INHIBITORY ACTIONS OF ZENECA-ZD7288 ON WHOLE-CELL HYPERPOLARIZATION-ACTIVATED INWARD CURRENT (I(F)) IN GUINEA-PIG DISSOCIATED SINOATRIAL NODE CELLS

1 ZENECA ZD7288 -ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyr imidinium chloride) is a sinoatrial node (SAN) modulating agent which produces a selective slowing of the heart rate. Its effects have been studied in single, freshly dissociated guinea-pig SAN cells, by standa rd patch clamp procedures. 2 Whole-cell inward currents were evoked by hyperpolarizing voltage clamp steps from a holding potential of -40 m V. ZD7288 inhibited the hyperpolarization activated cationic current ( If) in a concentration-dependent manner. The 'selective bradycardic ag ents' alinidine and UL-FS 49 (zatebradine) both also inhibited I(f). 3 The activation of I(f) was investigated by measuring tail current amp litudes at + 20 mV after hyperpolarizing steps to different potentials to activate the current. The reduction in I(f) resulted from both a s hift in the I(f) current activation curve in the negative direction on the voltage axis, and also a reduction in the activation curve amplit ude. 4 ZD7288 did not affect the ion selectivity of the I(f) channel, since the tail current reversal potential was unchanged in the presenc e of the drug. 5 With ZD7288 the inhibition of I(f) was not use-depend ent, whereas UL-FS 49 displayed use-dependence in the block of the I(f ) current. 6 Whereas ZD7288 had no significant effect on the delayed r ectifier current (I(k)) in these cells, both alinidine and UL-FS 49 si gnificantly reduced I(k) at the same concentrations which reduced If. 7 The data show that ZD7288 reduces I(f) by affecting the activation c haracteristics of the If current; this inhibition may account for this agent's selective bradycardic properties.