Assessment of salicylate derivatives for potential use in ulcerative colitis: proposal for a new action of 5-aminosalicylic acid?

The therapeutic efficacy of salicylate drugs for ulcerative colitis in vivo is related to the capacity of each drug to suppress fatty acid oxidation in colonocytes in vitro. The suppression index of fatty acid oxidation (SIFO) was assessed with 17 salicylate drugs of either known or unknown therapeutic efficacy. The high SIFO value of 5-aminosalicylic acid (5-ASA) was reduced to zero when the amino group was replaced with a methyl, nitro, hydroxyl or bromine group. The SIFO of 3-ASA was dose-related and 2- to 3-fold greater than the SIFO of 5-ASA. The antioxidants methyl- or propyl-4-hydroxybenzoate have a high SIFO, but show a 'toxic' action towards colonocytes not observed with 3-ASA, 4-ASA or 5-ASA. A new cellular action proposed for 5-ASA is that acetylation of the amino group of 5-ASA in colonocytes releases free CoA countering sequestration of CoA observed in epithelial cells during active colitis.

Effect of luminal or circulating nitrite on colonic ion movement in the rat.

The disposition of intravenously or luminally administered nitrite across the colonic mucosa and its effect on ion movement into or from the colon was assessed in anesthetized Porton rats using the isolated colon instilled either with sodium chloride (120 mM) or sodium chloride (80 mM) with sodium butyrate (40 mM). Ionic changes in the colon after intravenous injection of 10 mumol NaNO2 were compared with those occurring after injection of 10 mumol NaCl. After intravenous administration of nitrite, both nitrite and nitrate appeared in the colonic instillate in a ratio of 1:1. Nitrite increased chloride absorption (110%) and bicarbonate production (20%) when 40 mM butyrate was included in the instillate. Net sodium absorption, measured in the whole colon, was unchanged. Intravenous nitrite had no effect on ionic movement in the absence of butyrate. When NaNO2 (100 microM) was included luminally with the sodium chloride-butyrate instillate, bicarbonate production rate increased (25%), but sodium and chloride absorption were unaffected. Nitrite concentration in the instillate decreased during the 40-min experimental period at a rate of 0.275 nmol X min-1 X cm-2, and nitrate appeared at a rate of 0.037 nmol X min-1 X cm-2. We conclude that nitrate stimulates bicarbonate production in the colon, probably by stimulating the oxidation of butyrate, the main source of CO2 generation by the colonic mucosa.

Specific metabolic effect of sodium nitrite on fat metabolism by mucosal cells of the colon.

The effect on the mucosa of sodium nitrite that enters the colon from the ileum or transmucosally from the circulation is unknown. Isolated colonic mucosal cells and Roux-en-Y colostomies were used to test whether high doses of sodium nitrite (5-40 mM) had any harmful histological or inhibitory metabolic actions on the mucosa. Luminal instillation of 40 mM NaNO2 (3 ml/24 hr) for 7-14 days produced no microscopic changes in the mucosa either of damage (ulceration, mucus cell depletion) or of new growth (dysplasia, neoplasia). Beta oxidation of bacterial fatty acids (n-butyrate) by colonic epithelial cells in rat and man was enhanced by 50% (P less than 0.001) with 10 mM NaNO2, while oxidation of glucose and amino acid (proline) was not affected. Sodium nitrite significantly depressed ketogenesis (P less than 0.001) by the colonic mucosa of rat and man. In conclusion, sodium nitrite in the presence of bacteria has no damaging effect on the colonic mucosa but causes selective stimulation of fatty acid oxidation in the colonic mucosa of rat and man.

Anion control of sodium absorption in the colon.

The regulatory functions of anions in colonic absorption of sodium are unknown. Absorption of sodium ions was assessed with chloride, butyrate, nitrite, sulphate and oxalate anions in segments of proximal/distal colon and in defunctioned colon. Efficiency of sodium absorption was related to availability of CO2 in mucosal cells: CO2 availability was enhanced (P less than 0.01) by sodium nitrite or diminished (P less than 0.01) in defunctioned colon. Sodium nitrite stimulated absorption of sodium in the distal colon where bicarbonate secretion predominated and n-butyrate stimulated absorption of sodium in the proximal colon where hydrogen ion secretion predominated. Sodium absorption was very significantly diminished (P less than 0.01) in defunctioned colon. Results indicate that sodium absorption in the colon is both a double anion exchange system as well as cation/anion co-transport. Anions act differently on sodium absorption along the length of the colon and prolonged lack of anions plays a part in sodium malabsorption of the defunctioned colon.

The pathology of experimental chronic fibrosing pancreatitis--light microscopic and ultrastructural observations.

The light microscopic and ultrastructural changes seen in a canine model of chronic fibrosing pancreatitis are described. The distribution of the experimental lesion is similar to that of human chronic obstructive pancreatitis. The canine lesion is also compared to that of human chronic calcifying pancreatitis. It is suggested that the common denominator in all these conditions is an increased pressure in the terminal intercalated ducts which produces pressure atrophy of the acinar cells in the periphery of the obstructed lobules.