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Discrimination between subtypes of apamin‐sensitive Ca 2+ ‐ activated K + channels by gallamine and a novel bis ‐quaternary quinolinium cyclophane, UCL 1530
Author(s) -
Dunn P.M.,
Benton D.C.H.,
Rosa J. Campos,
Ganellin C.R.,
Jenkinson D.H.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15151.x
Subject(s) - apamin , chemistry , gallamine triethiodide , afterhyperpolarization , biophysics , membrane potential , pharmacology , endocrinology , biochemistry , biology , organic chemistry , calcium
1 Gallamine, dequalinium and a novel bis ‐quaternary cyclophane, UCL 1530 (8,19‐diaza‐3(1,4),5(1,4)‐ dibenzena‐1(1,4),7(1,4)‐diquinolina‐cyclononadecanephanedium) were tested for their ability to block actions mediated by the small conductance, apamin‐sensitive Ca 2+ ‐activated K + (SK Ca ) channels in rat cultured sympathetic neurones and guinea‐pig isolated hepatocytes. 2 SK Ca channel block was assessed in sympathetic neurones by the reduction in the slow afterhyperpolarization (AHP) that follows an action potential, and in hepatocytes by the inhibition of the SK Ca mediated net loss of K + that results from the application of angiotensin II. 3 The order of potency for inhibition of the AHP in sympathetic neurones was UCL 1530 > dequalinium > gallamine, with IC 50 values of 0.08 ± 0.02, 0.60 ± 0.05 and 68.0 XXXX 8.4 μ m respectively, giving an equi‐effective molar ratio between gallamine and UCL 1530 of 850. 4 The same three compounds inhibited angiotensin II‐evoked K + loss from guinea‐pig hepatocytes in the order dequalinium > UCL 1530 > gallamine, with an equi‐effective molar ratio for gallamine to UCL 1530 of 5.8, 150 fold less than in sympathetic neurones. 5 Dequalinium and UCL 1530 were as effective on guinea‐pig as on rat sympathetic neurones. 6 UCL 1530 at 1 μ m had no effect on the voltage‐activated Ca 2+ current in rat sympathetic neurones, but inhibited the hyperpolarization produced by direct elevation of cytosolic Ca 2+ . 7 Direct activation of SK ca channels by raising cytosolic Ca 2+ in hepatocytes evoked an outward current which was reduced by the three blockers, with dequalinium being the most potent. 8 These results provide evidence that the SK ca channels present in guinea‐pig hepatocytes and rat cultured sympathetic neurones are different, and that this is not attributable to species variation. UCL 1530 and gallamine should be useful tools for the investigation of subtypes of apamin‐sensitive K + channels.