The Effect of a‐Trinositol on Cholera Toxin‐Induced Hypersecretion and Morphological Changes in Pig Jejunum

Abstract

alpha-Trinositol (D-myo-inositol 1,2,6-trisphosphate, PP56) is a novel antiinflammatory drug. This study elucidates the effect of intravenous alpha-trinositol on basal and acute fluid transport and morphological changes following cholera toxin administration in pig jejunum in vivo. Using isolated jejunal tied-off loops, the fluid hypersecretory (accumulation) effect of different doses of cholera toxin was studied in pigs treated intravenously with saline added different doses (0, 4, 8, 16 and 32 mg x kg-1 x hr-1) of alpha-trinositol. Levels of alpha-trinositol, as well as stereomicroscopical, light microscopical and scanning electron microscopical morphological studies were performed. Cholera toxin evoked a dose-dependent fluid hypersecretion. Treatment with alpha-trinositol caused a dose-dependent inhibition of the cholera toxin-induced fluid hypersecretion and did not affect basal fluid absorption. The 16 mg x kg-1 x hr-1 alpha-trinositol dose gave a maximal inhibition of 36%. Morphological studies showed only minor changes following 6 hr of exposure to 20 micrograms x loop-1 cholera toxin. These changes consisted of dilation of the villus capillaries, an increase of apical membrane blebbing and a reduction of the intercellular space. Treatment with 16 mg x kg-1 x hr-1 alpha-trinositol alone did not induce any morphological changes, and did not alter the morphological changes induced by cholera toxin, which caused fluid hypersecretion and only minor acute morphological changes. In conclusion, alpha-trinositol treatment reduced cholera toxin-induced fluid hypersecretion without altering basal fluid absorption, basal morphology, or cholera toxin-induced morphological changes in pig jejunum in vivo.

Secretory pathways in Salmonella Typhimurium-induced fluid accumulation in the porcine small intestine

“…Both 5-HT and PGE2 induce secretion by direct stimulation of the enterocytes [35] and by activating the ENS [36]. Furthermore, PGE2 suppresses ileal Na+ and water absorption [37, 381. No intramural fluid accumulation was observed after CT stimulation, consistent with CT inducing secretion without histological changes [30].…”

Effect of α‐trinositol on secretion induced by Escherichia coli ST‐toxin in rat jejunum

“…Previous data have shown that a-trinositol was able to inhibit cholera toxin (CT)-induced intestinal secretion in the pig and rat jejunum in vivo (Nellgå rd et al 1992b, Hansen et al 1996, Tindholdt et al 1997. As the inflammatory changes induced in the gut wall by CT (Ohishi & Odagiri 1984) are far less pronounced than changes caused by E. coli heat-stable toxin (Salvemini et al 1999, Allcock et al 2001, the authors suggested another mechanisms of action.…”

“…The effects of a-trinositol on fluid transport in the small intestine were investigated in a number of studies showing that the compound was able to induce a dosedependent inhibition of cholera secretion in the pig and rat jejunum in vivo (Nellgå rd et al 1992b, Hansen et al 1996, Tindholdt et al 1997. In a recent study, a-trinositol was also shown to inhibit the fluid losses induced by obstruction of the jejunum in rats in vivo at a dose of 60 mg kg )1 h )1 parallel to a significant inhibition of oedema formation in the obstructed gut (Lahti et al 2002).…”

Effects of Indomethacin on Salmonella Typhimurium‐ and Cholera Toxin‐induced Fluid Accumulation in the Porcine Small Intestine

“…The secretory responses to CT and ST in the small intestine are often compared because they both induce fluid and electrolyte secretion (Klimpel et al., 1995; Grøndahl et al., 1998). The major difference in the pathophysiology between CT and ST is that CT induces no inflammatory or morphological changes (Klimpel et al., 1995; Hansen et al., 1996). This complicates a direct comparison of the potency of CT and ST.…”