ArticleMolecular pharmacology2009
The Na+/Ca2+ exchange inhibitor 2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate (KB-R7943) also blocks ryanodine receptors type 1 (RyR1) and type 2 (RyR2) channels.
Article in Molecular pharmacology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 42 citations in OpenAlex.
- Pacemaking in the lymphatic system.The Journal of physiology · 2026Review
- Excitation-contraction coupling in mammalian skeletal muscle: Blending old and last-decade research.Frontiers in physiology · 2022Review
- Role of Sodium/Calcium Exchangers in Tumors.Biomolecules · 2020Review
- Interactions of Dichlorodiphenyltrichloroethane (DDT) and Dichlorodiphenyldichloroethylene (DDE) With Skeletal Muscle Ryanodine Receptor Type 1.Toxicological sciences : an official journal of the Society of Toxicology · 2019Article
- Blockade of the forward NaBritish journal of pharmacology · 2019Article
- Adamantane-Isothiourea Hybrid Derivatives: Synthesis, Characterization, In Vitro Antimicrobial, and In Vivo Hypoglycemic Activities.Molecules (Basel, Switzerland) · 2017Article
- Pyrethroid Insecticides Directly Activate Microglia Through Interaction With Voltage-Gated Sodium Channels.Toxicological sciences : an official journal of the Society of Toxicology · 2017Article
- Chronic heart failure: Ca(2+), catabolism, and catastrophic cell death.Biochimica et biophysica acta · 2016Review
- Na+/Ca2+ exchange and Na+/K+-ATPase in the heart.The Journal of physiology · 2015Review
- Cholesterol removal from adult skeletal muscle impairs excitation-contraction coupling and aging reduces caveolin-3 and alters the expression of other triadic proteins.Frontiers in physiology · 2015Article
- Tetanic Ca2+ transient differences between slow- and fast-twitch mouse skeletal muscle fibres: a comprehensive experimental approach.Journal of muscle research and cell motility · 2014Article
- Ca2+ influx via the Na+/Ca2+ exchanger is enhanced in malignant hyperthermia skeletal muscle.The Journal of biological chemistry · 2014Article
- KB-R7943, a plasma membrane Na(+)/Ca(2+) exchanger inhibitor, blocks opening of the mitochondrial permeability transition pore.Biochemical and biophysical research communications · 2014Article
- Na/Ca exchange and contraction of the heart.Journal of molecular and cellular cardiology · 2013Review
- Functional comparison of the reverse mode of Na+/Ca2+ exchangers NCX1.1 and NCX1.5 expressed in CHO cells.Acta pharmacologica Sinica · 2013Article
- Genetic inhibition of Na+-Ca2+ exchanger current disables fight or flight sinoatrial node activity without affecting resting heart rate.Circulation research · 2013Article
- Effect of chronic perinatal hypoxia on the role of rho-kinase in pulmonary artery contraction in newborn lambs.American journal of physiology. Regulatory, integrative and comparative physiology · 2013Article
- Reverse-mode Na+/Ca2+ exchange is an important mediator of venous contraction.Pharmacological research · 2012Article
- Calcium dependence of damage to mouse motor nerve terminals following oxygen/glucose deprivation.Experimental neurology · 2012Article
- Gene dose influences cellular and calcium channel dysregulation in heterozygous and homozygous T4826I-RYR1 malignant hyperthermia-susceptible muscle.The Journal of biological chemistry · 2012Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Na(+)/Ca(2+) exchanger (NCX) is a plasma membrane transporter that moves Ca(2+) in or out of the cell, depending on membrane potential and transmembrane ion gradients. NCX is the main pathway for Ca(2+) extrusion from excitable cells. NCX inhibitors can ameliorate cardiac ischemia-reperfusion injury and promote high-frequency fatigue of skeletal muscle, purportedly by inhibiting the Ca(2+) inward mode of NCX. Here we tested two known NCX inhibitors, 2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)-isothiourea methanesulfonate (KB-R7943) and the structurally related 2-[[4-[(4-Nitrophenyl)methoxy]phenyl]methyl]-4-thiazoli dinecarboxylic acid ethyl ester (SN-6), for their influence on electrically or caffeine-evoked Ca(2+) transients in adult dissociated flexor digitorum brevis (FDB) skeletal muscle fibers and human embryonic kidney (HEK) 293 cells that have stable expression of type 1 ryanodine receptor (RyR1). KB-R7943 (< or = 10 microM) reversibly attenuates electrically evoked Ca(2+) transients in FDB and caffeine-induced Ca(2+) release in HEK 293, whereas the structurally related NCX inhibitor SN-6 does not, suggesting that KB-R7943 directly inhibits RyR1. In support of this interpretation, KB-R7943 inhibits high-affinity binding of [(3)H]ryanodine to RyR1 (IC(50) = 5.1 +/- 0.9 microM) and the cardiac isoform RyR2 (IC(50) = 13.4 +/- 1.8 microM). KB-R7943 interfered with the gating of reconstituted RyR1 and RyR2 channels, reducing open probability (P(o)), shortening mean open time, and prolonging mean closed time. KB-R7943 was more effective at blocking RyR1 with cytoplasmic conditions favoring high P(o) compared with those favoring low P(o). SN-6 has negligible activity toward altering [(3)H]ryanodine binding of RyR1 and RyR2. Our results identify that KB-R7943 is a reversible, activity-dependent blocker of the two most broadly expressed RyR channel isoforms and contributes to its pharmacological and therapeutic activities.
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