Pharmacological block of the slow component of the outward delayed rectifier current (I_Ks) fails to lengthen rabbit ventricular muscle QT_c and action potential duration

Abstract

1 The eects of I Ks block by chromanol 293B and L-735,821 on rabbit QT-interval, action potential duration (APD), and membrane current were compared to those of E-4031, a recognized I Kr blocker. Measurements were made in rabbit Langendor-perfused whole hearts, isolated papillary muscle, and single isolated ventricular myocytes. 2 Neither chromanol 293B (10 mM) nor L-735,821 (100 nM) had a signi®cant eect on QTc interval in Langendor-perfused hearts. E-4031 (100 nM), on the other hand, signi®cantly increased QTc interval (35.6+3.9%, n=8, P50.05).3 Similarly both chromanol 293B (10 mM) and L-735,821 (100 nM) produced little increase in papillary muscle APD (less than 7%) while pacing at cycle lengths between 300 and 5000 ms. In contrast, E-4031 (100 nM) markedly increased (30 ± 60%) APD in a reverse frequency-dependent manner. 4 In ventricular myocytes, the same concentrations of chromanol 293B (10 mM), L-735,821 (100 nM) and E-4031 (1 mM) markedly or totally blocked I Ks and I Kr , respectively. 5 I Ks tail currents activated slowly (at +30 mV, t=888.1+48.2 ms, n=21) and deactivated rapidly (at 740 mV, t=157.1+4.7 ms, n=22), while I Kr tail currents activated rapidly (at +30 mV, t=35.5+3.1 ms, n=26) and deactivated slowly (at 740 mV, t 1 =641.5+29.0 ms, t 2 =6531+343, n=35). I Kr was estimated to contribute substantially more to total current density during normal ventricular muscle action potentials (i.e., after a 150 ms square pulse to +30 mV) than does I Ks . 6 These ®ndings indicate that block of I Ks is not likely to provide antiarrhythmic bene®t by lengthening normal ventricular muscle QTc, APD, and refractoriness over a wide range of frequencies.

Density and Kinetics of I Kr and I Ks in Guinea Pig and Rabbit Ventricular Myocytes Explain Different Efficacy of I Ks Blockade at High Heart Rate in Guinea Pig and Rabbit

“…18,19 As with chromanol 293B in guinea pig, considerable prolongation of APD remains at short cycle length. 20 The extent of APD prolongation by chromanol 293B (23% to 31%) is comparable to that reported in single ventricular myocytes of guinea pig and humans 6 but much greater than that observed in multicellular ventricular tissue preparations of guinea pig, 21 rabbit, 22 and dog. 23 Different intracellular milieus might be involved in the discrepancy.…”

A Carbohydrate Fraction, AIP1, fromArtemisia IwayomogiReduces the Action Potential Duration by Activation of Rapidly Activating Delayed Rectifier K+Channels in Rabbit Ventricular Myocytes

“…4A and 4B). Previous studies have suggested that chromanol 293B-induced inhibition of IKs has only minimal effects on an in vitro system, when measuring APD in various species, including rabbit, without β-adrenergic stimulation [16][17][18]. Consistent with these findings, our recordings also showed that chromanol 293B alone had no effect on APD (Control: 381.6±15.1 ms, chromanol 293B: 380.5±18.3 ms) (Fig.…”

Adaptation of rabbit ventricular cell model to reproduce action potentials in isolated papillary muscle

“…However, APD 90 response to increases in these currents was relatively modest, such that substantial increase would be required to impact the adaptation to baseline. The I Kr current was not increased, as the model APD 90 prolongation due to I Kr inhibition was very similar to that recorded experimentally for a pure I Kr blocker [4]. The I tos current was also determined to be unsuitable due to the strongly reverse rate dependent impact on APD 90 .…”