title: Molecular analysis of the Na+ channel blocking actions of the novel class I anti-arrhythmic agent RSD 921.
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.
authors.affiliation: Department of Microbiology & Molecular Genetics, University of California, Irvine 92697-4025, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Pugsley
authors.forename: A L
authors.initials: AL
authors.lastname: Goldin
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004558:Electric Stimulation; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D018482:Muscle, Skeletal / Q000737:chemistry; D009154:Mutation; D009206:Myocardium / Q000737:chemistry; D009474:Neurons / Q000737:chemistry; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011758:Pyrroles / Q000494:pharmacology*; D012313:RNA / Q000096:biosynthesis; D051381:Rats; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*; D014158:Transcription, Genetic; D014982:Xenopus laevis
chemical_list: D000889:Anti-Arrhythmia Agents; D011758:Pyrroles; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013876:Thiophenes; C054718:PD 117302; D012313:RNA