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Comparative effects of azimilide and ambasilide on the human ether-a-go-go-related gene (HERG) potassium channel.
Cardiovasc Res. 2000 Oct; 48(1):44-58.CR

Abstract

OBJECTIVE

To evaluate the effects of azimilide and ambasilide on the biophysical properties of the human-ether-a-go-go-related (HERG) channel.

METHODS

HERG was stably transfected into Chinese hamster ovary (CHO-K1) cells and currents were measured using a whole cell, voltage-clamp technique.

RESULTS

Azimilide had a 'dual effect', inhibiting current at voltage steps above -40 mV and augmenting current at -40 and -50 mV. Tail current inhibition following a step to +30 mV did not vary with temperature (IC(50) 610 nM at 22 degrees C and 560 nM at 37 degrees C). The agonist effect at -50 mV was concentration-dependent and correlated with a hyperpolarizing shift in the V(1/2) of activation (r=0.98, P<0.05). Time constants of inactivation were faster and there was a -10 mV shift in the V(1/2) of steady state inactivation suggestive of open and inactivated state binding. By comparison, ambasilide inhibited HERG channels with lower potency (IC(50) 3.6 microM), in a voltage- and time-dependent but frequency-independent manner (0.03-1 Hz). Ambasilide had no effect on activation or inactivation gating but prolonged both fast and slow components of deactivation consistent with unbinding from the open state. The net effect of both drugs was similar during a voltage ramp which simulated a cardiac action potential.

CONCLUSIONS

Inhibition of HERG channels by azimilide and ambasilide exhibits a similar time and voltage-dependence. While both exhibit affinity for the open state, azimilide also binds to inactivated channels.

Authors+Show Affiliations

Department of Medicine, University of New South Wales and Victor Chang Cardiac Research Institute, St Vincent's Hospital, Sydney, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

11033107

Citation

Walker, B D., et al. "Comparative Effects of Azimilide and Ambasilide On the Human Ether-a-go-go-related Gene (HERG) Potassium Channel." Cardiovascular Research, vol. 48, no. 1, 2000, pp. 44-58.
Walker BD, Singleton CB, Tie H, et al. Comparative effects of azimilide and ambasilide on the human ether-a-go-go-related gene (HERG) potassium channel. Cardiovasc Res. 2000;48(1):44-58.
Walker, B. D., Singleton, C. B., Tie, H., Bursill, J. A., Wyse, K. R., Valenzuela, S. M., Breit, S. N., & Campbell, T. J. (2000). Comparative effects of azimilide and ambasilide on the human ether-a-go-go-related gene (HERG) potassium channel. Cardiovascular Research, 48(1), 44-58.
Walker BD, et al. Comparative Effects of Azimilide and Ambasilide On the Human Ether-a-go-go-related Gene (HERG) Potassium Channel. Cardiovasc Res. 2000;48(1):44-58. PubMed PMID: 11033107.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparative effects of azimilide and ambasilide on the human ether-a-go-go-related gene (HERG) potassium channel. AU - Walker,B D, AU - Singleton,C B, AU - Tie,H, AU - Bursill,J A, AU - Wyse,K R, AU - Valenzuela,S M, AU - Breit,S N, AU - Campbell,T J, PY - 2000/10/18/pubmed PY - 2001/2/28/medline PY - 2000/10/18/entrez SP - 44 EP - 58 JF - Cardiovascular research JO - Cardiovasc Res VL - 48 IS - 1 N2 - OBJECTIVE: To evaluate the effects of azimilide and ambasilide on the biophysical properties of the human-ether-a-go-go-related (HERG) channel. METHODS: HERG was stably transfected into Chinese hamster ovary (CHO-K1) cells and currents were measured using a whole cell, voltage-clamp technique. RESULTS: Azimilide had a 'dual effect', inhibiting current at voltage steps above -40 mV and augmenting current at -40 and -50 mV. Tail current inhibition following a step to +30 mV did not vary with temperature (IC(50) 610 nM at 22 degrees C and 560 nM at 37 degrees C). The agonist effect at -50 mV was concentration-dependent and correlated with a hyperpolarizing shift in the V(1/2) of activation (r=0.98, P<0.05). Time constants of inactivation were faster and there was a -10 mV shift in the V(1/2) of steady state inactivation suggestive of open and inactivated state binding. By comparison, ambasilide inhibited HERG channels with lower potency (IC(50) 3.6 microM), in a voltage- and time-dependent but frequency-independent manner (0.03-1 Hz). Ambasilide had no effect on activation or inactivation gating but prolonged both fast and slow components of deactivation consistent with unbinding from the open state. The net effect of both drugs was similar during a voltage ramp which simulated a cardiac action potential. CONCLUSIONS: Inhibition of HERG channels by azimilide and ambasilide exhibits a similar time and voltage-dependence. While both exhibit affinity for the open state, azimilide also binds to inactivated channels. SN - 0008-6363 UR - https://www.unboundmedicine.com/medline/citation/11033107/Comparative_effects_of_azimilide_and_ambasilide_on_the_human_ether_a_go_go_related_gene__HERG__potassium_channel_ DB - PRIME DP - Unbound Medicine ER -