KB-R7943 is a plasma membrane Na(+)/Ca(2+) exchanger inhibitor. KB-R7943 reversibly inhibits inward and outward Na+/Ca2+ exchange in a dose-dependent manner (MCU; IC50 = 5.5 μM), but it does not affect Na+-dependent transport systems or ionotropic glutamate receptors. In addition, the effects of KB-R7943 on Ca(2+) homeostasis provide new evidence for the role of mitochondria modulating Ca(2+)-release and regenerative Ca(2+)-oscillations. KB-R7943 (10 and 30 microM) suppressed the tonotropic effect of ouabain, and prolonged the onset time of extra-systole induced by ouabain in isolated atria. KB-R7943 suppresses ouabain-induced arrhythmias through inhibition of the reverse-mode NCX. KB-R7943 is also a potent blocker of the transient receptor potential channels (TRPC) TRPC3, TRPC5 and TRPC6.
|Cell lines||neurons, astrocytes, and microglia|
|Preparation method||Na+-Ca2+ Exchange Activity.
Na+-Ca2+ exchange activity was determined by assaying Na+-dependent Ca2+ uptake as reported previously (Takuma et al., 1994). Briefly, the cells were preincubated in Hanks' balanced saline solution (HBSS) for 20 min, and the medium was switched to HBSS containing Ca2+ and incubated for 5 min. To increase intracellular Na+ concentration, 1 mM ouabain plus 20 μM monensin (for astrocytes and microglia) and 10 μM monensin (for neurons) were used. Monensin was added simultaneously with the isotope. Ouabain was added 5 min before monensin in astrocytes and microglia. NCX inhibitors were added 5 min before monensin and present during Ca2+ uptake reaction.
|Concentrations||0~10 μ M|
|Incubation time||5 min|
|Animal models||cerebral cortex (A) and striatum (B) after MCA occlusion in rats|
|Formulation||20% soybean oil|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Source||J Cardiol (2015). Figure 2. KB-R7943|
|Concentrations||0.5, 1.0 and 5.0 μM|
|Results||KB-R7943 inhibited the activity of the VPBs but did not prevent pace-induced VF|
The plasma membrane Na+/Ca2+ exchange inhibitor KB-R7943 is also a potent inhibitor of the mitochondrial Ca2+ uniporter.
Santo-Domingo J, et al. Br J Pharmacol. 2007 Jul;151(5):647-54. PMID: 17471180.
SEA0400, a novel and selective inhibitor of the Na+-Ca2+ exchanger, attenuates reperfusion injury in the in vitro and in vivo cerebral ischemic models.
Matsuda T, et al. J Pharmacol Exp Ther. 2001 Jul;298(1):249-56. PMID: 11408549.
Effect of Na+/Ca2+ exchange inhibitor, KB-R7943 on ouabain-induced arrhythmias in guinea-pigs.
Watano T, et al. Br J Pharmacol. 1999 Aug;127(8):1846-50. PMID: 10482915.
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