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 Ca(2+)-activated K+ (SKCa) channels. Dequalinium blocked angiotensin II-evoked K+ loss with an IC50 of 1.5 +/- 0.1 microM and also inhibited 125I-monoiodoapamin binding with a KI of 1.1 +/- 0.1 microM. It is the most active non-peptide SKCa blocker so far described. The neuromuscular blocking agent vecuronium was also tested, and proved to be considerably less effective (IC50, 4.5 +/- 0.3 microM; KI, 3.6 +/- 0.5 microM). 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 cutaneous 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 microM. 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 SKCa channels.
Castle
N A
NA
Department of Pharmacology, University College London, UK.
Haylett
D G
DG
Morgan
J M
JM
Jenkinson
D H
DH
D000804:Angiotensin II / Q000037:antagonists & inhibitors; D000818:Animals; D001030:Apamin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D003868:Dequalinium / Q000494:pharmacology*; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects*; D011896:Rana temporaria; D051381:Rats; D017207:Rats, Sprague-Dawley; D014673:Vecuronium Bromide / Q000494:pharmacology
D015221:Potassium Channels; D000804:Angiotensin II; D001030:Apamin; D014673:Vecuronium Bromide; D003868:Dequalinium