Block of transient outward-type cloned cardiac K+ channel currents by quinidine

A. Yatani, M. Wakamori, G. Mikala, A. Bahinski

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46 Citations (Scopus)

Abstract

The antiarrhythmic drug quinidine has been shown to block several types of K+ channel currents in cardiac preparations including the transient outward current (I(to)). To characterize the molecular mechanism of quinidine block, a cloned I(to)-type cardiac K+ channel (RHK1) was expressed in Xenopus oocytes, and drug effects were examined on whole-cell and single-channel currents. Extracellular application of quinidine reduced whole-cell RHK1 current amplitude in a concentration-dependent manner. The block was voltage dependent, with an IC50 of 1.69 mM at 0 mV, and the value decreased to 875 μM at +60 mV. Quinidine significantly slowed the current inactivation time course during voltage-clamp pulses without changing the rate of activation or the steady-state inactivation. To test the channel-state dependence of quinidine block, the cells were 'rested' in the presence of quinidine (500 μM) for 2 to 3 minutes before applying depolarizing pulses to +60 mV. During the first pulse, the current inactivation rate was slower than control, but the peak current was only reduced by less than 5%. Subsequent pulses reduced the peak current amplitude to ≃50% of control. These results suggest that quinidine blocks the open channel and that the drug must first dissociate before the channel can close, thereby causing a crossover in current tracings. In measurements of single-channel current from cell-attached patches, open time was reduced by quinidine in a concentration-dependent manner. Single-channel current amplitude was not altered by quinidine. Application of quinidine to the intracellular side of inside-out patches had an effect similar to that obtained from cell-attached patches but at 10-fold lower concentrations. External quinidine may therefore have to pass into or through the cell membrane to reach its blocking site.

Original languageEnglish
Pages (from-to)351-359
Number of pages9
JournalCirculation research
Volume73
Issue number2
DOIs
Publication statusPublished - 1993

Keywords

  • K channel
  • antiarrhythmic drugs
  • quinidine
  • transient outward current

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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