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Dofetilide block involves interactions with open and inactivated states of HERG channels.
Pflugers Arch. 2002 Feb; 443(4):520-31.PA

Abstract

Rapidly activating delayed rectifier current (IKr) is the key target of class III antiarrhythmic drugs including dofetilide. Due to its complex gating properties, the precise channel state or states that interact with these agents remain poorly defined. We have undertaken a careful analysis of the state dependence of HERG channel block by dofetilide in Xenopus oocytes and Chinese Hamster Ovary (CHO) cells by devising a protocol in which brief sampling pulses were superimposed over a wide range of test potentials. The rate of block onset, maximal steady-state block and IC50 were similar for all test potentials over the activation range, demonstrating that the drug probably interacts with open and/or inactivated but not resting HERG channels with high affinity. Reducing the fraction of inactivated channels at 0 mV by augmenting the external potassium concentration did not alter the sensitivity to dofetilide. In contrast, the S631A and S620T HERG mutations both eliminated inward rectification and reduced dofetilide affinity by approximately 10- and approximately 100-fold respectively. We have also found a novel ultra-slow activation process which occurs in wild type HERG channels at threshold potentials. Overall, our data imply that dofetilide block occurs equally at all voltages positive to the activation threshold, and that the drug interacts with HERG channels in both the open and inactivated states.

Authors+Show Affiliations

Research Center, Montreal Heart Institute, Montréal, Canada,No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11907818

Citation

Weerapura, Manjula, et al. "Dofetilide Block Involves Interactions With Open and Inactivated States of HERG Channels." Pflugers Archiv : European Journal of Physiology, vol. 443, no. 4, 2002, pp. 520-31.
Weerapura M, Hébert TE, Nattel S. Dofetilide block involves interactions with open and inactivated states of HERG channels. Pflugers Arch. 2002;443(4):520-31.
Weerapura, M., Hébert, T. E., & Nattel, S. (2002). Dofetilide block involves interactions with open and inactivated states of HERG channels. Pflugers Archiv : European Journal of Physiology, 443(4), 520-31.
Weerapura M, Hébert TE, Nattel S. Dofetilide Block Involves Interactions With Open and Inactivated States of HERG Channels. Pflugers Arch. 2002;443(4):520-31. PubMed PMID: 11907818.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dofetilide block involves interactions with open and inactivated states of HERG channels. AU - Weerapura,Manjula, AU - Hébert,Terence E, AU - Nattel,Stanley, Y1 - 2001/10/11/ PY - 2001/06/26/received PY - 2001/08/21/revised PY - 2001/08/24/accepted PY - 2002/3/22/pubmed PY - 2002/8/24/medline PY - 2002/3/22/entrez SP - 520 EP - 31 JF - Pflugers Archiv : European journal of physiology JO - Pflugers Arch. VL - 443 IS - 4 N2 - Rapidly activating delayed rectifier current (IKr) is the key target of class III antiarrhythmic drugs including dofetilide. Due to its complex gating properties, the precise channel state or states that interact with these agents remain poorly defined. We have undertaken a careful analysis of the state dependence of HERG channel block by dofetilide in Xenopus oocytes and Chinese Hamster Ovary (CHO) cells by devising a protocol in which brief sampling pulses were superimposed over a wide range of test potentials. The rate of block onset, maximal steady-state block and IC50 were similar for all test potentials over the activation range, demonstrating that the drug probably interacts with open and/or inactivated but not resting HERG channels with high affinity. Reducing the fraction of inactivated channels at 0 mV by augmenting the external potassium concentration did not alter the sensitivity to dofetilide. In contrast, the S631A and S620T HERG mutations both eliminated inward rectification and reduced dofetilide affinity by approximately 10- and approximately 100-fold respectively. We have also found a novel ultra-slow activation process which occurs in wild type HERG channels at threshold potentials. Overall, our data imply that dofetilide block occurs equally at all voltages positive to the activation threshold, and that the drug interacts with HERG channels in both the open and inactivated states. SN - 0031-6768 UR - https://www.unboundmedicine.com/medline/citation/11907818/Dofetilide_block_involves_interactions_with_open_and_inactivated_states_of_HERG_channels_ L2 - https://dx.doi.org/10.1007/s004240100720 DB - PRIME DP - Unbound Medicine ER -