ABSTRACT
Activation of the volume-regulated anion channels (VRAC) is considered to be involved in arrhythmia, but it has not yet been fully elucidated because of the lack of its high affinitive and selective compounds. A newly synthesized compound, YM-198313 (sodium 4-({[2-(methylthio)benzyl]amino}-5-[(1-phenylethyl)thio]isothiazol-3-olate), strongly inhibited VRAC in HeLa cells with an IC50 of 3.03+/-0.05 microM. However, YM-198313 weakly affected both the Ca2+-activated Cl- channels in HTC cells and the cAMP-activated Cl- channels in T84 cells, demonstrating that this compound is selective for VRAC among Cl- channels. At 10 microM, YM-198313 almost completely (100+/-7.8%) inhibited the VRAC current in guinea pig atrial myocytes. However, at the same concentration, YM-198313 showed little inhibitory effect on the cardiac cation currents in ventricular myocytes. We believe that YM-198313 is a potent and selective VRAC inhibitor, therefore, it should be use to clarify the role VRAC plays in arrhythmia.
Subject(s)
Anti-Arrhythmia Agents/pharmacology , Benzyl Compounds/pharmacology , Chloride Channel Agonists , Thiazoles/pharmacology , Animals , Chloride Channels/physiology , Guinea Pigs , HeLa Cells , Heart Atria/drug effects , Heart Atria/metabolism , Humans , Male , Osmolar ConcentrationABSTRACT
The different actions of two I(h) channel blockers, zatebradine (UL-FS 49) and ZD7288, on rod photoresponses were analysed by computer simulation using a newly revised ionic current model of the rod photoreceptor, based on Hodgkin-Huxley equations. The model, adjusted to fit the experimental results of amphibian rods, shows that both of the blockers enhance the light-induced membrane hyperpolarization. Our model can also predict a mechanism of a damped oscillation arising during the recovery phase appeared only in the presence of zatebradine which, unlike ZD7288, reduces both I(h) and I(Kv). We suggest that the oscillation can appear due to the alternative activation of voltage-dependent Ca(2+) current (I(Ca)) and calcium-dependent current (I(K(Ca)) and I(Cl(Ca))) when I(Kv) is blocked, with I(K(Ca)) having a stronger effect than I(Cl(Ca)).
Subject(s)
Benzazepines/pharmacology , Cardiotonic Agents/pharmacology , Pyrimidines/pharmacology , Retinal Rod Photoreceptor Cells/drug effects , Action Potentials/drug effects , Calcium/metabolism , HumansABSTRACT
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.
