DEQUALINIUM - A POTENT INHIBITOR OF APAMIN-SENSITIVE K(+) CHANNELS IN HEPATOCYTES AND OF NICOTINIC RESPONSES IN SKELETAL-MUSCLE

The bisquaternary compound dequalinium has been tested for its ability to inhibit the loss of K+ which angiotensin II causes in guinea-pig hepatocytes and which occurs through apamin-sensitive Ca2+-activated K+ (SK(Ca)) channels. Dequalinium blocked angiotensin II-evoked K+ loss with an IC50 of 1.5 +/- 0.1 muM and also inhibited I-125-monoiodoapamin binding with a K(I) of 1.1 +/- 0.1 muM. It is the most active non-peptide SK(Ca) blocker so far described. The neuromuscular blocking agent vecuronium was also tested, and proved to be considerably less effective (IC50, 4.5 +/- 0.3 muM; K(I), 3.6 +/- 0.5 muM). Dequalinium was also examined for its actions at nicotinic receptors in skeletal muscle and was found to be a potent, non-competitive antagonist of carbachol contractions of the frog rectus abdominis. In the frog cutaneus pectoris muscle, end-plate depolarizations induced by carbachol became smaller and more transient in the presence of dequalinium at 10 nM. However, contractions of the frog sartorius and rat diaphragm in response to nerve stimulation were inhibited only by concentrations > 1 muM. These apparently discrepant effects of dequalinium on nicotinic responses could be explained either by open channel block of slow onset or by 'stabilization' of the desensitized state of the receptor. The potency of dequalinium will make it a useful agent for the study of nicotinic receptors as well as of SK(Ca) channels.