ABSTRACT
BACKGROUND: Duodenal mucosal bicarbonate secretion serves as a key defensive factor against mucosal injury. The purpose of the present study was to isolate human proximal duodenal enterocytes and identify their inherent acid/base transporters that participate in duodenal alkaline secretion. METHODS: Biopsy specimens were obtained from the duodenal bulb in 18 healthy volunteers. Individual duodenal epithelial cells were isolated by means of a combination of calcium chelation and collagenase. Intracellular pH (pHi) was measured by the pH-sensitive dye BCECF and dynamic fluorescence ratio imaging. RESULTS: Cytologic and histologic examination confirmed that isolated cells were of epithelial origin. In HCO3--free media, pHi recovery after acidification with NH4Cl was amiloride-sensitive and Na+-dependent, indicating the presence of an Na+/H+ exchanger. pHi recovery after acidification was significantly enhanced by the presence of HCO3-, showing the presence of an HCO3--dependent recovery mechanism (that is, a base loader/acid extruder). HCO3--dependent recovery required external Na+ yet was Cl-- and amiloride-insensitive, characteristic of an NaHCO3 cotransporter. In the presence of HCO3-, a Cl--dependent anion exchanger serving as a base extruder was shown, indicative of a Cl-/HCO3- exchanger. CONCLUSIONS: Human duodenal enterocytes contain at least three acid/base transporters: an Na+/H+ exchanger that serves as to extrude acid, an NaHCO3 cotransporter that functions as base loader, and a Cl-/HCO3- exchanger that operates as a base extruder.
Subject(s)
Duodenum/metabolism , Acid-Base Equilibrium , Adult , Antiporters/metabolism , Bicarbonates/metabolism , Biopsy , Carrier Proteins/metabolism , Chloride-Bicarbonate Antiporters , Duodenum/cytology , Epithelial Cells/metabolism , Female , Humans , Hydrogen-Ion Concentration , Male , Middle Aged , Sodium-Bicarbonate Symporters , Sodium-Hydrogen Exchangers/metabolism , Time FactorsABSTRACT
The proximal duodenal epithelium secretes bicarbonate into an adherent mucus layer, thereby protecting the mucosa from injury by gastric acid and pepsin. While bicarbonate secretion is stimulated and inhibited by a number of agonists and antagonists, the apical anion transport pathways have not been addressed fully. The objective was to assess if apical Cl-/HCO3- exchange and Cl-:HCO3- conductance are involved in duodenal mucosal bicarbonate secretion (DMBS). In healthy volunteers, the proximal 4 cm of duodenum was isolated, perfused with either saline or 4,4'-diisothiocyano-2,2'-disulfonic acid (DIDS), and bicarbonate secretion and transepithelial potential difference (PD) were stimulated by either PGE2 or the phosphodiesterase inhibitor theophylline to increase cyclic AMP. Luminal DIDS abolished PGE2-stimulated DMBS, yet had no effect on the increase in PD and failed to significantly alter theophylline-induced DMBS and PD. Therefore, in human proximal duodenum, it appears that PGE2 and cAMP activate distinct HCO3- transport pathways likely involving a DIDS-sensitive Cl-/HCO3- exchanger and DIDS-insensitive HCO3- conductance.
Subject(s)
Bicarbonates/metabolism , Duodenum/metabolism , Intestinal Mucosa/metabolism , 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid/pharmacology , Adult , Antiporters , Cyclic AMP/pharmacology , Dinoprostone/pharmacology , Female , Humans , Ion Transport , Male , Middle Aged , Theophylline/pharmacologyABSTRACT
BACKGROUND & AIMS: Eradication of Helicobacter pylori expedites duodenal ulcer healing and prevents recurrences. Most patients with duodenal ulcers have impaired proximal duodenal mucosal bicarbonate secretion (DMBS). In patients with inactive, healed duodenal ulcers and normal subjects, the effect of H. pylori infection on DMBS and proximal duodenal secretory function and structure were examined. METHODS: DMBS was quantitated before and after eradication of H. pylori. Mucosal structure (duodenal bulb histopathology) and function (DMBS at rest and stimulated, effect of active vs. healed ulcer and of age) were determined in patients with duodenal ulcers and normal subjects. RESULTS: In patients with duodenal ulcers, H. pylori eradication normalized proximal DMBS. Histological examination of duodenal biopsy samples was comparable in patients with duodenal ulcers and normal subjects without apparent relationship between inflammation and DMBS. Significantly impaired DMBS occurred in response to all agonists tested (luminal acid, prostaglandin E2, and cephalic-vagal stimulation) in patients with duodenal ulcers, suggesting a generalized secretory defect. Neither the presence of active (vs.inactive) ulcer nor age significantly affected bicarbonate secretion. CONCLUSIONS: In patients with duodenal ulcers, eradication of H. pylori normalized proximal DMBS and may thereby reduce ulcer recurrences. Altered DMBS in patients with duodenal ulcers was unrelated to histopathologic abnormalities. Impaired bicarbonate secretion in patients with duodenal ulcers could be caused by a cellular and/or physiological regulatory transport defect possibly related to H. pylori.
Subject(s)
Bicarbonates/metabolism , Duodenal Ulcer/metabolism , Duodenum/metabolism , Helicobacter Infections/drug therapy , Helicobacter pylori , Adult , Age Factors , Aged , Duodenal Ulcer/etiology , Duodenal Ulcer/pathology , Duodenum/microbiology , Duodenum/pathology , Female , Helicobacter Infections/complications , Humans , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Linear Models , Male , Middle Aged , Prospective Studies , RecurrenceABSTRACT
Increased levels of cholesterol, LDL-cholesterol, and VLDL-cholesterol are known risk factors for the development of coronary artery disease. There are multiple drugs that can be used for lowering cholesterol, including lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme step in cholesterol synthesis in the body. The pharmacology of this novel agent is discussed in this article.
