Electrophysiological effects of CRE‐1087 in guinea‐pig ventricular muscles

Abstract

1 The electrophysiological effects of CRE-1087, a new antiarrhythmic drug, were studied in guinea-pig papillary muscles. 2 CRE-1087 (10-7 M-O-4 M) produced a concentration-dependent decrease in the action potential amplitude and Vmax of the upstroke without altering the action potential duration or the resting membrane potential. 3 At 5 x 10-6 M, CRE-1087 produced a 5.0 ± 1.0% tonic Vmax block and this value was not modified at the different rates of stimulation tested. In the presence of CRE-1087, trains of stimuli at rates between 0.5 and 3 Hz led to an exponential decline in Vmax (frequency-dependent Vx,, block) which augmented at higher rates of stimulation. At 2 Hz the onset kinetics of the frequency-dependent Vmax block was fitted by a monoexponential function being the K value 0.099 ± 0.012 AP-'. The time constant for the recovery of Vmax from the frequency-dependent block was prolonged to 18.3 ± 1.5 s. 4 CRE-1087 (5 X 10-6 M) did not shift the membrane responsiveness curve. 5 CRE-1087 had no effect on the characteristics of the slow action potentials elicited by isoprenaline in ventricular fibres depolarized by 27 mM KCl, which suggested that CRE-1087 did not exhibit class IV (Ca antagonist) antiarrhythmic actions. 6 The slow onset and the slow offset kinetics of frequency-dependent Vmax block during repetitive activity suggested that in guinea-pig ventricular muscle fibres CRE-1087 exhibited class Ic antiarrhythmic actions.

Pharmacology of CRE‐1087, A New Antiarrhythmic Drug

“…Microelectrode recordings have been used to study the effects of CRE-1087 on the transmembrane potentials of guinea pig atrial and ventricular muscle fibers under a variety of conditions (8,9,10,13,37). At concentrations between 0.1 and 100 pA4 CRE-1087 decreased in a concentration-dependent manner the amplitude, overshoot, and maximal rate of depolarization ( V , , , an index of the fast inward sodium current) of the atrial and ventricular action potentials, and slowed intraventricular conduction velocity.…”

“…Excitability, i.e., slow action potentials, was restored by adding isoproterenol, histamine, or BaCI, to the perfusate. CRE-1087 (1-100 fl) had no effect on resting membrane potential, or on the amplitude, V, , , or duration of the slow action potentials measured at 90% repolarization (8,9,13,37). These results suggest that CRE-1087 did not exhibit class IV (CaZt antagonist) activity.…”

“…In isolated guinea pig right atria CRE-1087 produced a dose-dependent decrease in spontaneous atrial rate and prolonged the sinus node recovery time (37). This negative chronotropic effect was due to a progressive decrease in the slope of diastolic depolarization and a progressive shift of the threshold membrane potential to less negative values (9,37). CRE-1087 also inhibited the ventricular spontaneous activity as well as the ventricular automaticity induced by BaC1, or epinephrine in guinea pig papillary muscles (8,9,13,37) and decreased the amplitude of the late afterpotentials induced by ouabain in ventricular muscle fibers (13).…”

“…All these effects suggest that CRE-1087 exerted its electrophysiological effects by a selective decrease in the IN=, and thus it can be viewed as a class I antianythmic drug (8,9,13).…”

Class I and III antiarrhythmic actions of prazosin in guinea‐pig papillary muscles

“…The onset kinetics of frequency-dependent V,,,a, block can be defined as an event-dependent process, that can be fitted by a single or biexponential function (Courtney, 1987;Delpon et al, 1992 Number of action potentials 16.1 ± 1.5…”