Cytoprotective effect of bismuth subsalicylate in indomethacin-treated rats is associated with enhanced mucus bismuth concentration S. TANAKA, P. H. GUTH, O. R. CARRYL* & J. D. KAUNITZ Medical Service, West Los Angeles VA Medical Centre, and Department of Medicine, University of California, Los Angeles, California, USA; and *Procter & Gamble Health Care Products, Cincinnati, Ohio, USA Accepted for publication 22 January 1997 INTRODUCTION Bismuth salts have been used to treat gastrointestinal problems for hundreds of years. Clinical and animal studies have shown that bismuth salts are capable of protecting the gastric mucosa from injury due to a variety of stimuli, including nonsteroidal anti-in¯am- matory drugs (NSAIDs). 1±5 The mechanism underlying the gastroprotective effect of the bismuth compounds, however, is poorly understood. Since bismuth salts have no effect on acid secretion, their effects are thought to be mostly on gastric defensive mechanisms. The major site of their therapeutic actions is thought to be eroded or ulcerated areas of the mucosa. Bismuth preferentially coats ulcers in patients after taking colloidal bismuth subcitrate, 6 and in experimental gastric ulcers treated with bismuth subsalicylate 7 forming a glycoprotein- bismuth complex. 6 This bismuth coating over the lining of peptic ulcers is considered to provide a protective layer against acid-pepsin digestion. Other proposed mechanisms include stimulation of prostaglandin syn- thesis and bicarbonate secretion, 8, 9 inhibition of the proteolytic activity of pepsin, 10, 11 and antibacterial activity against Helicobacter pylori. 12 Since NSAIDs effectively inhibit prostaglandin synthesis, it is dif®cult to postulate a prostaglandin-dependent mechanism for the gastroprotective effects of bismuth. 1±5 SUMMARY Background: Bismuth compounds prevent gastric injury from the short-term administration of nonsteroidal anti- in¯ammatory drugs. We studied the mechanisms underlying the gastroprotective actions of bismuth subsalicylate against indomethacin-induced injury in rats. Methods: An in vivo microscopic technique was used in which acid output, surface cell intracellular pH (pH i ), gastric mucus gel thickness and mucosal blood ¯ow were measured simultaneously. Concentrations of bismuth in mucus were measured by atomic absorption. Results: Indomethacin (60 mg/kg) signi®cantly thinned the mucus gel layer and augmented the decrease of pH i during luminal acid superfusion, consistent with a weakened gastric mucosal barrier to acid. Bismuth subsalicylate partially reversed this effect of indomethacin on pH i , consistent with gastroprotection. Neither a prostaglandin-inhibiting but non-injurious dose of indomethacin (5 mg/kg), bismuth subsalicylate, or their combination affected mucus gel thickness or pH i homeostasis. In separate experiments, indomethacin (60 mg/kg) signi®cantly increased gastric mucus bismuth concentration in rats given bismuth subsalicylate. Conclusion: Bismuth accumulation in the gastric mucus during the evolution of mucosal injury may play an important role in the gastroprotective effect of bismuth subsalicylate against indomethacin injury. Correspondence to: Dr J. D. Kaunitz, CURE Digestive Diseases Research Centre, Building 115, Room 219, Wadsworth VA Medical Centre, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA. Aliment Pharmacol Ther 1997; 11: 605±612. Ó 1997 Blackwell Science Ltd 605