descending limb and into the peritubular fluid, increasing the solute concentration in the thin descending limb. • The arrival of the highly concentrated solution in the thick ascending limb accelerates the transport of sodium and chloride ions into the peritubular fluid of the medulla. Active transport at the apical surface moves sodium, potassium, and chloride ions out of the tubular fluid. The carrier is called a Na+-K+-2Cl- transporter, because each cycle of the pump carries a sodium ion, a potassium ion, and two chloride ions into the tubular cell.

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Figure4: Countercurrent multiplication. Potassium and chloride ions are pumped into the peritubular fluid as the sodiumpotassium exchange pump pumps sodium ions out of the tubular cell. The potassium ions then diffuse back into the lume3n of the tubule through potassium leak channels. The net result is that sodium and chloride enter the peritubular fluid of the renal medulla.

Figure5: Chloride reabsorption at DCT. In case of DCT the tubular cells actively transport sodium and chloride out of the tubular fluid.

Chloride VIII Bicarbonate ions are reabsorbed in exchange of chloride ions in the peritubular fluid of collecting duct. Here, chloride is secreted into the tubular fluid.

Figure6: Chloride secretion as HCL and ammonium chloride at collecting duct. The chloride-bicarbonate exchanger biological transport protein relies on the chloride ion to increase the blood's capacity of carbon dioxide, in the form of the bicarbonate ion. Anion Exchanger 1 (AE1) or Band 3 is a phylogenetically preserved transport protein responsible for mediating the electroneutral exchange of chloride (Cl-) for bicarbonate across a plasma membrane. It is ubiquitous throughout the vertebrates. In humans it is present in two specific sites:the erythrocyte (red blood cell) cell membrane and the basolateral surface of the alpha-intercalated cell (the acid secreting cell type) in the collecting duct of the kidney. A different isoform of AE1, known as kAE1 (which is 65 amino acids shorter than erythroid AE1) is found in the basolateral surface of the alpha-intercalated cell in the cortical collecting duct of the kidney. This is the principal acid secreting cell of the kidney, which generates hydrogen ions and bicarbonate ions from carbon dioxide and water-a reaction catalysed by Carbonic anhydrase.The hydrogen ions are pumped into the collecting duct tubule by vacuolar H+ATPase, the apical proton pump,which thus excretes acid into the urine.kAE1 exchanges bicarbonate for chloride on the basolateral surface, essentially returning bicarbonate to the blood.

Chloride IX Mutations of kidney AE1 cause distal (type1) renal tubular acidosis, which is an inability to acidify the urine, even if the blood is too acid. These mutations are disease causing as they cause mistargetting of the mutant band 3 proteins so that they are retained within the cell or occasionally addressed to the wrong (ie apical) surface. Importance of chloride balance Chloride blance have important physiological roles. For instance, in the central nervous system, the inhibitory action of glycine and some of the action of GABA relies on the entry of Cl− into specific neurons. Chloride imbalance causes either hypochloremia or hyperchoremia. Hypochloremia: Hypochloremia (or Hypochloraemia) is an electrolyte disturbance whereby there is an abnormally depleted level of the chloride ion in the blood. It can be caused by1. Salt- losing nephritis (inflammation of the kidney) associated with chronic pyelonephritis (inflammation of the kidney and its pelvis), leading to a probable lack of tubular reabsorption of chloride. 2. Metabolic acidosis such as found in diabetes mellitus and renal failure, causing either cxcessive production or diminished excretion of acids leading to the replacement of chloride by acetoacetate and phosphate. 3. Prolonged vomiting with loss of chloride as gastric HCl. 4. It can be associated with hypoventilation. Body Cl− usually follows body sodium, both ions being depleted together, but occasionally body Cl− is markedly reduced with relative preservation of sodium. Selective depletion of Cl− is most often seen in patients who have lost large amounts of gastric HCl from pyloric stenosis or self- induced vomiting and less often in patient who have received excessive diuretics combined with salts of potassium other than the chloride (usually bicarbonate or tartarate) to prevent potassium depletion. Usually patients shows signs of saline deplerion caused by an accompanying sodium deficit, and have a low plasma potassium but their disproportionate Cl− deficiency is shown by the existence of a hypochloraemic alkalosis and urinary Cl− concentrations and Cl− : Na+ ratios which are close to zero. When provided with NaCl or KCl these patients avidly retain Cl − and

Chloride X excrete an alkaline bicarbonate rich urine, thus correcting their Cl− deficiency and alkalosis while simultaneously restoring body Na+ and K+ . Hyperchloremia: Hyperchloremia is an electrolyte disturbance in which there is an abnormally elevated level of the chloride ion in the blood. Often hyperchloremia does not produce any symptoms. However, hyperchloremia is sometimes associated with excess fluid loss such as vomiting and diarrhea. If the sufferer were to be a diabetic, hyperchloremia could lead to poor control of blood sugar levels, which could cause them to become elevated. Hyperchloremia can be symptomatic with signs of Kussmaul's breathing, weakness, and intense thirst. Elevations in chloride may be associated with diarrhea, certain kidney diseases as Lightwood syndrome, and overactivity of the parathyroid glands. Hyperchloremia is often comorbid with diabetes or hyponatremia. Certain drugs, especially diuretics such as carbonic anhydrase inhibitors, hormonal treatments, and polypharmacy, may contribute to this disorder. As with most types of electrolyte imbalance, the treatment of high blood chloride levels is based on correcting the underlying cause.

If the patient is dehydrated, therapy consists of establishing and maintaining adequate hydration. If the condition is caused or exacerbated by medications or treatments, these may be altered or discontinued, if deemed prudent. If there is underlying kidney disease (which is likely if there are other electrolyte disturbances), then the patient will be referred to a nephrologist for further care. If there is an underlying dysfunction of the endocrine or hormone system, the patient will likely be referred to an endocrinologist for further assessment.

Conclusion: Chloride ions are the most abundant anions in the extra cellular fluid. It also helps keep the body's acid-base balance. Alternations in the serum chloride concentration are rarely a primary indicator of major medical problems. Chloride itself is not of primary diagnostic significance. It is usually measured to confirm the serum sodium concetration.Yet as a part of our body homeostasis it is important.

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