Hypochlorhydria Abstracts 10

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KCNE2 and the K (+) channel: the tail wagging the dog

         (Abbott 2012) Download

KCNE2, originally designated MinK-related peptide 1 (MiRP1), belongs to a five-strong family of potassium channel ancillary (beta) subunits that, despite the diminutive size of the family and its members, has loomed large in the field of ion channel physiology. KCNE2 dictates K (+) channel gating, conductance, alpha subunit composition, trafficking and pharmacology, and also modifies functional properties of monovalent cation-nonselective HCN channels. The Kcne2 (-/-) mouse exhibits cardiac arrhythmia and hypertrophy, achlorhydria, gastric neoplasia, hypothyroidism, alopecia, stunted growth and choroid plexus epithelial dysfunction, illustrating the breadth and depth of the influence of KCNE2, mutations which are also associated with human cardiac arrhythmias. Here, the modus operandi and physiological roles of this potent regulator of membrane excitability and ion secretion are reviewed with particular emphasis on the ability of KCNE2 to shape the electrophysiological landscape of both excitable and non-excitable cells.

Differences in action of topical and systemic cysteamine on gastric blood flow, gastric acid secretion and gastric ulceration in the rat

         (Abdel-Salam, Szolcsanyi et al. 1996) Download

The effect of cysteamine on gastric blood flow and on the indomethacin-induced gastric mucosal damage was studied. In anesthetized rats, cysteamine (280 mg/kg) given subcutaneously (s.c.) decreased gastric blood flow measured by the laser Doppler flowmetry technique. In contrast, cysteamine (1-60 mg/ml) applied topically to the serosal surface of the stomach evoked a concentration-dependent and long-lasting increase in gastric blood flow. At 60 mg/ml, cysteamine increased blood flow by 166.8 +/- 26.1% of predrug control value. Pretreatment with indomethacin (20 mg/kg, s.c.), intravenous (i.v.) atropine (1 mg/kg), propranolol (1 mg/kg, i.v.), combined H1 and H2-blockade or bilateral cervical vagotomy alone or combined with i.v. guanethidine (8 mg/kg), or pretreatment with the capsaicin analogue resiniferatoxin did not reduce the vasodilator response to cysteamine. The vasodilator response to topical capsaicin, was not reduced after s.c. cysteamine (280 mg/kg) pretreatment. In conscious pylonus-ligated rats, s.c. cysteamine (100 or 280 mg/kg) given simultaneously with indomethacin inhibited gastric acid output but had variable effects on the indomethacin-induced gastric mucosal damage. Cysteamine (100 or 280 mg/kg) administered s.c. 4 h prior to indomethacin enhanced gastric injury by s.c. indomethacin, but did not prevent the gastroprotective action of capsaicin. In contrast, orally administered cysteamine (60 mg/ml) reduced gastric injury induced by s.c. indomethacin plus intragastric HCl. These data provide the first evidence for the effect of cysteamine on gastric microcirculation in the rat and suggest a direct vasodilator effect for topical cysteamine. The microvascular effects of cysteamine are largely responsible for the different effects of this agent on experimental gastric injury.

Cysteamine: an old drug with new potential

         (Besouw, Masereeuw et al. 2013) Download

Cysteamine is an amino thiol with the chemical formula HSCH2CH2NH2. Endogenously, cysteamine is derived from coenzyme A degradation, although its plasma concentrations are low. Most experience with cysteamine as a drug originates from the field of the orphan disease cystinosis, in which cysteamine is prescribed to decrease intralysosomal cystine accumulation. However, over the years, the drug has been used for several other applications both in vitro and in vivo. In this article, we review the different applications of cysteamine, ending with an overview of ongoing clinical trials for new indications, such as neurodegenerative disorders and nonalcoholic fatty liver disease (NAFLD). The recent development of an enteric-coated cysteamine formulation makes cysteamine more patient friendly and will extend its applicability for both old and new indications.


Potential of cystamine and cysteamine in the treatment of neurodegenerative diseases

         (Gibrat and Cicchetti 2011) Download

Neurodegenerative disorders are a subset of disabling pathologies characterized, in part, by a progressive and specific loss of certain brain cell populations. Current therapeutic approaches for the treatment of these disorders are mainly designed towards symptom management and do not manifestly block their typified neuronal loss. However, research conducted over the past decade has reflected the increasing interest and need to find disease-modifying molecules. Among the several neuroprotective agents emerging from experimental animal work, cystamine, as well as its reduced form cysteamine, have been identified as potential candidate drugs. Given the significant benefits observed in a Huntington's disease (HD) model, cysteamine has recently leaped to clinical trial. Here, we review the beneficial properties of these compounds as reported in animal studies, their mechanistic underpinnings, and their potential implications for the future treatment of patients suffering from neurodegenerative diseases, and more specifically for HD and Parkinson's disease (PD).

No potassium, no acid: K+ channels and gastric acid secretion

         (Heitzmann and Warth 2007) Download

The gastric H+-K+-ATPase pumps H+ into the lumen and takes up K+ in parallel. In the acid-producing parietal cells, luminal KCNE2/KCNQ1 K+ channels play a pivotal role in replenishing K+ in the luminal fluid. Inactivation of KCNE2/KCNQ1 channels abrogates gastric acid secretion and dramatically modifies the architecture of gastric mucosa.

The Clinical Significance Of Primary Achlorhydria

(Schneider and Carey 1928) Download

The ninety-three cases of achlorhydria studied between February, 1921, and February, 1928, can be broadly classified as primary and secondary. The causes that may operate to produce a secondary achlorhydria are chronic cholecystitis, gastric carcinoma, gastric syphilis, alcoholism, old age (arteriosclerosis), chronic upper respiratory infection (sinusitis, tonsillitis, bronchitis), mouth infection (caries and pyorrhea), pregnancy, toxic goiter, myxedema and tuberculosis (both pulmonary and intestinal). Achlorhydria is also found often enough in certain other conditions, such as migraine, allergic conditions and skin diseases (acne rosacea, scleroderma), to make a direct relationship rather certain. There are a number of persons without free hydrochloric acid in the gastric secretions in whom none of these etiologic factors are demonstrable. In our records, forty-two cases were found which fell under some one of the foregoing classifications. Chronic cholecystitis and carcinoma of the stomach were not included, since the absence of acid in the former is rather

The aging oesophagus

         (Tack and Vantrappen 1997) Download


References

Abbott, G. W. (2012). "KCNE2 and the K (+) channel: the tail wagging the dog." Channels (Austin) 6(1): 1-10. [PMID: 22513486]

Abdel-Salam, O., J. Szolcsanyi, et al. (1996). "Differences in action of topical and systemic cysteamine on gastric blood flow, gastric acid secretion and gastric ulceration in the rat." J Physiol Paris 90(2): 63-73. [PMID: 8865086]

Besouw, M., R. Masereeuw, et al. (2013). "Cysteamine: an old drug with new potential." Drug Discov Today 18(15-16): 785-92. [PMID: 23416144]

Gibrat, C. and F. Cicchetti (2011). "Potential of cystamine and cysteamine in the treatment of neurodegenerative diseases." Prog Neuropsychopharmacol Biol Psychiatry 35(2): 380-9. [PMID: 21111020]

Heitzmann, D. and R. Warth (2007). "No potassium, no acid: K+ channels and gastric acid secretion." Physiology (Bethesda) 22: 335-41. [PMID: 17928547]

Schneider, J. P. and J. B. Carey (1928). "The Clinical Significance Of Primary Achlorhydria." JAMA 91(23): 1763-1768. [PMID:

Tack, J. and G. Vantrappen (1997). "The aging oesophagus." Gut 41(4): 422-4. [PMID: 9391234]