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Hyperpolarizing Shift (hyperpolarizing + shift)
Selected AbstractsExtracellular Acidosis Modulates Drug Block of Kv4.3 Currents by Flecainide and QuinidineJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 6 2003Suresh Singarayar M.D. Introduction: As a molecular model of the effect of ischemia on drug block of the transient outward potassium current, the effect of acidosis on the blocking properties of flecainide and quinidine on Kv4.3 currents was studied. Methods and Results: Kv4.3 channels were stably expressed in Chinese hamster ovary cells. Whole-cell, voltage clamp techniques were used to measure the effect of flecainide and quinidine on Kv4.3 currents in solutions of pH 7.4 and 6.0. Extracellular acidosis attenuated flecainide block of Kv4.3 currents, with the IC50 for flecainide (based on current-time integrals) increasing from7.8 ± 1.1 ,Mat pH 7.4 to125.1 ± 1.1 ,Mat pH 6.0. Similar effects were observed for quinidine (IC50 5.2 ± 1.1 ,Mat pH 7.4 and22.1 ± 1.3 ,Mat pH 6.0). Following block by either drug, Kv4.3 channels showed a hyperpolarizing shift in the voltage sensitivity of inactivation and a slowing in the time to recover from inactivation/block that was unaffected by acidosis. In contrast, acidosis attenuated the effects on the time course of inactivation and the degree of tonic- and frequency-dependent block for both drugs. Conclusion: Extracellular acidosis significantly decreases the potency of blockade of Kv4.3 by both flecainide and quinidine. This change in potency may be due to allosteric changes in the channel, changes in the proportion of uncharged drug, and/or changes in the kinetics of drug binding or unbinding. These findings are in contrast to the effects of extracellular acidosis on block of the fast sodium channel by these agents and provide a molecular mechanism for divergent modulation of drug block potentially leading to ischemia-associated proarrhythmia.(J Cardiovasc Electrophysiol, Vol. 14, pp. 641-650, June 2003) [source] Sporadic onset of erythermalgia: A gain-of-function mutation in Nav1.7ANNALS OF NEUROLOGY, Issue 3 2006Chongyang Han BS Objective Inherited erythermalgia (erythromelalgia) is an autosomal dominant disorder in which patients experience severe burning pain in the extremities, in response to mild thermal stimuli and exercise. Although mutations in sodium channel Nav1.7 have been shown to underlie erythermalgia in several multigeneration families with the disease that have been investigated to date, the molecular basis of erythermalgia in sporadic cases is enigmatic. We investigated the role of Nav1.7 in a sporadic case of erythermalgia in a Chinese family. Methods Genomic DNA from patients and their asymptomatic family members were sequenced to identify mutations in Nav1.7. Whole-cell patch clamp analysis was used to characterize biophysical properties of wild-type and mutant Nav1.7 channels in mammalian cells. Results A single amino acid substitution in the DIIS4-S5 linker of Nav1.7 was present in two children whose parents were asymptomatic. The asymptomatic father was genetically mosaic for the mutation. This mutation produces a hyperpolarizing shift in channel activation and an increase in amplitude of the response to slow, small depolarizations. Interpretation Founder mutations in Nav1.7, which can confer hyperexcitability on peripheral sensory neurons, can underlie sporadic erythermalgia. Ann Neurol 2006 [source] Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysisANNALS OF NEUROLOGY, Issue 3 2001Saïd Bendahhou PhD A novel mutation in a family with hypokalemic periodic paralysis is described. The mutation R672S is located in the voltage sensor segment S4 of domain II in the SCN4A gene encoding the human skeletal muscle voltage-gated sodium channel. Functional expression of the R672S channels in human embryonic kidney 293 cells revealed a small but significant hyperpolarizing shift in the steady-state fast inactivation, and a dramatic enhancement in channel slow inactivation. These two defects are mainly due to a slow recovery of the mutant channels from fast and/or slow inactivation. Our data may help explain the mechanism underlying hypokalemic periodic paralysis and the patient's worsening from acetazolamide. [source] BLOCK OF Na+ AND K+ CURRENTS IN RAT VENTRICULAR MYOCYTES BY QUINACAINOL AND QUINIDINECLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2005Michael K Pugsley SUMMARY 1.,The electrophysiological actions of quinacainol were investigated on sodium (INa), transient outward (ito) and sustained-outward plateau (iKsus) potassium currents in rat isolated cardiac myocytes using the whole-cell patch-clamp technique and compared with quinidine. 2.,Quinacainol blocked sodium currents in a concentration-dependent manner and with a potency similar to that of quinidine (mean (±SEM) EC50 50 ± 12 vs 95 ± 25 µmol/L for quinidine and quinacainol, respectively). However, quinacainol had a considerably prolonged onset and recovery from block compared with quinidine. 3.,Neither quinacainol nor quinidine significantly changed the steady state voltage dependence of activation of sodium currents. Quinidine produced a hyperpolarizing shift in the voltage dependence for sodium current inactivation, but no such shift was observed with quinacainol at doses that produced a substantial current block. 4.,Although quinacainol did not effectively block voltage-dependent potassium currents, even at concentrations as high as 1.5 mmol/L, quinidine, at a half-maximal sodium channel-blocking concentration, reduced peak ito current amplitude, increased the rate of inactivation of ito and blocked iKsus. 5.,These results indicate that quinacainol, a quinidine analogue, blocks sodium currents in cardiac myocytes with little effect on ito or iKsus potassium currents, which suggests that quinacainol may be exerting class 1c anti-arrhythmic actions. [source] | ||||||||||