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Cellular electrophysiological effects of changrolin in isolated rat cardiac myocytes.
Eur J Pharmacol. 2010 Nov 25; 647(1-3):139-46.EJ

Abstract

Changrolin (2, 6-bis[pyrrolidin-1-ylmethyl]-4-[quinazolin-4-ylamino] phenol) is an anti-arrhythmic drug derived from β-dichroine, an active component of the Chinese medicinal herb, Dichroa febrifuga Lour. To elucidate the mechanism underlying the anti-arrhythmic effect of changrolin, we used the whole-cell patch-clamp technique to characterize the electrophysiological actions of changrolin in isolated rat cardiomyocytes. In this study, changrolin inhibited delayed rectified K(+) currents (I(K)) in a concentration-dependent manner with inhibiting the current by 11.9%±4.7%, 27.8%±3.4%, 31.5%±3.6% and 40.8%±3.7% at 10, 30, 100 and 300 μM, respectively (n=7-8). Changrolin was less effective against transient outward K(+) currents (I(to)), and only showed significantly inhibitory effect at the highest concentration (300 μM). Changrolin also induced a concentration-dependent inhibition of sodium currents (I(Na)) with an IC(50) of 10.19 μM (Hill coefficient=-1.727, n=6-7). In addition, changrolin exerted a holding potential-dependent block on Na(+) channels, produced a hyperpolarizing shift in the steady-state inactivation curve, as well as exhibited a marked frequency-dependent component to the blockade of Na(+) channels. Finally, calcium currents (I(Ca)) was decreased by changrolin in a concentration-dependent manner with an estimated IC(50) of 74.73 μM (Hill coefficient=-0.9082, n=6). In conclusion, changrolin blocks Na(+) and Ca(2+) channels, and also blocks K(+) channels (I(to) and I(K)) to some extent. Notably, changrolin preferentially blocks the inactivated state of Na(+) channels. These effects lead to a modification of electromechanical function and likely contribute to the termination of arrhythmia.

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Authors+Show Affiliations

Chen WH
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Yang D
No affiliation info available
Wang WY
No affiliation info available
Zhang J
No affiliation info available
Wang YP
No affiliation info available

MeSH

Action PotentialsAnimalsAnti-Arrhythmia AgentsCalcium ChannelsDrugs, Chinese HerbalElectrophysiological PhenomenaHeart VentriclesMaleMyocytes, CardiacPatch-Clamp TechniquesPotassium ChannelsQuinazolinesRatsRats, Sprague-DawleySodium Channels

Pub Type(s)

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

Language

eng

PubMed ID

20826150

Citation

Chen, Wei-hai, et al. "Cellular Electrophysiological Effects of Changrolin in Isolated Rat Cardiac Myocytes." European Journal of Pharmacology, vol. 647, no. 1-3, 2010, pp. 139-46.
Chen WH, Yang D, Wang WY, et al. Cellular electrophysiological effects of changrolin in isolated rat cardiac myocytes. Eur J Pharmacol. 2010;647(1-3):139-46.
Chen, W. H., Yang, D., Wang, W. Y., Zhang, J., & Wang, Y. P. (2010). Cellular electrophysiological effects of changrolin in isolated rat cardiac myocytes. European Journal of Pharmacology, 647(1-3), 139-46. https://doi.org/10.1016/j.ejphar.2010.08.024
Chen WH, et al. Cellular Electrophysiological Effects of Changrolin in Isolated Rat Cardiac Myocytes. Eur J Pharmacol. 2010 Nov 25;647(1-3):139-46. PubMed PMID: 20826150.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cellular electrophysiological effects of changrolin in isolated rat cardiac myocytes. AU - Chen,Wei-hai, AU - Yang,Ding, AU - Wang,Wen-yi, AU - Zhang,Jie, AU - Wang,Yi-ping, Y1 - 2010/09/06/ PY - 2009/11/23/received PY - 2010/07/24/revised PY - 2010/08/25/accepted PY - 2010/9/10/entrez PY - 2010/9/10/pubmed PY - 2011/4/2/medline SP - 139 EP - 46 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 647 IS - 1-3 N2 - Changrolin (2, 6-bis[pyrrolidin-1-ylmethyl]-4-[quinazolin-4-ylamino] phenol) is an anti-arrhythmic drug derived from β-dichroine, an active component of the Chinese medicinal herb, Dichroa febrifuga Lour. To elucidate the mechanism underlying the anti-arrhythmic effect of changrolin, we used the whole-cell patch-clamp technique to characterize the electrophysiological actions of changrolin in isolated rat cardiomyocytes. In this study, changrolin inhibited delayed rectified K(+) currents (I(K)) in a concentration-dependent manner with inhibiting the current by 11.9%±4.7%, 27.8%±3.4%, 31.5%±3.6% and 40.8%±3.7% at 10, 30, 100 and 300 μM, respectively (n=7-8). Changrolin was less effective against transient outward K(+) currents (I(to)), and only showed significantly inhibitory effect at the highest concentration (300 μM). Changrolin also induced a concentration-dependent inhibition of sodium currents (I(Na)) with an IC(50) of 10.19 μM (Hill coefficient=-1.727, n=6-7). In addition, changrolin exerted a holding potential-dependent block on Na(+) channels, produced a hyperpolarizing shift in the steady-state inactivation curve, as well as exhibited a marked frequency-dependent component to the blockade of Na(+) channels. Finally, calcium currents (I(Ca)) was decreased by changrolin in a concentration-dependent manner with an estimated IC(50) of 74.73 μM (Hill coefficient=-0.9082, n=6). In conclusion, changrolin blocks Na(+) and Ca(2+) channels, and also blocks K(+) channels (I(to) and I(K)) to some extent. Notably, changrolin preferentially blocks the inactivated state of Na(+) channels. These effects lead to a modification of electromechanical function and likely contribute to the termination of arrhythmia. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/20826150/Cellular_electrophysiological_effects_of_changrolin_in_isolated_rat_cardiac_myocytes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(10)00828-9 DB - PRIME DP - Unbound Medicine ER -