Frequency and voltage dependent effects of AN-132, a new class I anti-arrhythmic agent, on max of action potential upstroke in guinea pig ventricular muscles

Abstract

The in vitro electrophysiological properties of a newly synthesised antiarrhythmic agent, AN-132, were evaluated by recording transmembrane action potentials from guinea pig papillary muscles. AN-132 (10-100 mumol.litre-1) caused a dose dependent decrease in the maximum upstroke velocity (Vmax) of the action potential without affecting the resting potential. In the presence of AN-132, trains of stimuli at rates greater than or equal to 0.1 Hz led to an exponential decline in Vmax. This use dependent block was enhanced at higher stimulation frequency. The time constant for the recovery of Vmax from the use dependent block was 39.5-41.2 s. The curves relating membrane potential and Vmax were shifted by AN-132 (100 mumol.litre-1) in the direction of more negative potentials (6.1 mV). In preparations treated with AN-132 (30 and 100 mumol.litre-1), the Vmax of test action potentials preceded by conditioning clamp pulses to 0 mV was progressively decreased with an increasing number of pulses. A single prolonged clamp pulse to 0 mV reduced Vmax much less than multiple brief clamp pulses. These findings suggest than AN-132 has use dependent inhibitory action on the fast sodium channel by binding to the channel mainly during its activated state and that the unbinding rate of the drug during diastole is very slow. This use dependency and its greater inhibition of Vmax in depolarised muscles through the increase in tonic block may play a major role in preventing ventricular arrhythmias.

Utilization of an Isolated, Blood-Perfused Canine Papillary Muscle Preparation as a Model to Assess Efficacy and Adversity of Class I Antiarrhythmic Drugs

“…For example, disopyramide and flecainide showed slow onset and long-lasting effects on IVCT after bolus injections, while the reverse was true for lidocaine and mexiletine in this study. The order of speed estimated by OHT(IVCT) and RHT(IVCT) in the present study was in good accordance with that classified by the onset rate for the use dependent block and the recovery time constant from the use dependent block in previous reports, respectively (14,(18)(19)(20). Therefore, these find ings indicate that the classification by the kinetics of bind ing and dissociation of class I drugs with Na+ channels is also valid in our preparation.…”

Cardiovascular Effects of AN‐132, a New Diamine Analogue of Lidocaine

“…AN-I32 was noted to possess rate-and voltage-dependent inhibitory effects on V,, of the action potential (5). With stimulation at a given frequency, V, , , in the presence of AN-132 fell progressively to a new level.…”

“…AN-132 depressed the maximum rate of rise (V,,,) of the cardiac action potential in right ventricular muscle of the dog heart without affecting the resting membrane potential. Chihara et al ( 5 ) reported that at a concentration of greater than 10 pM, AN-132 caused a concentration-dependent decrease in the V,, of the action potential in guinea pig papillary muscle. At 100 pM AN-132, the amplitude and duration of the action potential at 30% repolarization (APD,,) were also decreased significantly, but neither the resting membrane potential nor APD, were affected.…”