Calcium influx through ion channels located on the release face of the presynaptic nerve terminal gates the release of neurotransmitters by the fusion of the secretory vesicle and the discharge of its contents[2]. The flux of calcium ions (Ca2+) into the cytosol, where they serve as intracellular messengers, is regulated by two distinct families of Ca2+ channel proteins. These are the intracellular Ca2+ release channels, which allow Ca2+ to enter the cytosol from intracellular stores, and the plasma membrane Ca2+ channels, which control Ca2+ entry from the extracellular space. The intracellular channels include the large Ca2+ channels ("ryanodine receptors") that participate in cardiac and skeletal muscle excitation-contraction coupling, and smaller inositol trisphosphate (InsP3)-activated Ca2+ channels[3]. NS-638 is a small nonpeptide molecule with Ca2+-channel blocking properties. K+-stimulated intracellular Ca2+-elevation is blocked with an IC50 value of 3.4 μM. NS-638 dose dependently inhibits K+-stimulated [45 Ca2+]-uptake in chick cortical synaptosomes and 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA)-stimulated [3H]GABA-release from cultured cortical neurons with IC50 values of 2.3 and 4.3 uM, respectively. K+-stimulated intracellular Ca2+-elevation in cultured cerebellar granule cells is equipotently blocked with an IC50 value of 3.4 μM. At this concentration no effect on Ca2+-induced contractions in K+-depolarized guinea pig taenia coli is observed. NS-638 reversibly blocks N- and L-type Ca2+-channels in cultured chick dorsal root ganglion cells in the concentration range of 1-30 μM. In the mouse middle cerebral artery occlusion model, NS-638 administered i.p. (50 mg/kg) at 1 h and 6 h post-ischemia, and once a day for the next two days, results in a 48% reduction in total infarct volume. It does not show protection against ischemic neuronal damage in the gerbil model of bilateral carotid artery occlusion[4].
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