Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells

1 The effect of the bradycardic agent S 16257 on the main ionic mechanisms of diastolic depolarization in sinoatrial node cells isolated from rabbit heart, was investigated by the patch-clamp technique in whole-cell and macro-patch recordings. 2 In whole-cell conditions, S 16257 induced a marked exponential use-dependent blockade of the hyperpolarization-activated I-f current, without shift of the voltage range of its activation curve. The rate of block increased with the drug concentration. The ICS, for the block of I-f was 2.8 x 10(-6) M. 3 A similar use-dependent decline of I-f was obtained with 3 mu M S 16257, in cell-attached and in inside-out macro-patch configurations, suggesting that the bradycardic agent interacts with I-f channels from the inside of the cell. 4 A high concentration of S 16257 (10 mu M) had no detectable effect on T-type calcium current and slightly decreased L-type calcium current (-18.12+/-10.66%), without significant use-dependent blockade. 5 S 16257 had no effect on the delayed outward potassium current I-K at 3 mu M and slightly decreased it only at high concentrations, -16.3+/-1.2% at 10 mu M. In contrast, zatebradine, another bradycardic agent, reduced I-K by 20.3+/-2.5% at 3 mu M. 6 In conclusion, S 16257 may lower heart rate without significant negative inotropic action. In comparison with zatebradine, S 16257 had less effect on I-K suggesting less prolongation of repolarization time.