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Use-dependent Block (use-dependent + block)

Distribution by Scientific Domains

Medical Sciences	75%

Selected Abstracts

A Common SCN5A Variant Alters the Responsiveness of Human Sodium Channels to Class I Antiarrhythmic Agents

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 4 2007
MOSSAAB SHURAIH M.D.
Background: The potential pathophysiological role of common SCN5A polymorphisms in cardiac arrhythmias has been increasingly recognized. However, little is known about the impact of those polymorphisms on the pharmocological response of hNav1.5 to various antiarrhythmic agents. Methods and Results: The known SCN5A polymorphism, S524Y, was studied in comparison with the wild type (WT) define the SCN5A-Q1077del variant. The ion channel gating kinetics and pharmacology were evaluated using whole-cell patch-clamp methods in HEK-293 cells. Consistent with a previous report, the basal ion channel gating kinetics of S524Y were indistinguishable from the WT. Quinidine (20 ,M) caused similar extent of tonic block reduction of sodium currents at ,120 mV in WT and S524Y. Surprisingly, quinidine (20 ,M) exerted a more use-dependent block by a 10 Hz pulse train in S524Y than in WT at 22°C (Ki: WT, 51.3 ,M; S524Y, 20.3 ,M). S524Y significantly delayed recovery from the use-dependent block, compared with the WT (,= 88.6 ± 7.9 s vs 41.9 ± 6.6 s, P < 0.005). Under more physiological conditions using a 2 Hz pulse train at 37°C, S524Y similarly enhanced the use-dependent block by quinidine. In addition, S524Y enhanced the use-dependent block by flecainide (12.5 ,M), but not by mexiletine (100 ,M). Conclusion: A common SCN5A polymorphism, S524Y, can enhance a use-dependent block by class Ia and Ic antiarrhythmic agents. Our findings may have clinical implications in pharmacological management of cardiac arrhythmias since this common SCN5A polymorphism might be a contributing factor to the variable antiarrhythmic response. [source]

Increased rigidity of the chiral centre of tocainide favours stereoselectivity and use-dependent block of skeletal muscle Na+ channels enhancing the antimyotonic activity in vivo

BRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2001
Sophie Talon
Searching for the structural requirements improving the potency and the stereoselectivity of Na+ channel blockers as antimyotonic agents, new derivatives of tocainide, in which the chiral carbon atom is constrained in a rigid ,-proline or pyrrolo-imidazolic cycle, were synthesized as pure enantiomers. Their ability to block Na+ currents, elicited from ,100 to ,20 mV at 0.3 Hz (tonic block) and 2 , 10 Hz (use-dependent block) frequencies, was investigated in vitro on single fibres of frog semitendinosus muscle using the vaseline-gap voltage-clamp method. The ,-proline derivative, To5, was 5 and 21 fold more potent than tocainide in producing tonic and 10 Hz-use-dependent block, respectively. Compared to To5, the presence of one methyl group on the aminic (To6) or amidic (To7) nitrogen atom decreased use-dependence by 2- and 6-times, respectively. When methylene moieties were present on both nitrogen atoms (To8), both tonic and use-dependent block were reduced. Contrarily to tocainide, all proline derivatives were stereoselective in relation to an increased rigidity. A further increase in the molecular rigidity as in pyrrolo-imidazolic derivatives markedly decreased the drug potency with respect to tocainide. Antimyotonic activity, evaluated as the shortening of the time of righting reflexes of myotonic adr/adr mice upon acute drug in vivo administration was 3 fold more effective for R-To5 than for R-Tocainide. Thus, constraining the chiral centre of tocainide in ,-proline cycle leads to more potent and stereoselective use-dependent Na+ channel blockers with improved therapeutic potential. British Journal of Pharmacology (2001) 134, 1523,1531; doi:10.1038/sj.bjp.0704366 [source]

Stereospecific synthesis of "para -hydroxymexiletine" and sodium channel blocking activity evaluation

CHIRALITY, Issue 2 2004
Alessia Catalano
Abstract Both enantiomers of "para -hydroxymexiletine" (PHM), one of the main metabolites of mexiletine, were synthesized and fully characterized. Properties of (R)- and (S)-PHM, in terms of blocking potency and stereoselectivity on frog skeletal muscle Na+ channels, were evaluated. The presence of a hydroxy group on the aryloxy moiety in the 4-position, as in PHM, reduced potency with respect to mexiletine in reducing INa max. However, PHM showed clear use-dependent behavior similar to that of mexiletine and, in contrast with what is observed with the parent compound, maintained its stereoselectivity during the use-dependent block. Chirality 16:72,78, 2004. © 2004 Wiley-Liss, Inc. [source]