Eicosanoid-mediated Cl- secretion induced by the antitumor drug, irinotecan (CPT-11), in the rat colon.

Irinotecan (CPT-11) is active against a broad range of human cancer. One of the side-effects of irinotecan is a strong diarrhoea. In order to investigate the mechanism underlying this diarrhoea, the effect of irinotecan on anion secretion across the isolated rat distal colon was studied. Irinotecan caused a concentration-dependent increase in short-circuit current (Isc). The increase in Isc was completely dependent on the presence of Cl- ions and was suppressed by furosemide and the Cl- channel blocker NPPB (5-nitro-2-(3-phenylpropylamino)-benzoate), indicating that it is caused by a Cl- secretion. The secretory response was inhibited by indomethacin, 1-benzylimidazole, a thromboxane synthase inhibitor, and SK&F 88046 ((N,N'-bis[7-(3-Chlorobenzeneaminosulfonyl)-1,2,3,4-tetrahydroi soquinolyl) disulfonylimide), a thromboxane A2 receptor blocker. In isolated crypts irinotecan had no effect on the membrane potential. Consequently, the secretion induced by irinotecan is an indirect one, caused by the stimulation of eicosanoid production, e.g. thromboxane A2, in the subepithelial tissue.

Effect of somatostatin on cell volume, Cl- currents, and transepithelial Cl- transport in rat distal colon.

Somatostatin (10(-10)-10(-7) mol/l) caused a concentration-dependent increase of the diameter of isolated crypts from the rat distal colon. Cell swelling was restricted to the upper one-third of the crypt and was dependent on the presence of Na+ and Cl- ions, indicating that it was caused by the stimulation of NaCl absorption by the hormone. Swelling was followed by a regulatory volume decrease, which could be inhibited by K+ and Cl- channel blockers. Also a lipoxygenase inhibitor and a leukotriene D4 receptor blocker inhibited volume regulation. Whole cell recordings performed in parallel revealed that somatostatin induced a depolarization of the cells at the upper one-third of the crypt but had no effect in the deeper parts of the crypt. This depolarization was concomitant with an increase in Cl- (and partially also HCO3-) conductance and was suppressed by a leukotriene D4 receptor blocker. In contrast, when Cl- secretion was stimulated by vasoactive intestinal peptide, a secretagogue acting on the adenosine 3',5'-cyclic monophosphate (cAMP) pathway, the effect of somatostatin was reversed from a depolarization into a hyperpolarization, an effect that was also observed in deeper parts of the crypt. Consequently, in crypts stimulated via the cAMP pathway, somatostatin inhibits the activation of apical Cl- channels. Somatostatin also partially inhibited the increase of K+ conductance induced by carbachol, a secretagogue acting on the Ca2+ pathway. Ussing chamber experiments showed that somatostatin caused a concentration-dependent decrease of short-circuit current. This decrease was dependent on the presence of Cl- and HCO3- ions. Measurements of unidirectional ion fluxes indicated that somatostatin stimulated Cl- absorption by an increase of the mucosa-to-serosa flux of this ion. The stimulation of Cl- absorption was completely suppressed by a Cl- channel blocker and by a lipoxygenase inhibitor. Consequently, the activation of a volume/leukotriene-sensitive basolateral Cl- conductance seems to be involved in the stimulation of Cl- absorption by somatostatin.