The deactivation kinetics of the delayed rectifier components I-Kr and I-Ks in guinea-pig isolated ventricular myocytes

The deactivation kinetics of the delayed rectifier potassium current (I-K) were studied in guinea-pig isolated ventricular myocytes at 35-36 degrees C using 5 mu M E4031 to selectively block the rapidly activating component (I-Kr) and 300 mu M thiopentone to selectively suppress the slowly activating component (I-Ks). I-K was activated by depolarization of 400 or 1000 ms duration to +40 mV, and tail currents were analysed on repolarization to potentials between -30 and -60 mV. Before exposure to drugs, the deactivation of total I-K was fitted by two exponential functions at all potentials and, at -40 mV, the time constants were 188 +/- 12 and 2510 +/- 185 ms (n = 25); increasing the pulse duration from 400 to 1000 ms (expected to increase I-Ks rather than I-Kr under these conditions) caused a significant increase in the amplitude of only the fast component of deactivation at -40 mV (from 372 +/- 32 to 479 +/- 46 pA). The decay of I-Kr was biexponential at all potentials when detected as the E4031-sensitive current and at -30 to -50 mV when detected as the thiopentone-resistant current and was accelerated as the membrane potential was made more negative. The amplitudes of the two components of decay of I-Kr (as either E4031-sensitive or thiopentone-resistant current) were similar and neither were significantly increased when pulse duration was increased from 400 to 1000 ms. The decay of I-Ks detected as the E4031-resistant current was biexponential at -30 mV and, in some cells, at -40 mV, but decayed with predominately a single, fast component of deactivation at -50 and -60 mV, which was accelerated at the more negative potentials. A slow component of decay of I-Ks was detected in more cells when thiopentone was used to isolate I-Ks although it was of much smaller amplitude than the fast component of decay. The presence of a slow component of decay of the thiopentone-sensitive I-Ks may result from a slight block of I-Kr by thiopentone. The amplitude of only the fast decay phase of I-Ks (detected using either drug) was increased when pulse duration was lengthened from 400 to 1000 ms. It seems likely that the relative importance of I-Kr and I-Ks in rate-dependent shortening of action potential duration may need to be re-evaluated in view of the relatively rapid deactivation of I-Ks, together with the prominence of the slow component of deactivation of I-Kr compared with that of I-Ks.