Chloride ion secretion

Mucoviscidosis or cystic fibrosis (CF) is indeed one of the most common autosomal recessive diseases. It is characterized by the production of a viscous secretion in the excretory glands. Accordingly, pancreatic cystic fibrosis can be observed in the pancreatic area and cylindrical bronchiectases in the pulmonary area. The inspissation of bile and mucus leads to obstruction of the bile canaliculi and subsequently to cholestasis. The gene product is characterized as cystic fibrosis transmembrane regulator (CFTR). (252) The gene defect, which is located on chromosome 7, causes a disorder of the intracellular transport of chloride ions (probably also of chloride ion secretion) and thus triggers the occurrence of CF. The incidence of mucoviscidosis is about 1 2,000-4,500. 

Two phase I clinical trials have tested the regimen of 72-h continuous infusion every two weeks in humans (83, 84). Seventy-six patients were treated in the NCI phase I trial. The dose-limiting toxicity (DLT) was secretory diarrhea with a maximally tolerated dose (MTD) of 50 mg/m2/day for 3 days. Flavopiridol was later found to induce chloride ion secretion in intestinal epithelial cells (85) and to have an enterohepatic circulation that may play a role in potentiating this toxicity (86). With antidiarrheal prophylaxis a higher MTD is reachable at 78 mg/m2/day for 3 days with orthostatic hypotension as the DLT. At the MTD in this study,... 

Ataka H, Ogata N, Morino H. 1999. [Creosote as a chloride ion secretion inhibitor], Japan Kokai 99335290, issued 7 Dec 1999. (Japanese). 

OPC s have poor bioavailability and consequently do not appear to be effective systemically, which reduces their potential side effects and toxicity. The mechanism of action of OPC s seems to be related to blockade of chloride ion secretion, which directly addresses the cause of water loss in diarrhea [96]. 

Most pathology of cholera is thought to result from an enterotoxin that increases cyclic adenosine monophosphate-mediated secretion of chloride ion into the intestinal lumen, which results in isotonic secretion (primarily in the small intestine) exceeding the absorptive capacity of the intestinal tract (primarily the colon). 

Figure 2.3 Absorption of bile acids by the cholangiocyte in the cholehepatic shunt. Bile acids are absorbed at the apical membrane of the cholangioc5de by the apical sodium-dependent bile-acid transporter (ASBT) that causes cholehepatic shunting of bile acids back to the hepatocyte. Absorbed bile adds are exported across the basolateral membrane by multi-drug-resistance-associated protein 3 (MRP3), a truncated form of ASBT or by the het-eromeric organic solute (OST) a and p forms. Bile adds cause choleresis that is rich in bicarbonate ions secreted by the chloride/bicarbonate ion exchanger.

The nephronic parts of the kidney are the principal diuretic active sites for secreting ede-matic fluid from the organism. Diuretics basically increase secretion of water and salts from the kidneys by suppressing reabsorption of a few main ions (primarily sodium and chloride ions) however, secretion of calcium, potassium, magnesium, and hydrocarbonate ions also increases to some degree. 

Acetazolamide is an aromatic sulfonamide used as a carbonic anhydrase inhibitor. It facilitates production of alkahne urine with an elevated biocarbonate, sodium, and potassium ion concentrations. By inhibiting carbonic anhydrase, the drug suppresses reabsorption of sodium ions in exchange for hydrogen ions, increases reflux of bicarbonate and sodium ions and reduces reflux of chloride ions. During this process, chloride ions are kept in the kidneys to cover of insufficiency of bicarbonate ions, and for keeping an ion balance. Electrolytic contents of fluid secreted by the kidneys in patients taking carbonic anhydrase inhibitors are characterized by elevated levels of sodium, potassium, and bicarbonate ions and a moderate increase in water level. Urine becomes basic, and the concentration of bicarbonate in the plasma is reduced. 

Lubiprostone has used as a novel PG compound for an oral treatment of constipation with a unique action directed to the target tissue, although it has low systemic availability following oral administration. It activates a locally acting chloride channel, which is a normal constituent of the apical membrane of the human intestine, and enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentration in the serum. In fasted rats administered doses of 1, 10, or lOOpg/kg of the compound, dose-dependent increases in the concentration of chloride ions in the bowel were detected, indicating that the compound opens chloride channels and promotes chloride ion transport in vivo [45]. 

Adrenocorticoid hormones are produced in the adrenal glands. They regulate a variety of metaholic processes. The most important mineralo-corticoid is aldosterone, an aldehyde as well as a ketone, which regulates the reahsorption of sodium and chloride ions in the kidney, and increases the loss of potassium ions. Aldosterone is secreted when hlood sodium ion levels are too low to cause the kidney to retain sodium ions. If sodium levels are elevated, aldosterone is not secreted, so some sodium will he lost in the urine and water. Aldosterone also controls swelling in the tissues. 

The active Irunsport of chloride has also been demonstrated across ihe wall of the IVog stomach, rat ileum, dog ileum, and the human ileum. Experiments have produced a double exchange model in which bicarbonate secretion and chloride absorption are linked hy an isoelectric mechanism to hydrogen ion secretion and sodium absorption across the human ileum. In 1972. a group of researchers proposed a similar model of coupled transport... 

Elevated intracellular concentrations of cAMP in crypt cells activate the CFTR, resulting in secretion of chloride ions into the lumen. 

A potassium chloride co-transporter must be closely related to the H /K -ATPase during proton secretion. Potassium and chloride ions move across the apical membrane together with secreted protons Figure 4.1) [15-17]. Potassiiun is recycled while hydrochloric acid of the gastric juice is formed by chloride ions together with the secreted protons. Stimulation of gastric acid secretion across the apical membrane may predominantly reflect the activation or insertion of an active potassium chloride co-transporter rather than direct activation of HVK -ATPase [1]. 

Hydrochloric acid is secreted by parietal cells via H, K -ATPase pumps (proton pumps), of which there are more than one million per cell. The H, K -ATPase pumps utilize the phosphorylation of ATP to exchange water-solvated protons (protonated water, hydroxonium ion, H30 ) for potassium ions. In conjunction with parallel potassium and chloride ion conductances, this ATPase is responsible for the secretion of hydrochloric acid into the secretory canaliculus of the parietal cell, the enclosed space reaching a pH of near 1.0 (Rabon Reuben 1990). In the resting parietal cell, these pumps reside within the membranes of vesicles in the cell cytoplasm. When activated by histamine and gastrin, the parietal cells alter their shape and the vesicles merge with the outer cell membrane to form secretory canaliculi. 

All tissues of the body contain potassium. It is found mainly in the muscle followed by the skeleton. Excretion of potassium via urine is also controlled by hemostatic mechanisms the kidney regulates this so that there is normally no major loss of this essential element. The amount of potassium excreted depends on the chloride ion concentration and the adrenal hormone secretion level. 

Cystic fibrosis is a hereditary disorder caused by mutation in the cystic fibrosis transmembrane conductance regulator gene that encodes a cyclic adenosine monophosphate-regulated chloride channel. Defects in chloride ion transport in the airway epithelia lead to abnormal airway secretions, impaired mucociliary clearance, chronic bacterial infection, bronchiectasis, and premature death. Delivery of the cystic fibrosis transmembrane conductance regulator cDNA by adenovirus vectors or the plasmid-liposome complex resulted in transient correction of the defects in patients with cystic fibrosis. Formulations of cationic lipid-DNA complexes for aerosol delivery are being explored to improve on the gene therapy approach. 

Recently, Cl" channels have been discovered. These channels have no sequence relationship to the voltage-gated Na, and Ca channels. One such channel is involved in the disease, cystic fibrosis. In this disease, regulation of the channel is defective. The altered function of the channel in epithelia causes elevated levels of sodium and chloride ions in sweat and, through unknown processes, the accumulation of mucus in the respiratory tract and failure of exocrine secretion in glands, such as the pancreas. Blockage of airways leads to chronic lung infections that, with other effects of the Cl" transport deficiency, can be fatal. 

The chloride ion transport dysfunction results in thickened secretions that typically lead to obstruction, infection, and inflammation in the airways. These, in turn, lead to most of the morbidity and mortality associated with CF. 

Henle (e.g., furosemide, bumetanide, and torsemide) and distal convoluted tubule (thiazides), have most commonly been associated with the generation of metabolic alkalosis. These agents promote the excretion of sodium and potassium almost exclusively in association with chloride, without a proportionate increase in bicarbonate excretion. Collecting duct hydrogen ion secretion is stimulated directly by the increased luminal flow rate and sodium delivery, and indirectly by intravascular volume contraction, which results in secondary hyperaldosteronism. Renal ammoniagenesis may also be stimulated by concomitant hypokalemia, further augmenting net acid excretion. 

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