Inhibitory effects of dihydropyridines on macroscopic K+ currents and on the large-conductance Ca(2+)-activated K+ channel in cultured cerebellar granule cells.
In cultured cerebellar granule cells, we examined the effects of dihydropyridines (DHPs) on K+ currents, using the whole-cell recording configuration of the patch-clamp technique and on Ca(2+)-activated K+ channels ("maxi K+ channels") using outside-out patches. We found that micromolar concentrations of nicardipine, nifedipine, (+) and (-) BAY K 8644, nitrendipine, nisoldipine and (-) nimodipine block 10-60% of macroscopic K+ currents. The most potent of these DHPs was nicardipine and the least potent, (-) BAY K 8644. (+) Nimodipine had no effect on this current. The inhibitory effects of nifedipine and nicardipine were not additive with those of 1 mM tetraethylammonium (TEA). Outside-out recordings of "maxi K+ channels" showed a main conductance of 200 pS (in 77% of the patches) and two subconductance states (in 23% of the patches). Neither nifedipine nor nicardipine affected the main conductance, but decreased the values of the subconductance levels. In 10% of these patches, nicardipine induced a flickering activity of the channel. These findings show that both Ca2+ and K+ channels have DHP-sensitive sites, suggesting similarity in electrostatic binding properties of these channels. Furthermore, cerebellar granule cells may express different subtypes of "maxi K+ channels" having different sensitivities to DHPs. These drugs may provide new tools for the molecular study of K+ channels.
Fagni
L
L
CNRS UPR 9023, C.C.I.P.E., Montpellier, France.
Bossu
J L
JL
Bockaert
J
J
D000818:Animals; D002118:Calcium; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004095:Dihydropyridines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D009529:Nicardipine / Q000037:antagonists & inhibitors; D015221:Potassium Channels / Q000187:drug effects*; D013757:Tetraethylammonium Compounds / Q000494:pharmacology
D004095:Dihydropyridines; D015221:Potassium Channels; D013757:Tetraethylammonium Compounds; D009529:Nicardipine; D002118:Calcium