A CHROMANOL TYPE OF K+ CHANNEL BLOCKER INHIBITS FORSKOLIN-MEDIATED BUT NOT CARBACHOL-MEDIATED CL- SECRETION IN RAT AND RABBIT COLON

In a previous study [Lohrmann et al: Pflugers Arch Eur J Physiol 1995;429:517-530] we have shown that chromanol K+ channel blockers inhibit Cl- secretion in rabbit colon. Their effect was easily demonstrable after stimulation by hormones acting through increases of cytosolic cAMP. The present study was undertaken to test in more detail the mechanism of action of one of these compounds (293 B). Two types of studies were performed: Ussing chamber experiments in rabbit distal colon and whole cell patch clamp studies in the isolated in vitro perfused rat colonic crypts. Carbachol (CCH, 100 mu mol/l) enhanced Cl- secretion, quantified as equivalent short circuit current (I-sc), in rabbit colon significantly more than did prostaglandin E(2) (PGE(2)). In whole cell patch clamp studies in rat colonic crypt cells from the base, CCH hyperpolarized the membrane voltage (V-m) and enhanced whole cell conductance (G(m)). In agreement with previous impalement studies, 10 mu mol/l 293 B depolarized V-m in forskolin-treated rat colonic crypt base cells even further and reduced G(m). In Ussing chamber experiments in rabbit colon, 293 B abolished the I-sc induced by PGE(2). CCH, in the continued presence of 293 B, still induced a large I-sc. These data indicate that 293 B specifically inhibits the forskolin- but not the CCH-induced Cl- secretion, and supports our previous conclusion that this class of substances inhibits a cAMP-regulated K+ conductance.