UK-68,798, A Class III Antiarrhythmic Drug with Antifibrillatory Properties

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74787/1/j.1527-3466.1992.tb00244.x.pd

Re-Evaluation of the Action Potential Upstroke Velocity as a Measure of the Na+ Current in Cardiac Myocytes at Physiological Conditions

Background: The SCN5A encoded sodium current (INa) generates the action potential (AP) upstroke and is a major determinant of AP characteristics and AP propagation in cardiac myocytes. Unfortunately, in cardiac myocytes, investigation of kinetic properties of INa with near-physiological ion concentrations and temperature is technically challenging due to the large amplitude and rapidly activating nature of INa, which may seriously hamper the quality of voltage control over the membrane. We hypothesized that the alternating voltage clamp-current clamp (VC/CC) technique might provide an alternative to traditional voltage clamp (VC) technique for the determination of INa properties under physiological conditions. Principal Findings: We studied INa under close-to-physiological conditions by VC technique in SCN5A cDNA-transfected HEK cells or by alternating VC/CC technique in both SCN5A cDNA-transfected HEK cells and rabbit left ventricular myocytes. In these experiments, peak INa during a depolarizing VC step or maximal upstroke velocity, dV/dtmax, during VC/CC served as an indicator of available INa. In HEK cells, biophysical properties of INa, including current density, voltage dependent (in)activation, development of inactivation, and recovery from inactivation, were highly similar in VC and VC/CC experiments. As an application of the VC/CC technique we studied INa in left ventricular myocytes isolated from control or failing rabbit hearts

Block of delayed rectifier potassium current, IK, by flecainide and E-4031 in cat ventricular myocytes.

Block of the delayed rectifier potassium current, IK, by the class IC antiarrhythmic agent, flecainide, and by the novel selective class III antiarrhythmic agent, E-4031, were compared in isolated cat ventricular myocytes using the single suction-pipette, voltage-clamp technique. Flecainide (10 microM) markedly reduced IK elicited on depolarization steps to plateau voltages (+10 mV) and nearly completely blocked the "tail currents" elicited on repolarization to -40 mV (93 +/- 4% block at +40 mV, n = 3). E-4031 (1 microM) produced similar effects (96 +/- 3% block at +40 mV, n = 3). Slow voltage ramps from -100 to +40 mV confirmed inward rectifying properties of IK and showed that flecainide and E-4031 have no effects on the background potassium current, IK1. Thus, the results demonstrate that block of IK is a common feature of flecainide and E-4031. IK block by E-4031 most likely underlies the drug's potent class III antiarrhythmic properties. On the other hand, flecainide block of IK during an action potential would tend to prolong repolarization, but this effect may be obscured by concomitant block of plateau Na+ channels to produce little or no change in action potential duration, consistent with its class IC classification.</jats:p