Some properties of the UL-FS 49 block of the hyperpolarization-activated current (i f) in sino-atrial node myocytes

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Abstract
Block of the hyperpolarization-activated “pacemaker” current (i f) by the bradycardic agent UL-FS 49 was studied in isolated sino-atrial (SA) node myocytes. Using repetitive activation/deactivation protocols, micromolar concentrations of UL-FS 49 blockedi f in a dose-dependent fashion. Block development was slow, with time constants decreasing with drug concentration and ranging from 25.8 s at 10 μM to 75.5 s at 1 μM UL-FS 49. Block did not develop in cells held at −35 mV, at which voltagei f channels are closed, indicating that channels must open before blocking occurs. Apparently in contrast with the requirement of negative voltages for block development, block was relieved by hyperpolarization with a time course slower than current kinetics. Due to the hyperpolarization-induced block relief, current/voltage (I/V) relations in the presence of UL-FS 49 displayed inward-going rectification. Experimental data fitted the hypothesis that UL-FS 49 behaves as an “open channel” blocker of “single-ion”i f channels. Block occurs within the pore, at a distance of about 39% of the membrane thickness from its internal side.