Blocking action of chromanol 293B on the slow component of delayed rectifier K + current in guinea‐pig sino‐atrial node cells

In guinea‐pig sino‐atrial (SA) node cells the delayed rectifier K + current ( I K ) is composed of rapidly and slowly activating components of I K ( I Kr and I Ks , respectively). The present study was undertaken to characterize the blocking action of the chromanol derivative 293B on I Ks in guinea‐pig SA node cells using whole‐cell patch‐clamp technique. Bath application of 293B blocked I Ks , elicited by 4‐s depolarizing voltage pulses from a holding potential of −50 mV, under conditions in which the L‐type Ca 2+ current ( I Ca,L ) and I Kr were inhibited; the effect was concentration‐dependent with an IC 50 of 5.3 μ M , when evaluated by the decrease in the amplitude of I Ks tail current following 4‐s depolarizing voltage steps to +50 mV. The 293B block of I Ks progressed with time during depolarizing voltage steps with a more rapid block at higher concentrations. The block of I Ks by 293B was fully reversed within a few minutes after washing off the drug, even when a maximal effect (a nearly full block) was achieved at high drug concentration (50 μ M ). Bath application of 293B at 50 μ M greatly and reversibly reduced the amplitude of I Ks which is maximally stimulated by β‐adrenergic agonist isoprenaline (1 μ M ), while the degree of 293B block of the isoprenaline‐stimulated I Ks was slightly but significantly smaller than that of non‐stimulated I Ks (94.0±0.98% block, n =6 vs 99.4±0.45% block, n =6; P <0.01). We conclude that, in guinea‐pig SA node cells (i) 293B is a potent and fully reversible blocker of I Ks in control and during β‐adrenergic stimulation and (ii) block with 293B occurs in a time‐dependent manner during depolarizing voltage steps.British Journal of Pharmacology (2002) 137 , 253–262. doi: 10.1038/sj.bjp.0704861