title: Inhibitory effect of YM-244769, a novel Na+/Ca2+exchanger inhibitor on Na+/Ca2+exchange current in guinea pig cardiac ventricular myocytes.
abstract: Recently, YM-244769 (N-(3-aminobenzyl)-6-{4-[(3-fluorobenzyl)oxy]phenoxy} nicotinamide) has been reported as a new potent and selective Na+/Ca2+exchange (NCX) inhibitor by using various cells transfected with NCX using the45Ca2+fluorescent technique. However, the electrophysiological study of YM-244769 on NCX had not been performed in the mammalian heart. We examined the effects of YM-244769 on NCX current (INCX) in single cardiac ventricular myocytes of guinea pigs by using the whole-cell voltage clamp technique. YM-244769 suppressed the bidirectional INCXin a concentration-dependent manner. The IC50values of YM-244769 for the bidirectional outward and inward INCXwere both about 0.1 μM. YM-244769 suppressed the unidirectional outward INCX(Ca2+entry mode) with an IC50value of 0.05 μM. The effect on the unidirectional inward INCX(Ca2+exit mode) was less potent, with 10 μM of YM-244769 resulting in the inhibition of only about 50 %. At 5 mM intracellular Na+concentration, YM-244769 suppressed INCXmore potently than it did at 0 mM [Na+]i. Intracellular application of trypsin via the pipette solution did not change the blocking effect of YM-244769. In conclusion, YM-244769 inhibits the Ca2+entry mode of NCX more potently than the Ca2+exit mode, and inhibition by YM-244769 is [Na+]i-dependent and trypsin-insensitive. These characteristics are similar to those of other benzyloxyphenyl derivative NCX inhibitors such as KB-R7943, SEA0400, and SN-6. The potency of YM-244769 as an NCX1 inhibitor is higher than those of KB-R7943 and SN-6 and is similar to that of SEA0400.
authors.affiliation: Division of Pharmacological Science, Department of Health Science, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Kanna
authors.initials: K
authors.lastname: Yamashita
authors.affiliation: Division of Pharmacological Science, Department of Health Science, Hamamatsu University School of Medicine, Hamamatsu, Japan. w-yasu@hama-med.ac.jp.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Kita
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Iwamoto
authors.affiliation: Department of Pharmacology, School of Medicine, Fukushima Medical University, Fukushima, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Kimura
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D008564:Membrane Potentials; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014357:Trypsin / Q000378:metabolism
chemical_list: D049990:Membrane Transport Modulators; C516554:N-(3-aminobenzyl)-6-(4-((3-fluorobenzyl)oxy)phenoxy)nicotinamide; D019831:Sodium-Calcium Exchanger; D009536:Niacinamide; D012964:Sodium; D014357:Trypsin; D002118:Calcium
keywords: Benzyloxyphenyl derivative; Cardiac myocytes; Membrane current; Na+/Ca2+ exchange current (INCX); Patch-clamp method; YM-244769