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The influence of extracellular acidosis on the effect of IKr blockers.
J Cardiovasc Pharmacol Ther. 2005 Mar; 10(1):67-76.JC

Abstract

BACKGROUND

Myocardial infarction causes the acidification of the cellular environment and the resultant acidosis maybe arrhythmogenic. The effect of acidosis on the action of antiarrhythmic drugs, an important issue in the antiarrhythmic drug therapy after myocardial infarction, remains to be studied.

METHODS

To evaluate the effect of acidosis on rectifier potassium current (Ikr) blockers, the human ether-a-go-go-related gene (HERG), which encodes IKr, was expressed in Xenopus laevis oocytes. The two electrodes voltage clamp technique was used and the experiments were performed at room temperature.

RESULTS

Quinidine (10 microM) inhibited HERG tail current by 37% +/- 5% at pH7.4. The block decreased to 5% +/- 2% with extracellular pH at 6.2. Dofetilide (0.3 microM) inhibited HERG tail current by 34% +/- 3% and 1% +/- 2% at extracellular pH 7.4 and 6.2, respectively. Azimilide (10 microM) inhibited HERG tail current by 59% +/- 3% and 17% +/- 3% at extracellular pH 7.4 and 6.2. There were significant differences in the HERG inhibition by quinidine, dofetilide, and azimilide between pH 7.4 and pH 6.2 (P < .01). The drug concentration blocking 50% of current (IC50) was 5.8 +/- 0.3 microM for azimilide, 9.9 +/- 1.0 microM for quinidine, and 0.5 +/- 0.02 microM for dofetilide at pH 7.4. When extracellular pH was decreased from 7.4 to 6.2, the IC50 increased to 95.5 +/- 11.3 microM for azimilide, 203.2 +/- 15.7 microM for quinidine, and 12.6 +/- 1.2 microM for dofetilide. Unlike quinidine, dofetilide, and azimilide, there was no significant difference in the percentage of current block by amiodarone between pH 6.2 and 7.4. For amiodarone, the IC50 was 38.3 +/- 8.5 microM at pH 7.4 and 27.3 +/- 1.6 microM at pH 6.2.

CONCLUSION

Our data show that the Ikr blocking effect of azimilide, dofetilide, and quinidine was attenuated at acid pH, whereas this was not the case for amiodarone. These observations may explain the efficacy of amiodarone in reducing arrhythmic death in patients after a myocardial infarction compared with other IKr blockers.

Authors+Show Affiliations

Department of Pharmacology, Rush University Medical Center, Chicago, IL 60612, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15821840

Citation

Lin, Congrong, et al. "The Influence of Extracellular Acidosis On the Effect of IKr Blockers." Journal of Cardiovascular Pharmacology and Therapeutics, vol. 10, no. 1, 2005, pp. 67-76.
Lin C, Ke X, Cvetanovic I, et al. The influence of extracellular acidosis on the effect of IKr blockers. J Cardiovasc Pharmacol Ther. 2005;10(1):67-76.
Lin, C., Ke, X., Cvetanovic, I., Ranade, V., & Somberg, J. (2005). The influence of extracellular acidosis on the effect of IKr blockers. Journal of Cardiovascular Pharmacology and Therapeutics, 10(1), 67-76.
Lin C, et al. The Influence of Extracellular Acidosis On the Effect of IKr Blockers. J Cardiovasc Pharmacol Ther. 2005;10(1):67-76. PubMed PMID: 15821840.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The influence of extracellular acidosis on the effect of IKr blockers. AU - Lin,Congrong, AU - Ke,Xiaogang, AU - Cvetanovic,Ivana, AU - Ranade,Vasant, AU - Somberg,John, PY - 2005/4/12/pubmed PY - 2005/7/1/medline PY - 2005/4/12/entrez SP - 67 EP - 76 JF - Journal of cardiovascular pharmacology and therapeutics JO - J Cardiovasc Pharmacol Ther VL - 10 IS - 1 N2 - BACKGROUND: Myocardial infarction causes the acidification of the cellular environment and the resultant acidosis maybe arrhythmogenic. The effect of acidosis on the action of antiarrhythmic drugs, an important issue in the antiarrhythmic drug therapy after myocardial infarction, remains to be studied. METHODS: To evaluate the effect of acidosis on rectifier potassium current (Ikr) blockers, the human ether-a-go-go-related gene (HERG), which encodes IKr, was expressed in Xenopus laevis oocytes. The two electrodes voltage clamp technique was used and the experiments were performed at room temperature. RESULTS: Quinidine (10 microM) inhibited HERG tail current by 37% +/- 5% at pH7.4. The block decreased to 5% +/- 2% with extracellular pH at 6.2. Dofetilide (0.3 microM) inhibited HERG tail current by 34% +/- 3% and 1% +/- 2% at extracellular pH 7.4 and 6.2, respectively. Azimilide (10 microM) inhibited HERG tail current by 59% +/- 3% and 17% +/- 3% at extracellular pH 7.4 and 6.2. There were significant differences in the HERG inhibition by quinidine, dofetilide, and azimilide between pH 7.4 and pH 6.2 (P < .01). The drug concentration blocking 50% of current (IC50) was 5.8 +/- 0.3 microM for azimilide, 9.9 +/- 1.0 microM for quinidine, and 0.5 +/- 0.02 microM for dofetilide at pH 7.4. When extracellular pH was decreased from 7.4 to 6.2, the IC50 increased to 95.5 +/- 11.3 microM for azimilide, 203.2 +/- 15.7 microM for quinidine, and 12.6 +/- 1.2 microM for dofetilide. Unlike quinidine, dofetilide, and azimilide, there was no significant difference in the percentage of current block by amiodarone between pH 6.2 and 7.4. For amiodarone, the IC50 was 38.3 +/- 8.5 microM at pH 7.4 and 27.3 +/- 1.6 microM at pH 6.2. CONCLUSION: Our data show that the Ikr blocking effect of azimilide, dofetilide, and quinidine was attenuated at acid pH, whereas this was not the case for amiodarone. These observations may explain the efficacy of amiodarone in reducing arrhythmic death in patients after a myocardial infarction compared with other IKr blockers. SN - 1074-2484 UR - https://www.unboundmedicine.com/medline/citation/15821840/The_influence_of_extracellular_acidosis_on_the_effect_of_IKr_blockers_ L2 - https://journals.sagepub.com/doi/10.1177/107424840501000108?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -