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.
???displayArticle.abstract???
1. RP58866 possesses a unique electrophysiological property: highly effective against various types of arrhythmias including ventricular fibrillation in animal models, noticeably those occurring during ischaemia with depolarized membrane due to elevated extracellular K+ concentrations. To understand the potential ionic mechanisms, we performed detailed studies on the effects of RP58866 on the HERG channels expressed in Xenopus oocytes, which are believed to be important compositions of the rapid component of delayed rectifier K+ current in the hearts. 2. RP58866 significantly inhibited the HERG channels in a concentration-dependent manner, with approximately 50% decrease in the current amplitude at a concentration of 1 microM. RP58866 produced more pronounced inhibition with voltage protocols which favoured inactivation of the HERG channels. It caused substantial negative shift of the inactivation curves but did not alter the activation properties. The inhibition was considerably relieved by elevating [K+]o from 5 - 20 mM, which weakened the channel inactivation. More importantly, the potency was reduced by approximately 100 fold on the mutated HERG channels (S631A) in which the C-type inactivation was substantially weakened. 4. We conclude that blockade of the HERG channels by RP58866 is mainly associated with the binding of the drugs to the inactivated channels. This unique property of HERG blockade might explain some previously reported but unexplained observations: RP58866 maintains its efficacy in APD prolongation with depolarized membrane potential and in arrhythmias during ischaemia with manifested membrane depolarization.
Andersen,
Dofetilide reduces the incidence of ventricular fibrillation during acute myocardial ischaemia. A randomised study in pigs.
1994, Pubmed
Andersen,
Dofetilide reduces the incidence of ventricular fibrillation during acute myocardial ischaemia. A randomised study in pigs.
1994,
Pubmed
Black,
The antifibrillatory actions of UK-68,798, a class III antiarrhythmic agent.
1991,
Pubmed
De Biasi,
Open channel block of human heart hKv1.5 by the beta-subunit hKv beta 1.2.
1997,
Pubmed
,
Xenbase
Escande,
RP 58866 and its active enantiomer RP 62719 (terikalant): blockers of the inward rectifier K+ current acting as pure class III antiarrhythmic agents.
1992,
Pubmed
Ficker,
Molecular determinants of dofetilide block of HERG K+ channels.
1998,
Pubmed
,
Xenbase
Herzberg,
Transfer of rapid inactivation and sensitivity to the class III antiarrhythmic drug E-4031 from HERG to M-eag channels.
1998,
Pubmed
Jurkiewicz,
Mechanism of action potential prolongation by RP 58866 and its active enantiomer, terikalant. Block of the rapidly activating delayed rectifier K+ current, IKr.
1996,
Pubmed
,
Xenbase
Mortensen,
Class III antiarrhythmic action and inotropy: effects of dofetilide in acute ischemic heart failure in dogs.
1992,
Pubmed
Rees,
Specific IK1 blockade: a new antiarrhythmic mechanism? Effect of RP58866 on ventricular arrhythmias in rat, rabbit, and primate.
1993,
Pubmed
Rees,
Which cardiac potassium channel subtype is the preferable target for suppression of ventricular arrhythmias?
1996,
Pubmed
Sanguinetti,
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
1995,
Pubmed
,
Xenbase
Schönherr,
Molecular determinants for activation and inactivation of HERG, a human inward rectifier potassium channel.
1996,
Pubmed
,
Xenbase
Smith,
The inward rectification mechanism of the HERG cardiac potassium channel.
1996,
Pubmed
Spector,
Fast inactivation causes rectification of the IKr channel.
1996,
Pubmed
,
Xenbase
Suessbrich,
The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase
Wang,
Time, voltage and ionic concentration dependence of rectification of h-erg expressed in Xenopus oocytes.
1996,
Pubmed
,
Xenbase
Wang,
Effects of flecainide, quinidine, and 4-aminopyridine on transient outward and ultrarapid delayed rectifier currents in human atrial myocytes.
1995,
Pubmed
Wang,
Differential distribution of inward rectifier potassium channel transcripts in human atrium versus ventricle.
1998,
Pubmed
Wang,
A quantitative analysis of the activation and inactivation kinetics of HERG expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase
Wang,
Comparison of binding and block produced by alternatively spliced Kvbeta1 subunits.
1996,
Pubmed
Zou,
A mutation in the pore region of HERG K+ channels expressed in Xenopus oocytes reduces rectification by shifting the voltage dependence of inactivation.
1998,
Pubmed
,
Xenbase
