Block of the cardiac pacemaker current (I_f) in the rabbit sino-atrial node and in canine Purkinje fibres by 9-amino-1,2,3,4-tetrahydroacridine

We have investigated the action of 9-amino-1, 2, 3, 4-tetrahydroacridine (THA) on the pacemaker current I_f in rabbit sino-atrial node myocytes and in canine Purkinje fibres. THA at concentrations in the range 3-300 μM blocked I_f in a voltage-independent manner, as revealed by measurements on the fully activated I/V relation for I_f. The dose/response relationship of the I_f maximal slope conductance (G_f) can be fitted by assuming a cooperative binding reaction where two THA molecules are required to block one I_f channel. Half-maximal block occurred at 18.2 μM in the sino-atrial node and 36.6 μM in Purkinje fibres. THA also affected the I_f kinetic properties. This was examined in the sino-atrial node where the current activation curve was shifted in the negative direction on the voltage axis (-21 mV at 30 μM THA). The delayed rectifier current, I_k, was also reduced by THA in sino-atrial node myocytes: at -40 mV the I_k fully activated value was decreased to 37% of its control value by 30 μM THA, with only a minor modification of the position of the activation curve at the same potential. Thus, although THA blocks I_f at a lower concentration than other known I_f-channel blockers [DiFrancesco (1982) J Physiol (Lond) 329:485-507], its action on the pacemaker current is not specific.