Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/117388
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Type: Journal article
Title: Pharmacological and toxicological activity of RSD921, a novel sodium channel blocker
Author: Walker, M.
Hayes, E.
Saint, D.
Adaikan, G.
Abraham, S.
Goldin, A.
Beatch, G.
MacLeod, B.
Wall, R.
Pugsley, M.
Citation: Biomedicine and Pharmacotherapy, 2018; 106:510-522
Publisher: Elsevier
Issue Date: 2018
ISSN: 0753-3322
1950-6007
Statement of
Responsibility: 
M.J.A. Walker, E.S.Hayes, D.A. Saint, G. Adaikan, S. Abraham, A.L. Goldin, G.N. Beatch, B.A. MacLeod, R.A. Wall, M.K. Pugsley
Abstract: BACKGROUND:RSD921, the R,R enantiomer of the kappa (k) agonist PD117,302, lacks significant activity on opioid receptors. METHODS:The pharmacological and toxicological actions were studied with reference to cardiovascular, cardiac, antiarrhythmic, toxic and local anaesthetic activity. RESULTS:In rats, dogs and baboons, RSD921 dose-dependently reduced blood pressure and heart rate. In a manner consistent with sodium channel blockade it prolonged the PR and QRS intervals of the ECG. Furthermore, in rats and NHP, RSD921 increased the threshold currents for induction of extra-systoles and ventricular fibrillation (VFt), and prolonged effective refractory period (ERP). In rats, RSD921 was protective against arrhythmias induced by electrical stimulation and coronary artery occlusion. Application of RSD921 to voltage-clamped rat cardiac myocytes blocked sodium currents. RSD921 also blocked transient (ito) and sustained (IKsus) outward potassium currents, albeit with reduced potency relative to sodium current blockade. Sodium channel blockade due to RSD921 in myocytes and isolated hearts was enhanced under ischaemic conditions (low pH and high extracellular potassium concentration). When tested on the cardiac, neuronal and skeletal muscle forms of sodium channels expressed in Xenopus laevis oocytes, RSD921 produced equipotent tonic block of sodium currents, enhanced channel block at reduced pH (6.4) and marked use-dependent block of the cardiac isoform. RSD921 had limited but quantifiable effects in subacute toxicology studies in rats and dogs. Pharmacokinetic analyses were performed in baboons. Plasma concentrations producing cardiac actions in vivo after intravenous administration of RSD921 were similar to the concentrations effective in the in vitro assays utilized. CONCLUSIONS:RSD921 primarily blocks sodium currents, and possesses antiarrhythmic and local anaesthetic activity.
Keywords: RSD921; sodium and potassium blocker; antiarrhythmic; toxicology; electrophysiology; pharmacokinetics; myocyte; Langendorff; neuromuscular; local anesthetic
Rights: © 2018 Elsevier Masson SAS. All rights reserved.
RMID: 0030095391
DOI: 10.1016/j.biopha.2018.06.157
Appears in Collections:Pharmacology publications

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