Somatostatin peptides prevent increased human colonic epithelial permeability induced by hypoxia.

Abstract

Mesenteric ischemia increases gut permeability and bacterial translocation. In human colon, chemical hypoxia induced by 2,4-dinitrophenol (DNP) activates basolateral intermediate conductance K⁺ (IK) channels (designated KCa3.1 or KCNN4) and increases paracellular shunt conductance/permeability (G_S), but whether this leads to increased macromolecule permeability is unclear. Somatostatin (SOM) inhibits IK channels and prevents hypoxia-induced increases in G_S. Thus, we examined whether octreotide (OCT), a synthetic SOM analog, prevents hypoxia-induced increases G_S in human colon and hypoxia-induced increases in total epithelial conductance (G_T) and permeability to FITC-dextran 4000 (FITC) in rat colon. The effects of serosal SOM and OCT on increases in G_S induced by 100 µM DNP were compared in isolated human colon. The effects of OCT on DNP-induced increases in G_T and transepithelial FITC movement were evaluated in isolated rat distal colon. G_S in DNP-treated human colon was 52% greater than in controls (P = 0.003). G_S was similar when 2 µM SOM was added after or before DNP treatment, in both cases being less (P < 0.05) than with DNP alone. OCT (0.2 µM) was equally effective preventing hypoxia-induced increases in G_S, whether added after or before DNP treatment. In rat distal colon, DNP significantly increased G_T by 18% (P = 0.016) and mucosa-to-serosa FITC movement by 43% (P = 0.01), and 0.2 µM OCT pretreatment completely prevented these changes. We conclude that OCT prevents hypoxia-induced increases in paracellular/macromolecule permeability and speculate that it may limit ischemia-induced gut hyperpermeability during abdominal surgery, thereby reducing bacterial/bacterial toxin translocation and sepsis.NEW & NOTEWORTHY Somatostatin (SOM, 2 µM) and octreotide (OCT, 0.2 µM, a long-acting synthetic analog of SOM) were equally effective in preventing chemical hypoxia-induced increases in paracellular shunt permeability/conductance in isolated human colon. In rat distal colon, chemical hypoxia significantly increased total epithelial conductance and transepithelial movement of FITC-dextran 4000, changes completely prevented by 0.2 µM OCT. OCT may prevent or limit gut ischemia during abdominal surgery, thereby decreasing the risk of bacterial/bacterial toxin translocation and sepsis.