Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Br J Pharmacol
1999 May 01;1271:9-18. doi: 10.1038/sj.bjp.0702488.
Show Gene links
Show Anatomy links
Molecular analysis of the Na+ channel blocking actions of the novel class I anti-arrhythmic agent RSD 921.
Pugsley MK
,
Goldin AL
.
???displayArticle.abstract???
RSD 921 is a novel, structurally unique, class I Na+ channel blocking drug under development as a local anaesthetic agent and possibly for the treatment of cardiac arrhythmias. The effects of RSD 921 on wild-type heart, skeletal muscle, neuronal and non-inactivating IFMQ3 mutant neuronal Na+ channels expressed in Xenopus laevis oocytes were examined using a two-electrode voltage clamp. RSD 921 produced similarly potent tonic block of all three wild-type channel isoforms, with EC50 values between 35 and 47 microM, whereas the EC50 for block of the IFMQ3 mutant channel was 110+5.5 microM. Block of Na+ channels by RSD 921 was concentration and use-dependent, with marked frequency-dependent block of heart channels and mild frequency-dependent block of skeletal muscle, wild-type neuronal and IFMQ3 mutant channels. RSD 921 produced a minimal hyperpolarizing shift in the steady-state voltage-dependence of inactivation of all three wild-type channel isoforms. Open channel block of the IFMQ3 mutant channel was best fit with a first order blocking scheme with k(on) equal to 0.11+/-0.012x10(6) M(-1) s(-1) and k(off) equal to 12.5+/-2.5 s(-1), resulting in KD of 117+/-31 microM. Recovery from open channel block occurred with a time constant of 14+/-2.7 s(-1). These results suggest that RSD 921 preferentially interacts with the open state of the Na+ channel, and that the drug may produce potent local anaesthetic or anti-arrhythmic action under conditions of shortened action potentials, such as during anoxia or ischaemia.
Armstrong,
Destruction of sodium conductance inactivation in squid axons perfused with pronase.
1973, Pubmed
Armstrong,
Destruction of sodium conductance inactivation in squid axons perfused with pronase.
1973,
Pubmed
Auld,
A neutral amino acid change in segment IIS4 dramatically alters the gating properties of the voltage-dependent sodium channel.
1990,
Pubmed
,
Xenbase
Bailey,
The electrophysiologic basis for cardiac electrical activity: normal and abnormal.
1981,
Pubmed
Barrett,
A model of myocardial ischemia for the simultaneous assessment of electrophysiological changes and arrhythmias in intact rabbits.
1997,
Pubmed
Bean,
Lidocaine block of cardiac sodium channels.
1983,
Pubmed
Bennett,
On the molecular nature of the lidocaine receptor of cardiac Na+ channels. Modification of block by alterations in the alpha-subunit III-IV interdomain.
1995,
Pubmed
,
Xenbase
Cahalan,
Local anesthetic block of sodium channels in normal and pronase-treated squid giant axons.
1978,
Pubmed
Cascio,
Electrophysiologic changes in ischemic ventricular myocardium: I. Influence of ionic, metabolic, and energetic changes.
1995,
Pubmed
Clark,
Highly selective kappa opioid analgesics. Synthesis and structure-activity relationships of novel N-[(2-aminocyclohexyl)aryl]acetamide and N-[(2-aminocyclohexyl)aryloxy]acetamide derivatives.
1988,
Pubmed
Clark,
PD117302: a selective agonist for the kappa-opioid receptor.
1988,
Pubmed
Goldin,
Preparation of RNA for injection into Xenopus oocytes.
1992,
Pubmed
,
Xenbase
Grant,
The role of inactivation in open-channel block of the sodium channel: studies with inactivation-deficient mutant channels.
1996,
Pubmed
HODGKIN,
A quantitative description of membrane current and its application to conduction and excitation in nerve.
1952,
Pubmed
Hille,
Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction.
1977,
Pubmed
Hondeghem,
Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels.
1977,
Pubmed
Isom,
Primary structure and functional expression of the beta 1 subunit of the rat brain sodium channel.
1992,
Pubmed
,
Xenbase
Isom,
Structure and function of the beta 2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motif.
1995,
Pubmed
,
Xenbase
Kallen,
Primary structure and expression of a sodium channel characteristic of denervated and immature rat skeletal muscle.
1990,
Pubmed
Kléber,
Extracellular K+ and H+ shifts in early ischemia: mechanisms and relation to changes in impulse propagation.
1987,
Pubmed
Kontis,
Site-directed mutagenesis of the putative pore region of the rat IIA sodium channel.
1993,
Pubmed
,
Xenbase
Lansman,
Blockade of current through single calcium channels by Cd2+, Mg2+, and Ca2+. Voltage and concentration dependence of calcium entry into the pore.
1986,
Pubmed
Martin,
Pharmacology of opioids.
1983,
Pubmed
Pugsley,
Antiarrhythmic effects of U-50,488H in rats subject to coronary artery occlusion.
1992,
Pubmed
Pugsley,
Cardiovascular actions of the kappa-agonist, U-50,488H, in the absence and presence of opioid receptor blockade.
1992,
Pubmed
Pugsley,
Electrophysiological and antiarrhythmic actions of the kappa agonist PD 129290, and its R,R (+)-enantiomer, PD 129289.
1993,
Pubmed
Pugsley,
An electrophysiological basis for the antiarrhythmic actions of the kappa-opioid receptor agonist U-50,488H.
1994,
Pubmed
Pugsley,
Tonic and use-dependent block of sodium currents in isolated cardiac myocytes by bisaramil.
1995,
Pubmed
Pugsley,
Effects of bisaramil, a novel class I antiarrhythmic agent, on heart, skeletal muscle and brain Na+ channels.
1998,
Pubmed
,
Xenbase
Pugsley,
Sodium channel-blocking properties of spiradoline, a kappa receptor agonist, are responsible for its antiarrhythmic action in the rat.
1998,
Pubmed
Ragsdale,
Molecular determinants of state-dependent block of Na+ channels by local anesthetics.
1994,
Pubmed
,
Xenbase
Ragsdale,
Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels.
1996,
Pubmed
Sanchez-Chapula,
Voltage- and use-dependent effects of lidocaine on sodium current in rat single ventricular cells.
1983,
Pubmed
Sheridan,
Quantification of state-dependent drug interactions with the sodium channel.
2000,
Pubmed
Smith,
Functional analysis of the rat I sodium channel in xenopus oocytes.
1998,
Pubmed
,
Xenbase
Strichartz,
An integrated view of the molecular toxinology of sodium channel gating in excitable cells.
1987,
Pubmed
Trimmer,
Primary structure and functional expression of a mammalian skeletal muscle sodium channel.
1989,
Pubmed
,
Xenbase
Valenzuela,
Class III antiarrhythmic effects of zatebradine. Time-, state-, use-, and voltage-dependent block of hKv1.5 channels.
1996,
Pubmed
Walker,
Determination of an arylacetamide antiarrhythmic in rat blood and tissues using reversed-phase high-performance liquid chromatography.
1996,
Pubmed
West,
A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation.
1992,
Pubmed
,
Xenbase
Wong,
Effects of drugs interacting with opioid receptors during normal perfusion or ischemia and reperfusion in the isolated rat heart--an attempt to identify cardiac opioid receptor subtype(s) involved in arrhythmogenesis.
1990,
Pubmed
