Role of the 293b-sensitive, slowly activating delayed rectifier potassium current, iKs, in pacemaker activity of rabbit isolated sino-atrial node cells

Abstract

Objectives: (i) to characterize the electrophysiological properties of the slowly activating delayed rectifier potassium current, iKs, defined as the 293b-sensitive current, during the action potential (AP) of rabbit sino-atrial node (SAN) pacemaker cells; (ii) to evaluate the contribution of iKs to the pacemaker AP under physiological conditions and during β-adrenergic stimulation. Methods: Rabbit SAN pacemaker cells were studied using the perforated patch clamp technique in voltage-, AP- and current-clamp modes. Results: Voltage-clamp findings. Block of iKs by 293b is dose-dependent, with an IC50 (half block) in rabbit SAN cells of 1.35 μM and an IC80 (sub-maximal block) of 5 μM. Sub-maximal concentrations of 293b have no significant effects on long-lasting and transient inward calcium currents, iCa,L and iCa,T, inward hyperpolarization activated current, if, and transient outward current, ito. AP-clamp experiments. The 293b-sensitive current activates near the peak of the SAN pacemaker action potential, reaches a mean maximal current density of 1.0±0.3 pA/pF (n=8, cell capacitances 27 to 62 pF, mean 35±4.0 pF) during late repolarization, and inactivates towards the end of repolarization. Additionally, in two smaller cells (cell capacitances 15 and 23 pF), no discernible 293b-sensitive current component was detected. Current-clamp data. In spontaneously beating SAN cells under control conditions, sub-maximal block of iKs by 5 μM 293b has negligible effects on action potential characteristics and does not change average cycle length (n=11). In contrast, after pre-treatment with 10 nM isoprenaline to mimic β-adrenergic stimulation, cells showed a 293b-induced depolarization of maximum diastolic potential by 2.2±1%, a decrease in diastolic depolarization rate by 9.9±4%, and a slowing of late action potential repolarization by 28.7±10.2%, resulting in a prolongation of spontaneous cycle length by 9.8±3.0% (P<0.05, n=10; for all parameters). Conclusion: Our findings suggest that in rabbit SAN: (i) iKs is activated during the normal pacemaker AP; (ii) the contribution of iKs to beating rate is small under control conditions; and (iii) iKs contributes significantly to spontaneous pacemaker rate during β-adrenergic stimulation. © 2002 Elsevier Science B.V. All rights reserved.