![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 57, Issue 1, 101-107, January 2000
KPQ
Mutant by the Class IC Antiarrhythmic Flecainide
Department of Medicine, Section of Cardiology, University of
Wisconsin, Madison, Wisconsin
Flecainide block of Na+ current (INa) was
investigated in wild-type (WT) or the long QT syndrome 3 (LQT3) sodium
channel 
subunit mutation with three amino acids deleted (
KPQ)
stably transfected into human embryonic kidney 293 cells using
whole-cell, patch-clamp recordings. Flecainide (1-300 mM) caused tonic
and use-dependent block (UDB) of INa in a
concentration-dependent manner. Compared with WT, KPQ
INa was more sensitive to flecainide, and flecainide
preferentially inhibited late INa (mean current between 20 and 23.5 ms after depolarization) compared with peak INa.
The IC50 value of peak and late INa for WT was
127 ± 6 and 44 ± 2 µM (n = 20) and
for KPQ was 80 ± 9 and 19 ± 2 µM
(n = 31) respectively. UDB of peak INa
was greater and developed more slowly during pulse trains for KPQ
than for WT. The IC50 value for UDB of peak INa
for WT was 29 ± 4 µM (n = 20) and for
KPQ was 11 ± 1 µM (n = 26). For KPQ,
UDB of late INa was greater than for peak INa.
Recovery from block was slower for KPQ than for WT. We conclude that
KPQ interacts differently with flecainide than with WT, leading to
increased block and slowed recovery, especially for late
INa. These data provide insights into mechanisms for
flecainide block and provide a rationale at the cellular and molecular
level that open channel block may be a useful pharmacological property
for treatment of LQT3.
This article has been cited by other articles:
|
|
 |
|
  K. S. Stokoe, G. Thomas, C. A. Goddard, W. H. Colledge, A. A. Grace, and C. L.-H. Huang Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a+/{Delta} murine hearts modelling long QT syndrome 3 J. Physiol., January 1, 2007; 578(1): 69 - 84. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Fredj, N. Lindegger, K. J. Sampson, P. Carmeliet, and R. S. Kass Altered Na+ Channels Promote Pause-Induced Spontaneous Diastolic Activity in Long QT Syndrome Type 3 Myocytes Circ. Res., November 24, 2006; 99(11): 1225 - 1232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M.R. Orth, J. C. Hesketh, C. K.H. Mak, Y. Yang, S. Lin, G. N. Beatch, A. M. Ezrin, and D. Fedida RSD1235 blocks late INa and suppresses early afterdepolarizations and torsades de pointes induced by class III agents Cardiovasc Res, June 1, 2006; 70(3): 486 - 496. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-F. Xiao, L. Ma, S.-Y. Wang, M. E. Josephson, G. K. Wang, J. P. Morgan, and A. Leaf Potent block of inactivation-deficient Na+ channels by n-3 polyunsaturated fatty acids Am J Physiol Cell Physiol, February 1, 2006; 290(2): C362 - C370. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Clancy and R. S. Kass Inherited and Acquired Vulnerability to Ventricular Arrhythmias: Cardiac Na+ and K+ Channels Physiol Rev, January 1, 2005; 85(1): 33 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Bechtold, X. Yue, R. M. Evans, M. Davies, N. A. Gregson, and K. J. Smith Axonal protection in experimental autoimmune neuritis by the sodium channel blocking agent flecainide Brain, January 1, 2005; 128(1): 18 - 28. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-Y. Wang, J. Mitchell, E. Moczydlowski, and G. K. Wang Block of Inactivation-deficient Na+ Channels by Local Anesthetics in Stably Transfected Mammalian Cells: Evidence for Drug Binding Along the Activation Pathway J. Gen. Physiol., November 29, 2004; 124(6): 691 - 701. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Ramos and M. E O'Leary State-dependent trapping of flecainide in the cardiac sodium channel J. Physiol., October 1, 2004; 560(1): 37 - 49. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-F. Desaphy, A. D. E. Luca, M. P. Didonna, A. L. George Jr, and D. C. Camerino Different flecainide sensitivity of hNav1.4 channels and myotonic mutants explained by state-dependent block J. Physiol., January 15, 2004; 554(2): 321 - 334. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. K. Wang, C. Russell, and S.-Y. Wang State-dependent Block of Wild-type and Inactivation-deficient Na+ Channels by Flecainide J. Gen. Physiol., August 25, 2003; 122(3): 365 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. W. Veldkamp, R. Wilders, A. Baartscheer, J. G. Zegers, C. R. Bezzina, and A. A.M. Wilde Contribution of Sodium Channel Mutations to Bradycardia and Sinus Node Dysfunction in LQT3 Families Circ. Res., May 16, 2003; 92(9): 976 - 983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. L Tan, C. R Bezzina, J. P.P Smits, A. O Verkerk, and A. A.M Wilde Genetic control of sodium channel function Cardiovasc Res, March 15, 2003; 57(4): 961 - 973. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Liu, M. Tateyama, C. E. Clancy, H. Abriel, and R. S. Kass Channel Openings Are Necessary but not Sufficient for Use-dependent Block of Cardiac Na+ Channels by Flecainide: Evidence from the Analysis of Disease-linked Mutations J. Gen. Physiol., June 24, 2002; 120(1): 39 - 51. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. C. Viswanathan, C. R. Bezzina, A. L. George Jr., D. M. Roden, A. A.M. Wilde, and J. R. Balser Gating-Dependent Mechanisms for Flecainide Action in SCN5A-Linked Arrhythmia Syndromes Circulation, September 4, 2001; 104(10): 1200 - 1205. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Abriel, X. H. T. Wehrens, J. Benhorin, B. Kerem, and R. S. Kass Molecular Pharmacology of the Sodium Channel Mutation D1790G Linked to the Long-QT Syndrome Circulation, August 22, 2000; 102(8): 921 - 925. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
