Blocking action of chromanol 293B on the slow component of delayed rectifier K(+) current in guinea-pig sino-atrial...

1. 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. 2. 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 microM, when evaluated by the decrease in the amplitude of I(Ks) tail current following 4-s depolarizing voltage steps to +50 mV. 3. The 293B block of I(Ks) progressed with time during depolarizing voltage steps with a more rapid block at higher concentrations. 4. 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 microM). 5. Bath application of 293B at 50 microM greatly and reversibly reduced the amplitude of I(Ks) which is maximally stimulated by beta-adrenergic agonist isoprenaline (1 microM), 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). 6. 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 beta-adrenergic stimulation and (ii) block with 293B occurs in a time-dependent manner during depolarizing voltage steps.