Contribution of potassium accumulation in narrow extracellular spaces to the genesis of nicorandil-induced large inward tail current in guinea-pig ventricular cells

Abstract

The mechanism of nicorandil-induced large inward tail current (I _tail) in single guinea-pig ventricular cells was investigated using the whole-cell patch-clamp technique. In the presence of 0.5–1.0 mM nicorandil, an activator of adenosine 5′-triphosphate (ATP)-sensitive K⁺ current (I _KATP), a depolarization pulse causing a large outward current was followed by a large inward I _tail on the repolarization step to the holding potential at-85 mV. The larger the outward current, the greater the I _tail. The amplitude of I _tail increased as a single exponential function (τ=74.9 ms) as the duration of preceding depolarization was prolonged. Both the outward current and I _tail were inhibited nearly completely after application of glibenclamide (1 μM), a specific blocker of I _KATP. Substitution of K⁺ with Cs⁺ in both the external and internal solutions resulted in a virtual elimination of I _tail. I _tail was well preserved under the condition where Ca²⁺ entry during the preceding depolarization was largely inhibited or where external Na⁺ was replaced by Li⁺. A transient positive shift of reversal potential for the net current was observed at the peak of I _tail. At 30 mM external K⁺ concentration, I _tail was almost eliminated. From these findings, it is concluded that the I _tail is a K⁺ current associated with an alteration of the K⁺ equilibrium potential (E _K) following a substantial K⁺ efflux. This E _K change is most likely explained by an accumulation of K⁺in transverse tubules (T-tubules) since I _tail was not induced in atrial cells in which T-tubules are poorly developed.