Electrophysiological properties of the propafenone-analogue GE 68 (1-[3-(phenylethyl)-2-benzofuryl]-2-(propylamino)-ethanol) in isolated preparations and ventricular myocytes of guinea-pig hearts

Abstract

GE 68 ((Rac.)-1-[3-(Phenylethyl)-2-benzofuryl]-2-(propylamino)-ethanol hydrochloride) is structurally related to propafenone, and exerts negative inotropic and negative chronotropic effects similar to the parent drug, but lacks any beta-adrenoceptor blocking activity contrary to propafenone. Thus, the electrophysiological effects of GE 68 were studied in papillary muscles, left atria, Purkinje fibres, sinoatrial nodes and ventricular myocytes of the guinea-pig heart with the intracellular microelectrode technique and the patch-clamp technique in the cell-attached mode. The decrease of the maximum upstroke velocity (Vmax) by GE 68 (1 to 10 microM) was use- and frequency-dependent. Vmax recovered from the use-dependent block with a time constant of 4.1 +/- 0.6 s. In papillary muscles and Purkinje fibres action potential duration was shortened, while it was prolonged in left atria and sinoatrial nodes. Half-maximal steady-state inactivation of the sodium channels was shifted to more negative membrane potentials (control: -91.5 +/- 0.8 mV, 10 microM GE 68: -97.9 +/- 2.5 mV). The peak of the current-voltage relationship and the reversal potential were not changed by GE 68. The amplitude of the unitary current remained unaltered, while open state probability was decreased. The most striking effect of GE 68 was an increase of the number of sweeps without single channel openings (1 microM: 2fold, 10 microM: 6fold). GE 68 also caused a decrease of the mean open times, and an increase of the mean closed times in unmodified and pronase-modified sodium channels. Besides the lack of beta-adrenoceptor blocking activity, data present a faster recovery from the use-dependent block by GE 68 and a lower affinity to inactivated sodium channels compared to the reference drug propafenone, as well as differences in the effect on single channel kinetics.

Atrium-Selective Sodium Channel Block as a Strategy for Suppression of Atrial Fibrillation

“…Previous studies involving sodium channel blockers (quinidine, prajmaline, GE 68), including inactivated-state blockers (lidocaine), have failed to demonstrate atrioventricular differences in I Na inhibition, 8,16,17 comparable to those here reported with ranolazine, suggesting that ranolazine may be unique in this respect. Interestingly, AZD7009, which blocks I Kr , I Na , and I Kur, , prolongs ERP and reduces DTE and CV preferentially in canine atria versus ventricles in vivo but produces similar V max reduction in isolated superfused atrial and ventricular tissue preparations.…”

“…Propafenone (I Na and I Kr blocker), like ranolazine, selectively prolongs atrial APD 90 but suppresses I Na -dependent parameters in both the atrial and the ventricular preparations to a similar extent, 12 as does GE 68, a propafenone analog. 16 Lidocaine abbreviates both atrial and ventricular APD 90 but still shows an atrial selectivity in Figure 6. Use-dependent binding/unbinding kinetics of ranolazine and lidocaine to the sodium channel in the ventricle approximated from depression and recovery of the maximum rate of rise of the AP upstroke (V max ).…”

Atrial-Selective Sodium Channel Blockers: Do They Exist?

“…Under voltage-clamp conditions, lidocaine blocks I Na similarly in human atrial and ventricular myocytes26 and moricizine blocks ventricular I Na more effectively than atrial I Na in guinea pig myocytes 27. GE 68, a propafenone analog lacking β-adrenoreceptor blocking activity, does not show any atrial selectivity in V max reduction in the guinea pig 28. Tedisamil reduces V max predominantly in human superfused ventricular versus atrial tissue slices 29.…”

hERG (KCNH2 or Kv11.1) K+ Channels: Screening for Cardiac Arrhythmia Risk

“…This type of phenomenon can easily be deciphered in a Purkinje experiment. Measuring the changes in the maximal rate of depolarization (Vmax) will provide a clear indication of sodium channel liability and potential for AV block [54][55][56]. In a similar manner, inhibition of Cav1.2 can have effects on APD 50 as well as on the action potential morphology.…”