Inhibition of potassium outward currents and pacemaker current in sheep cardiac Purkinje fibres by the verapamil derivative YS 035

Abstract

The electrophysiologic mode of action and potency of the verapamil derivative YS 035 (N,N-bis-(3,4-dimethoxyphenethyl)-N-methyl amine) were investigated in sheep cardiac Purkinje fibres. Action potential duration measured at a repolarization level of -60 mV (APD-60) and membrane currents recorded with the two-microelectrode voltage-clamp technique were evaluated. At 10 mumols/l YS 035 APD-60 was increased to about 115% of reference. Prolongation measured as percentage of the respective control exhibited on the average no dependence on stimulation frequency (0.17-2 Hz). At 100 mumols/l membrane became depolarized to about -50 mV and action potentials could no longer be elicited. Further study was focussed on effects on outward currents, mostly activated at a frequency of 0.05 Hz. Transient outward current (ito) was completely blocked at 100 mumols/l and half-maximal inhibition occurred at about 14 mumols/l. Inwardly rectifying potassium current (ik1) was reduced to 47% of reference at 100 mumols/l. An initially activating outward current at positive membrane potentials (iinst) was reduced to 73% at 100 mumols/l. Time-dependent (delayed) outward current (iK) was on the average not affected up to 100 mumols/l. Besides inhibition of repolarizing outward currents YS 035 completely blocked pacemaker current (if) at 100 mumols/l and half-maximal reduction was achieved at 5 mumols/l. YS 035 (1-100 mumols/l) did not clearly affect time constants of activation at selected test potentials (IK: +35 mV; if: -90 mV) or inactivation (ito: 0 mV). Voltage-dependent control mechanisms of currents (ito, if) were not influenced by YS 035 but the amount of available current was reduced.(ABSTRACT TRUNCATED AT 250 WORDS)