Effects of 4-aminopyridine on inward rectifying and pacemaker currents of cardiac Purkinje fibres.

1. 4-Aminopyridine (4-AP), in a concentration of 1-5 mM, prolongs the action potential duration, induces spontaneous activity and depolarizes sheep cardiac Purkinje strands. These effects are different from those obtained with 0.1 mM and are reversible. 2. Voltage clamp experiments demonstrate that the higher drug concentrations affect membrane currents measured in the potential range between -100 and -40 mV, in addition to the reduction of the transient outward current already described for small amounts of the drug (0.1--0.5 mM). 3. The analysis of membrane current modifications by 4-AP in the presence of cesium and barium ions indicates that 4-AP, in the higher concentration range, reduces the inward rectifying time independent potassium current iK1 and modified the voltage dependence of the time and voltage dependent pacemaker current. The steady-state activation curve of the pacemaker current is shifted towards less negative potentials and is less steeply voltage dependent. The time constant (tau) curve has an increased maximum, displaced towards less negative potentials. 4. The modifications by 4-AP of the iK1 and pacemaker currents explain the changes in resting potential, action potential duration and the induction of spontaneous activity. The latter effect is not the result of an indirect effect of 4-AP through increased release of neurotransmitters from sympathetic nerve endings. A possible action of 4-AP at the inside of the membrane, explaining the multiple actions, is discussed.