Effects of a new antiarrhythmic drug SS-68 on electrical activity in working atrial and ventricular myocardium of mouse and their ionic mechanisms

Abstract

SS-68 is a derivative of indole, which demonstrated strong antiarrhythmic effects not associated with significant QT prolongation in dog models of atrial fibrillation. Therefore, SS-68 was proposed as a new antiarrhythmic drug and the present study is the first describing its effects on action potentials (APs) configuration and elucidating the ionic mechanisms of these effects. Sharp microelectrodes were used to record APs in isolated preparations of mouse atrial and ventricular myocardium. In both types of myocardium 10(-6) M SS-68 produced reduction of AP duration, 3 × 10(-6) M failed to alter AP waveform and 10(-5) - 3 × 10(-5) M prolonged APs. Sensitivity of main ionic currents to SS-68 was determined using whole-cell patch clamp. Transient potassium current Ito was slightly inhibited by SS-68 with IC50 = 1.43 × 10(-4) M. IKur was more sensitive with IC50 = 1.84 × 10(-5) M. Background inward rectifier showed very low sensitivity to SS-68 - only 10(-4) M SS-68 caused significant reduction of IK1. ICaL was significantly inhibited by 10(-6)M - 3 × 10(-5) M SS-68. The IC50 value for the ICaL was 1.84 × 10(-6) M. Thus, main ionic currents of mouse cardiomyocytes are inhibited by SS-68 in the following order of potency: ICaL > IKur > Ito > IK1. While lower concentration of SS-68 shorten APs via suppression of ICaL, higher concentrations inhibit K(+)-currents leading to APs prolongation.

PharmaLab: A Tool to Study the Drug Action on the Mouse Ventricular Myocyte

“…The drug SS-68 [20] was able to decrease the cytosolic Ca 2+ concentration caused by CPVT [19] to values close to the control, but it generated a decrease in contraction force that should be considered in future tests. The concentration of Niferidil that best acted in SQTS [21] was 25µM, because it reached values close to the control.…”

“…With PO1 and PO2 being the probabilities of the ryanodine receptors being open, [Ca 2+ ]JSR and [Ca 2+ ]SS are the Ca 2+ concentrations at the junction and in the sarcoplasmic reticulum (SR) subspace in µM, PRyR a factor modulating calcium release, and v1 is the Ca 2+ flux. Next, the application of the antiarrhythmic SS-68 [20] which acts on the ICaL current to try to correct the mutation was simulated. The simulation protocols were: total simulation time of 200s, frequency of 1Hz, stimulus current of 20pA and duration of each pulse of 1ms [13].…”

Pharmacokinetic Studies Derived Indole Ss-68 With Antiarrhythmic and Antianginal Properties

“…High antiarrhythmic efficacy of SS-68 is connected with the blocking of ion currents (in maximal to acetylcholine-depended K + current, Ca 2+ L-type current and fast K + current of the detained straightening), choline-and adrenoreceprores of cardiomiocites and neurons [8][9][10][11].…”