DISCRIMINATION BETWEEN SUBTYPES OF APAMIN-SENSITIVE CA2-ACTIVATED K+ CHANNELS BY GALLAMINE AND A NOVEL BIS-QUATERNARY QUINOLINIUM CYCLOPHANE, UCL-1530()

1 Gallamine, dequalinium and a novel bis-quaternary cyclophane, UCL 15 30 1(1,4),7(1,4)-diquinolina-cyclononadcanephanedium) were tested for their ability to block actions mediated by the small conductance, apam in-sensitive Ca2+-activated K+ (SKCa) channels in rat cultured sympath etic neurones and guinea-pig isolated hepatocytes. 2 SKCa channel bloc k was assessed in sympathetic neurones by the reduction in the slow af terhyperpolarization (AHP) that follows an action potential, and in he patocytes by the inhibition of the SKCa mediated net loss of K+ that r esults from the application of angiotensin II 3 The order of potency f or inhibition of the AHP in sympathetic neurones was UCL 1530 > dequal inium > gallamine, with IC50 values of 0.08 +/- 0.02, 0.60 +/- 0.05 an d 68.0 +/- 8.4 mu M respectively, giving an equi-effective molar ratio between gallamine and UCL 1530 of 850. 4 The same three compounds inh ibited angiotensin II-evoked K+ loss from guinea-pig hepatocytes in th e order dequalinium>UCL 1530 > gallamine, with an equi-effective molar ratio for gallamine to UCL 1530 of 5.8, 150 fold less than in sympath etic neurones. 5 Dequalinium and UCL 1530 were as effective on guinea- pig as on rat sympathetic neurones. 6 UCL 1530 at 1 mu M had no effect on the voltage-activated Ca2+ current in rat sympathetic neurones, bu t inhibited the hyperpolarization produced by direct elevation of cyto solic Ca2+. 7 Direct activation of SKCa channels by raising cytosolic Ca2+ in hepatocytes evoked an outward current which was reduced by the three blockers, with dequalinium being the most potent. 8 These resul ts provide evidence that the SKCa channels present in guinea-pig hepat ocytes and rat cultured sympathetic neurones are different, and that t his is not attributable to species variation. UCL 1530 and gallamine s hould be useful tools for the investigation of subtypes of apamin-sens itive K+ channels.