Electrophysiological and antiarrhythmic effects of the K‐channel opener, BRL 34915, in cardiac purkinje fibers

Abstract

The effects of BRL 34915 (6-cyano-3,4-dihydro-2,2-dimethyl-frans-4-[2-oxo-l-pyrrolidyl]-2H-benzo [b]pyran-3-oI, to be referred to as BRL) on the electromechanical properties of superfused dog and sheep ventricular Purkinje fibers were studied in vitro. At 5 pM, BRL shortened the action potential and decreased contractile force; these effects were greater in dog than in sheep Purkinje fibers. BRL reduced the slope and amplitude of diastolic depolarization measured during interruptions of drive. BRL suppressed spontaneous activity and antagonized the enhancement of automatic discharge induced by norepinephrine (0.5 pM), barium (50 pM), or strophanthidin (0.5 pM). BRL reduced or abolished the oscillatory potentials induced by high [Ca2+], (10.8 mM). It also antagonized the spontaneous responses in low [K+], (1 mM) and hyperpolarized fibers depolarized in a K-free solution. It is concluded that BRL modifies the action potential and force and has antiarrhythmic actions as it antagonizes abnormal pacemaker activity in Purkinje fibers by modifying potassium conductance and secondarily reducing intracellular calcium.

On the mechanism of increased potassium conductance by the potassium channel opener BRL 34915 in Isolated ventricular myocytes

“…Therefore, while the action of BRL on membrane potential is direct, that on contraction [see Liu et al, 1988) is an indirect consequence of the shortening of the action potential.…”

“…In turn, these changes shorten the action potential as the depolarizing effect of an undiminished ISi is decreased by the reduction of inward rectification. Therefore, while the action of BRL on membrane potential is direct, that on contraction [see Liu et al, 1988) is an indirect consequence of the shortening of the action potential.…”

“…A shortening of the action potential also reduces the steady-state slow inward current [Reuter, 19791, thereby antagonizing those arrhythmias that depend on calcium overload (e.g., those caused by cardiac glycosides). Even in the absence of calcium overload, a decrease in intracellular calcium leads to a less steep diastolic depolarization [Tamargo and Vassalle, 19871, and this might explain a reduction of the slope of diastolic depolarization and of normal pacemaker discharge by BRL [Liu et al, 1988).…”

KATPChannels in the Cardiovascular System

“…An argument could therefore be made that K ATP channel opening may be anti-arrhythmic since the outward current generated will oppose these arrhythmogenic triggers. Indeed, in cellular assays, K ATP channel openers inhibit experimentally induced abnormal automaticity (481, 505, 753), or triggered arrhythmias elicited by early afterpotentials (234, 753) or late afterpotentials (481, 505,753). A counter argument, however, is that K ATP channel opening may be pro-arrhythmic (at least to some extent) since they contribute partially to the primary defect, which is the loss of K ϩ from ischemic cells and K ϩ accumulation in the ischemic zone.…”

Potassium channel openers: pharmacological and clinical aspects

“…The latter may reflect inhibition of the inwardly rectifying background K+ current, I,, (McCullough et al, 1990). In Purkinje fibres, cromakalim (5 pM) antagonizes abnormal pacemaker activity, conferring potentially antiarrhythmic properties to the drug (Liu et al, 1988).…”