Cell swelling has differential effects on the rapid and slow components of delayed rectifier potassium current in guinea pig cardiac myocytes

Cell swelling has been shown to cause activation of a variety of cardiac sarcolemmal ionic conductances including potassium channels. The aim of this study was to investigate the effect of swelling on the two subtypes of delayed rectifier potassium current (J(Kr) and I-Ks) in single guinea pig myocytes using the whole-cell configuration of the patch clamp technique. When the holding potential was set at -40 mV and stepped to +40 mV for 1 s under isoosmotic conditions (300 mOsm) a delayed rectifier current (I-K) was activated (0.86 +/- 0.05 nA; n = 43). Switching to a hypoosmotic solution (200 mOsm) caused a rapid increase in I-K to a mean value of 1.43 +/- 0.10 nA (p < 0.05; n = 43), The effect of swelling on the two subtypes of I-K was studied by analysis of deactivating tail currents using an. envelope of tails protocol (stepping from -40 to +40 mV for 18 different pulse durations between 50 ms and 2.9 s; n = 16). Swelling caused a decrease in current amplitude measured at the end of the pulse (and I-Ktail) at short durations (less than or equal to 150 ms) however, when the pulse duration was >1 s swelling caused a significant increase in current. Using a pulse protocol to measure I-Kr with minimal contamination by I-ks (voltage step from -40 to -10 mV for 250 ms) a 50-100 pA current was elicited which could be completely blocked by dofetilide (0.2 mu M; n = 3). Introduction of hypoosmotic solution caused a significant decrease in IK, and when dofetilide (0.2 or 1.0 mu M) was introduced the current remaining was decreased further (p < 0.05; n = 5), but was not completely blocked, thus suggesting that swelling had decreased the ability of dofetilide to block I-Kr. Similar results were obtained over a range of dofetilide concentrations and with a second I-Kr blocker, La3+. In Ca2+-free external solutions, pulsing to -10 mV for 500 ms to measure I-Kr in the absence of I-Ks, and to + 60 mV for 5 s (with 0.2 mu M dofetilide) to evoke only I-Ks, it was clear that swelling significantly increased I-Ks (pulse and tail currents) and decreased I-Kr. In addition, when measured using the perforated patch method, swelling modulated I-Kt and I-Ks in a similar fashion. We conclude that swelling has differential effects on the subtypes of the classical cardiac I-K, which may have important implications in our understanding of the mechanisms underlying ischaemia- and reperfusion-induced arrhythmogenesis.