Enhancement of the protective qualities of gastric mucus by sucralfate: role of phosphoinositides.
The effects of intragastric administration of sucralfate on the physicochemical properties of gastric mucus, and the mechanism of its protective action against alcohol-induced mucosal injury were investigated using in vivo and in vitro models. The experiments in vivo were conducted with groups of rats receiving a dose of 100 mg sucralfate twice daily for 5 consecutive days. The animals were sacrificed 16 hours after the last dose, their stomachs dissected, and the mucosa subjected to physicochemical measurements. In the in vitro studies, gastric mucosa was cultured in the presence of sucralfate, ethanol, or both. The in vivo results revealed that sucralfate elicited an 8% increase in mucus gel dimension, while its sulfo- and sialomucin content increased by 63% and 81%, respectively. The changes in mucus gel mucin content with sucralfate were accompanied by a 9.5% increase in mucus hydrogen ion (H+) retardation capacity, 1.9-fold increase in viscosity, and a 60% increase in the gel hydrophobicity. The mucus elaborated in the presence of sucralfate exhibited 14% lower protein content and 62% higher content of carbohydrate than that of control, and contained more neutral lipids. Furthermore, the gastric mucus of the sucralfate group showed a marked increase in mucus glycoprotein polymeric form. The data obtained with gastric mucosal culture demonstrated that sucralfate elicited a significant increase in mucin synthesis, which was reflected in the enhanced metabolism of mucosal phosphoinositides. In contrast, ethanol, which exhibited detrimental effects on mucin synthesis, also caused alterations in the phosphoinositide signal pathway. The changes in mucin and phosphoinositide distribution patterns evoked by ethanol were prevented by sucralfate. Our results suggest that the mucosal strengthening action of sucralfate occurs through the stimulation of the metabolism of phosphoinositide-derived messenger molecules.
Slomiany
B L
BL
Research Center, University of Medicine and Dentistry, Newark, New Jersey Dental School 07103-2400.
Piotrowski
J
J
Tamura
S
S
Slomiany
A
A
D000818:Animals; D002241:Carbohydrates / Q000737:chemistry; D005752:Gastric Mucins / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism; D005753:Gastric Mucosa / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D007295:Inositol Phosphates / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D008297:Male; D015394:Molecular Structure; D009077:Mucins / Q000737:chemistry; D010716:Phosphatidylinositols / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D011506:Proteins / Q000737:chemistry; D051381:Rats; D011919:Rats, Inbred Strains; D052116:Sialomucins; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D013392:Sucralfate / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014783:Viscosity
D002241:Carbohydrates; D005752:Gastric Mucins; D007295:Inositol Phosphates; D008055:Lipids; D009077:Mucins; D010716:Phosphatidylinositols; D011506:Proteins; D052116:Sialomucins; C012564:sulfomucin; D013392:Sucralfate