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Acidification alters antiarrhythmic drug blockade of the ether-a-go-go-related Gene (HERG) Channels.
Basic Clin Pharmacol Toxicol. 2004 May; 94(5):209-12.BC

Abstract

Acidosis is one of the important deleterious factors during myocardial ischaemia and reperfusion. The ether-a-go-go-related gene, HERG, is a primary target for blockade by many drugs including dofetilide, quinidine and azimilide. While most drugs lose their efficacy against arrhythmias associated with myocardial ischaemia and reperfusion, dofetilide remains effective. The unique ability of dofetilide to terminate ischaemia-induced arrhythmias is not yet fully explained. The aim of the present study is to elucidate the acidification modulation of antiarrhythmic drugs blockade of HERG channels. The human gene HERG encoding K+ channels were expressed in Xenopus oocytes, and Whole-cell macroscopic currents of Xenopus oocytes were recorded with conventional two-electrode techniques. The inhibitory effects of dofetilide (0.25 microM) were significantly enhanced with decreasing pH (from 7.5 to 6.5). The percent block of dofetilide under pH 6.5 at 0 mV was 69+/-6.1% versus 54+/-3.0% under pH 7.5 (n=7, P<0.05). The IC50 values, determined by the Hill equation with the currents recorded at 0 mV, were decreased by approximately half from 192+/-23 nM with pH 7.5 to 93+/-15 nM with pH 6.5 (P<0.01). Acidification weakened the inhibitory effects of quinidine and azimilide on HERG channels. At 0 mV, the percent block of quinidine (10 microM) under pH 6.5 was 24+/-2.8% versus 62.5+/-9.0% under pH 7.5 (n=4, P<0.01), The percent block of azimilide (10 microM) under pH 6.5 was similar to that under pH 7.5 (n=6). Acidification markedly potentiated dofetilide blockade of the HERG channels but weakened the inhibitory effects of quinidine and azimilide.

Authors+Show Affiliations

Department of Pharmacology, Harbin Medical University, Heilongjiang Key Laboratory of Bio-pharmaceutical-engineering, Harbin, 150086, P. R. China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

15125690

Citation

Dong, De-Li, et al. "Acidification Alters Antiarrhythmic Drug Blockade of the Ether-a-go-go-related Gene (HERG) Channels." Basic & Clinical Pharmacology & Toxicology, vol. 94, no. 5, 2004, pp. 209-12.
Dong DL, Li Z, Wang HZ, et al. Acidification alters antiarrhythmic drug blockade of the ether-a-go-go-related Gene (HERG) Channels. Basic Clin Pharmacol Toxicol. 2004;94(5):209-12.
Dong, D. L., Li, Z., Wang, H. Z., Du, Z. M., Song, W. H., & Yang, B. F. (2004). Acidification alters antiarrhythmic drug blockade of the ether-a-go-go-related Gene (HERG) Channels. Basic & Clinical Pharmacology & Toxicology, 94(5), 209-12.
Dong DL, et al. Acidification Alters Antiarrhythmic Drug Blockade of the Ether-a-go-go-related Gene (HERG) Channels. Basic Clin Pharmacol Toxicol. 2004;94(5):209-12. PubMed PMID: 15125690.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Acidification alters antiarrhythmic drug blockade of the ether-a-go-go-related Gene (HERG) Channels. AU - Dong,De-Li, AU - Li,Zhe, AU - Wang,Hui-Zhen, AU - Du,Zhi-Min, AU - Song,Wei-Hua, AU - Yang,Bao-Feng, PY - 2004/5/6/pubmed PY - 2004/9/10/medline PY - 2004/5/6/entrez SP - 209 EP - 12 JF - Basic & clinical pharmacology & toxicology JO - Basic Clin. Pharmacol. Toxicol. VL - 94 IS - 5 N2 - Acidosis is one of the important deleterious factors during myocardial ischaemia and reperfusion. The ether-a-go-go-related gene, HERG, is a primary target for blockade by many drugs including dofetilide, quinidine and azimilide. While most drugs lose their efficacy against arrhythmias associated with myocardial ischaemia and reperfusion, dofetilide remains effective. The unique ability of dofetilide to terminate ischaemia-induced arrhythmias is not yet fully explained. The aim of the present study is to elucidate the acidification modulation of antiarrhythmic drugs blockade of HERG channels. The human gene HERG encoding K+ channels were expressed in Xenopus oocytes, and Whole-cell macroscopic currents of Xenopus oocytes were recorded with conventional two-electrode techniques. The inhibitory effects of dofetilide (0.25 microM) were significantly enhanced with decreasing pH (from 7.5 to 6.5). The percent block of dofetilide under pH 6.5 at 0 mV was 69+/-6.1% versus 54+/-3.0% under pH 7.5 (n=7, P<0.05). The IC50 values, determined by the Hill equation with the currents recorded at 0 mV, were decreased by approximately half from 192+/-23 nM with pH 7.5 to 93+/-15 nM with pH 6.5 (P<0.01). Acidification weakened the inhibitory effects of quinidine and azimilide on HERG channels. At 0 mV, the percent block of quinidine (10 microM) under pH 6.5 was 24+/-2.8% versus 62.5+/-9.0% under pH 7.5 (n=4, P<0.01), The percent block of azimilide (10 microM) under pH 6.5 was similar to that under pH 7.5 (n=6). Acidification markedly potentiated dofetilide blockade of the HERG channels but weakened the inhibitory effects of quinidine and azimilide. SN - 1742-7835 UR - https://www.unboundmedicine.com/medline/citation/15125690/Acidification_alters_antiarrhythmic_drug_blockade_of_the_ether_a_go_go_related_Gene__HERG__Channels_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&amp;sid=nlm:pubmed&amp;issn=1742-7835&amp;date=2004&amp;volume=94&amp;issue=5&amp;spage=209 DB - PRIME DP - Unbound Medicine ER -