Multiple inhibitory effects of zatebradine (UL-FS 49) on the electrophysiological properties of retinal rod photoreceptors.

Effects of the bradycardiac agent zatebradine (UL-FS 49) were determined in intracellular and patch-clamp experiments of amphibian rod photoreceptors. Zatebradine (0.3-100 microM) greatly enhanced the bright-light-induced hyperpolarization of membrane potential in frog retinal rods and caused damped oscillations during the membrane potential recovery phase. In inner segments of the rod photoreceptor cells, the hyperpolarization-activated inward current ( Ih) contributes to the recovery of the photoresponse. Patch-clamp recordings from newt rod photoreceptor cells revealed that zatebradine caused use- and concentration-dependent (0.1-100 microM) inhibition of Ih: conductance was reduced without effects on the reversal potential or activation voltage. Our data confirmed that the pharmacological properties of Ih in rod photoreceptors were similar to those of Ih in cardiac myocytes. In addition, zatebradine inhibited voltage-gated outward K+ currents ( IK), but did not affect L-type Ca2+ currents ( ICa). These results are consistent with the inhibition of IK and Ih by zatebradine in other cells, and may explain the oscillations evoked during the recovery phase of the membrane potential. These multiple actions of zatebradine on channels in rod photoreceptors may explain its effects on the electroretinogram (ERG) in vivo and its adverse effects on vision in clinical studies.