Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes

TY - JOUR

T1 - Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes

AU - Stengl, Milan

AU - Volders, Paul G A

AU - Thomsen, Morten Bækgaard

AU - Spätjens, Roel L H M G

AU - Sipido, Karin R

AU - Vos, Marc A

PY - 2003/9/15

Y1 - 2003/9/15

N2 - In guinea-pig ventricular myocytes, in which the deactivation of slowly activating delayed rectifier potassium current (IKs) is slow, IKs can be increased by rapid pacing as a result of incomplete deactivation and subsequent current accumulation. Whether accumulation of IKs occurs in dogs, in which the deactivation is much faster, is still unclear. In this study the conditions under which accumulation occurs in canine ventricular myocytes were studied with regard to its physiological relevance in controlling action potential duration (APD). At baseline, square pulse voltage clamp experiments revealed that the accumulation of canine IKs could occur, but only at rather short interpulse intervals (<100 ms). With action potential (AP) clamp commands of constant duration (originally recorded at rate of 2 Hz), an accumulation was only found at interpulse intervals close to 0 ms. Transmembrane potential recordings with high-resistance microelectrodes revealed, however, that at the fastest stimulation rates with normally captured APs (5 Hz) the interpulse interval exceeded 50 ms. This suggested that no IKs accumulation occurs, which was supported by the lack of effect of an IKs blocker, HMR 1556 (500 nM), on APD. In the presence of the beta-adrenergic receptor agonist isoproterenol (isoprenaline, 100 nM) the accumulation with AP clamp commands of constant duration was much more pronounced and a significant accumulating current was found at a relevant interpulse interval of 100 ms. HMR 1556 prolonged APD, but this lengthening was reverse rate dependent. AP clamp experiments in a physiologically relevant setting (short, high rate APs delivered at a corresponding rate) revealed a limited accumulation of IKs in the presence of isoproterenol. In conclusion, a physiologically relevant accumulation of IKs was only observed in the presence of isoproterenol. Block of IKs, however, led to a reverse rate-dependent prolongation of APD indicating that IKs does not have a dominant role at short cycle lengths.

AB - In guinea-pig ventricular myocytes, in which the deactivation of slowly activating delayed rectifier potassium current (IKs) is slow, IKs can be increased by rapid pacing as a result of incomplete deactivation and subsequent current accumulation. Whether accumulation of IKs occurs in dogs, in which the deactivation is much faster, is still unclear. In this study the conditions under which accumulation occurs in canine ventricular myocytes were studied with regard to its physiological relevance in controlling action potential duration (APD). At baseline, square pulse voltage clamp experiments revealed that the accumulation of canine IKs could occur, but only at rather short interpulse intervals (<100 ms). With action potential (AP) clamp commands of constant duration (originally recorded at rate of 2 Hz), an accumulation was only found at interpulse intervals close to 0 ms. Transmembrane potential recordings with high-resistance microelectrodes revealed, however, that at the fastest stimulation rates with normally captured APs (5 Hz) the interpulse interval exceeded 50 ms. This suggested that no IKs accumulation occurs, which was supported by the lack of effect of an IKs blocker, HMR 1556 (500 nM), on APD. In the presence of the beta-adrenergic receptor agonist isoproterenol (isoprenaline, 100 nM) the accumulation with AP clamp commands of constant duration was much more pronounced and a significant accumulating current was found at a relevant interpulse interval of 100 ms. HMR 1556 prolonged APD, but this lengthening was reverse rate dependent. AP clamp experiments in a physiologically relevant setting (short, high rate APs delivered at a corresponding rate) revealed a limited accumulation of IKs in the presence of isoproterenol. In conclusion, a physiologically relevant accumulation of IKs was only observed in the presence of isoproterenol. Block of IKs, however, led to a reverse rate-dependent prolongation of APD indicating that IKs does not have a dominant role at short cycle lengths.

KW - Action Potentials

KW - Adrenergic beta-Agonists

KW - Animals

KW - Dogs

KW - Female

KW - Heart

KW - Heart Ventricles

KW - Isoproterenol

KW - Male

KW - Myocytes, Cardiac

KW - Patch-Clamp Techniques

KW - Potassium Channels

KW - Potassium Channels, Voltage-Gated

KW - Ventricular Function

U2 - 10.1113/jphysiol.2003.044040

DO - 10.1113/jphysiol.2003.044040

M3 - Journal article

C2 - 12819301

SN - 0022-3751

VL - 551

SP - 777

EP - 786

JO - The Journal of Physiology

JF - The Journal of Physiology

IS - Pt 3

ER -