Inhibitory effect of ATP-sensitive K+ channel regulators on forskolin-stimulated short-circuit current across the isolated mucosa of the rat colon

Forskolin concentration-dependently increased the short-circuit current (Isc) across the isolated mucosa of rat colon, which was carried mainly by Cl- secretion from the mucosal membrane. The sulfonylureas such as glibenclamide, tolbutamide, glipizide and the ATP-sensitive K+ channel opener cromakalim inhibited the forskolin (1 microM)-induced increase of short-circuit current (delta Isc) when these drugs were applied to the basolateral side. The rank order of potency for inhibition of delta Isc was: glibenclamide > cromakalim > tolbutamide > glipizide. Glibenclamide (100 microM) and cromakalim (100 microM) caused transient or small reduction of the A23187-induced delta Isc when applied to the basolateral side. Glibenclamide, tolbutamide and cromakalim decreased the forskolin-induced delta Isc when applied to the mucosal side; however, the responses produced by basolateral application were greater and faster than those elicited by mucosal application. None of these four agents affected the basal transepithelial current. The results indicate that the cAMP-dependent Cl- secretion in the rat colon could be modulated by ATP-sensitive K+ channel regulators.