Tedisamil blocks single large-conductance Ca(2+)-activated K+ channels in membrane patches from smooth muscle cells of the guinea-pig portal vein.
Enzymatically dispersed smooth muscle cells of the guinea-pig portal vein were studied by the patch-clamp technique. They were found to have Ca(2+)-dependent K+ channels with the typical properties of the "BK" channel, i.e. a reversal potential at the calculated equilibrium potential for K+ ions, a striking voltage dependence, and a conductance of approximately 200 pS ([K+]o 50 mM, [K+]i 150 mM, positive patch potentials). Tedisamil, a new bradycardic agent with an inhibitory action on K+ currents in heart muscle, reduced the open probability of the BK channels concentration-dependently (1-100 microM) when applied at the cytosolic side of membrane inside-out patches. At 100 microM [Ca2+]i, the IC50 of tedisamil was 13.8 microM (mean, n = 5). Tedisamil increased the frequency of channel closures, and reduced the mean duration of openings from 8 ms to less than 1 ms, while the mean duration of closures within bursts (1-2 ms) was not altered. Tedisamil did not affect long closures (greater than 160 ms) between bursts, either. The mean time of residence of tedisamil at the BK channel was estimated to be 1-2 ms. Hence, tedisamil, in comparison to the "slow" blocker Ba2+ and the "fast" blocker tetraethylammonium, holds the position of an "intermediate" K+ channel blocker.
Pfründer
D
D
II. Physiologisches Institut, Universität Heidelberg, Federal Republic of Germany.
Kreye
V A
VA
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002118:Calcium / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D003521:Cyclopropanes / Q000494:pharmacology*; D004553:Electric Conductivity / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology / Q000648:ultrastructure; D011169:Portal Vein; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002316:Cardiotonic Agents; D003521:Cyclopropanes; D015221:Potassium Channels; C059921:tedisamil; D002118:Calcium