Effects of the two enantiomers, S‐16257‐2 and S‐16260‐2, of a new bradycardic agent on guinea‐pig isolated cardiac preparations

Abstract

1 The electromechanical effects of two enantiomers, S-16257-2 (S57) and S-16260-2 (R60), were studied and compared in guinea-pig isolated atria and ventricular papillary muscles. The possible stereoselectivity of the interaction on the cardiac Na' channel was analysed by comparing the effects of the two enantiomers on the onset and recovery kinetics of the frequency-dependent V,,.S block. 2 In spontaneously beating right atria, S57 and R60 (10-8 M-10-4 M) exerted a negative chronotropic effect (pIC50 = 5.07 ± 0.19 and 4.76 ± 0.18, respectively) and prolonged the sinus node recovery time, this effect being more marked with S57. In electrically driven left atria, S57 decreased (P<0.05) contractile force only at 10-4 M and R60 at concentrations > 5 x 10-5 M, whereas in papillary muscles the negative inotropic effect appeared at concentrations > 10-5 M. 3 In papillary muscles driven at 1 Hz, S57 and R60 at concentrations higher than 5 x 10-6 M produced a concentration-dependent decrease in the maximum upstroke velocity (V,,,.,) and amplitude of the cardiac action potential without altering the resting membrane potential or the action potential duration. S57 and R60 had no effect on the characteristics of the slow action potentials elicited by isoprenaline in ventricular muscle fibres depolarized in high K+ (27 mM) solution. 4 At 5 x 10-5 M, S57 and R60 produced a small tonic V,,, block. However, in muscles driven at rates between 0.5 and 3 Hz both enantiomers produced an exponential decline in V,,,, (frequency-dependent V,,,<. block) which augmented at higher rates of stimulation. The onset and offset rates of the frequencydependent Vm... block were similar for both drugs. Both S57 and R60 prolonged the recovery time constant from the frequency-dependent block from 20.1 ± 2.9 ms to 2-3 s.5 At 5 x 10-1 M, S57 and R60 shifted the membrane responsiveness curve in a hyperpolarizing direction. 6 It can be concluded that S57 and R60, the two enantiomers of the new bradycardic agent, produced a similar frequency-dependent V,,,, block which indicated that the interaction with the Na+ channel was not stereospecific. The analysis of the onset and offset kinetics of the frequency-dependent V,.,, block suggested that both enantiomers can be considered as Na+ channel blockers with intermediate kinetics, e.g., class IA antiarrhythmic drugs.

Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells

“…Such observations are in favour of the absence of significant class III antiarrhythmic activity of the drug. Perez et al (1995) reported that the fast sodium inward current was blocked by S 16257 at concentrations higher than S x 10-6 M. This block probably plays a role in the effects of S 16257 on the activity of Purkinje cells and sinus node subsidiary cells, where INa is present. In the primary pacemaker cells, it has been reported that the fast sodium inward current is absent or not normally activated (Irisawa et al, 1993 …”

New Therapeutic Targets in Cardiology

“…Effects on cardiac Na + channels 69 and on Kv1.5 potassium channels 70 were reported only in vitro at very high concentrations (30-100 μmol/L), so these nonspecific effects seem unlikely to arise at therapeutically relevant concentrations, as in clinical practice. The electrophysiological effects of a single intravenous administration of ivabradine were studied in patients with normal baseline electrophysiology.…”

Antiarrhythmic properties of novel antianginal drugs in dog and human cardiac preparations

“…In these situations inhibition of other potassium channels may lead to unexpectedly augmented APD prolongation, resulting in proarrhythmic reactions. In previous studies the investigators found that ivabradine at 3 and 10 μM prolongs repolarization in guinea-pig papillary muscles [91,101]. Our results support the action potential lengthening effect of ivabardine also in dog and human cardiac preparations especially in case of attenuated repolarization reserve.…”