Tedisamil blocks single large-conductance Ca²⁺-activated K⁺ channels in membrane patches from smooth muscle cells of the guinea-pig portal vein

Abstract

Enzymatically dispersed smooth muscle cells of the guinea-pig portal vein were studied by the patch-clamp technique. They were found to have Ca²⁺-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⁺]₀ 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 μM) when applied at the cytosolic side of membrane inside-out patches. At 100 μM [Ca²⁺]_i, the IC₅₀ of tedisamil was 13.8 μM (¯x, n=5). Tedisamil increased the frequency of channel closures, and reduced the mean duration of openings from 8 ms to < 1 ms, while the mean duration of closures within bursts (1–2 ms) was not altered. Tedisamil did not affect long closures (> 160 ms) between bursts, either. The mean time of residence of tedisamil at the BK channel was estimated to be 1–2ms. Hence, tedisamil, in comparison to the “slow” blocker Ba²⁺ and the “fast” blocker tetraethylammonium, holds the position of an “intermediate” K⁺ channel blocker.