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Blockade of HERG channels by the class III antiarrhythmic azimilide: mode of action.
Br J Pharmacol. 1998 Jan; 123(1):23-30.BJ

Abstract

1. The class III antiarrhythmic azimilide has previously been shown to inhibit I(Ks) and I(Kr) in guinea-pig cardiac myocytes and I(Ks) (minK) channels expressed in Xenopus oocytes. Because HERG channels underly the conductance I(Kr), in human heart, the effects of azimilide on HERG channels expressed in Xenopus oocytes were the focus of the present study. 2. In contrast to other well characterized HERG channel blockers, azimilide blockade was reverse use-dependent, i.e., the relative block and apparent affinity of azimilide decreased with an increase in channel activation frequency. Azimilide blocked HERG channels at 0.1 and 1 Hz with IC50s of 1.4 microM and 5.2 microM respectively. 3. In an envelope of tail test, HERG channel blockade increased with increasing channel activation, indicating binding of azimilide to open channels. 4. Azimilide blockade of HERG channels expressed in Xenopus oocytes and I(Kr) in mouse AT-1 cells was decreased under conditions of high [K+]e, whereas block of slowly activating I(Ks) channels was not affected by changes in [K+]e. 5. In summary, azimilide is a blocker of cardiac delayed rectifier channels, I(Ks) and HERG. Because of the distinct effects of stimulation frequency and [K+]e on azimilide block of I(Kr) and I(Ks) channels, we conclude that the relative contribution of block of each of these cardiac delayed rectifier channels depends on heart frequency. [K+]e and regulatory status of the respective channels.

Authors+Show Affiliations

Institute of Physiology I, Eberhard-Karls University of Tübingen, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

9484850

Citation

Busch, A E., et al. "Blockade of HERG Channels By the Class III Antiarrhythmic Azimilide: Mode of Action." British Journal of Pharmacology, vol. 123, no. 1, 1998, pp. 23-30.
Busch AE, Eigenberger B, Jurkiewicz NK, et al. Blockade of HERG channels by the class III antiarrhythmic azimilide: mode of action. Br J Pharmacol. 1998;123(1):23-30.
Busch, A. E., Eigenberger, B., Jurkiewicz, N. K., Salata, J. J., Pica, A., Suessbrich, H., & Lang, F. (1998). Blockade of HERG channels by the class III antiarrhythmic azimilide: mode of action. British Journal of Pharmacology, 123(1), 23-30.
Busch AE, et al. Blockade of HERG Channels By the Class III Antiarrhythmic Azimilide: Mode of Action. Br J Pharmacol. 1998;123(1):23-30. PubMed PMID: 9484850.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Blockade of HERG channels by the class III antiarrhythmic azimilide: mode of action. AU - Busch,A E, AU - Eigenberger,B, AU - Jurkiewicz,N K, AU - Salata,J J, AU - Pica,A, AU - Suessbrich,H, AU - Lang,F, PY - 1998/3/4/pubmed PY - 1998/3/4/medline PY - 1998/3/4/entrez SP - 23 EP - 30 JF - British journal of pharmacology JO - Br J Pharmacol VL - 123 IS - 1 N2 - 1. The class III antiarrhythmic azimilide has previously been shown to inhibit I(Ks) and I(Kr) in guinea-pig cardiac myocytes and I(Ks) (minK) channels expressed in Xenopus oocytes. Because HERG channels underly the conductance I(Kr), in human heart, the effects of azimilide on HERG channels expressed in Xenopus oocytes were the focus of the present study. 2. In contrast to other well characterized HERG channel blockers, azimilide blockade was reverse use-dependent, i.e., the relative block and apparent affinity of azimilide decreased with an increase in channel activation frequency. Azimilide blocked HERG channels at 0.1 and 1 Hz with IC50s of 1.4 microM and 5.2 microM respectively. 3. In an envelope of tail test, HERG channel blockade increased with increasing channel activation, indicating binding of azimilide to open channels. 4. Azimilide blockade of HERG channels expressed in Xenopus oocytes and I(Kr) in mouse AT-1 cells was decreased under conditions of high [K+]e, whereas block of slowly activating I(Ks) channels was not affected by changes in [K+]e. 5. In summary, azimilide is a blocker of cardiac delayed rectifier channels, I(Ks) and HERG. Because of the distinct effects of stimulation frequency and [K+]e on azimilide block of I(Kr) and I(Ks) channels, we conclude that the relative contribution of block of each of these cardiac delayed rectifier channels depends on heart frequency. [K+]e and regulatory status of the respective channels. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/9484850/Blockade_of_HERG_channels_by_the_class_III_antiarrhythmic_azimilide:_mode_of_action_ L2 - https://doi.org/10.1038/sj.bjp.0701575 DB - PRIME DP - Unbound Medicine ER -