YM-244769 is a potent, selective and orally active Na + /Ca 2+ exchanger ( NCX ) inhibitor. YM-244769 preferentially inhibits NCX3 and suppresses the unidirectional outward NCX current (Ca 2+ entry mode), with IC 50 s of 18 nM and 50 nM, respectively. YM-244769 efficiently protects against hypoxia/reoxygenation-induced SH-SY5Y neuronal cell damage. YM-244769 can also increase urine volume and urinary excretion of electrolytes in mice
In Vitro
YM-244769 (0.003-1 μM) inhibits dose dependently the initial rates of 45 Ca 2+ uptake into NCX1, NCX2, and NCX3 transfectants with IC 50 values of 68 ± 2.9, 96 ± 3.5, and 18 ± 1.0 nM, respectively. YM-244769 (0.3 or 1 μM) efficiently protects against the hypoxia/reoxygenation-induced lactate dehydrogenase (LDH) release in SH-SY5Y cells and in LLC-PK 1 cells (1 μM). YM-244769 possesses reverse mode-selectivity. YM-244769 (1 and 10 μM) inhibits NCX current (I NCX ) in a concentration- and [Na + ] i -dependent manner, the IC 50 against the unidirectional outward I NCX (Ca 2+ entry mode) is 0.05 μM. The IC 50 values against the bidirectional outward and inward I NCX are similar and approximately 100 nM with a Hill coefficient of about 1. YM-244769 is trypsin-insensitive. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Viability AssayCell Line: SH-SY5Y cells treated with NCX1 or NCX3 antisense Concentration: 0.3 and 1 μM Incubation Time: Result: Hypoxia/reoxygenation-induced LDH release was significantly attenuated: reduction in cell damage was greater in cells treated with NCX3 antisense (by 61%) than in cells treated with NCX1 antisense (by 35%).\n0.3 or 1 μM efficiently suppressed the hypoxia/reoxygenation-induced cell damage in SH-SY5Y cells treated with NCX1 antisense more than in those treated with NCX3 antisense.
In Vivo
YM-244769 (0.1-1 mg/kg; p.o.; once) exhibits dose-dependently natriuretic action in mice and significantly increases urinary excretion of Ca 2+ as well as Ca 2+ /Cr ratio. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Wild-type C57BL/6J mice and NCX-KO miceDosage: 0.1, 0.3 and 1 mg/kg Administration: Oral administration, once Result: Caused a dose-dependent increase (up to approximately 200%) in urine volume and urinary excretion of electrolytes (Na + , K + and Cl - ). Natriuretic actions were equivalently observed in NCX1-KO and WT, but disappeared in NCX2-KO and double KO.
