Effects Of Sodium Channel Blockade Research Articles

Mechanism of the effects of sodium channel blockade on the arrhythmogenic substrate of Brugada syndrome.

The mechanisms by which sodium channel blockade and high-rate pacing modify electrogram (EGM) substrates of Brugada syndrome (BrS) have not been elucidated. The purpose of this study was to determine the effect of ajmaline and high pacing rate on the BrS substrates. Thirty-two patients with BrS (mean age 40 ± 12 years) and frequent ventricular fibrillation episodes underwent right ventricular outflow tract substrate electroanatomical and electrocardiographic imaging (ECGI) mapping before and after ajmaline administration and during high-rate atrial pacing. In 4 patients, epicardial mapping was performed using open thoracotomy with targeted biopsies. Ajmaline increased the activation time delay in the substrate (33%; P = .002), ST-segment elevation in the right precordial leads (74%; P < .0001), and the area of delayed activation (170%; P < .0001), coinciding with the increased substrate size (75%; P < .0001). High atrial pacing rate increased the abnormal EGM duration at the right ventricular outflow tract areas from 112 ± 48 to 143 ± 66 ms (P = .003) and produced intermittent conduction block and/or excitation failure at the substrate sites, especially after ajmaline administration. Biopsies from the 4 patients with thoracotomy showed epicardial fibrosis where EGMs were normal at baseline but became fractionated after ajmaline administration. In some areas, local activation was absent and unipolar EGMs had a monophasic morphology resembling the shape of the action potential. Sodium current reduction with ajmaline severely compromises impulse conduction at the BrS fibrotic substrates by producing fractionated EGMs, conduction block, or excitation failure, leading to the Brugada ECG pattern and favoring ventricular fibrillation genesis.

Case Study of Fatal Stroke Following Intranasal Lidocaine.

A 39-year-old man presented with new onset right hemiparesis and aphasia within an hour of using approximately 120 mL lidocaine 4% topical solution intranasally. Lidocaine had been prescribed over a 3-week period for pain due to multiple debridements of the nasal septum. A total of 650 mL of 4% lidocaine (26 g) had been dispensed to the patient during this time. The patient had a significant history of drug abuse, including snorting crushed tablets. Otherwise he was a healthy man with no chronic diseases or conditions. On arrival, and from previous exams, EKGs were normal without conduction delays. Electrolytes and CBC results were within normal range. The MRI/MRA showed a new thrombus with left middle cerebral artery distribution affecting one-third of the brain mass, including brain stem. Lidocaine likely contributed to cardiovascular embolic development, possibly from a sudden drop in blood pressure and known cardiovascular effects of sodium channel blockade. The patient expired from acute respiratory failure secondary to brainstem damage. Solutions of topical lidocaine should not be prescribed for use on open wounds or abraded skin as drug absorption will be increased, especially in highly vascularized nasal passages.

Potassium channel activators differentially modulate the effect of sodium channel blockade on cardiac conduction

Diminished repolarization reserve contributes to the arrhythmogenic substrate in many disease states. Pharmacological activation of K(+) channels has been suggested as a potential antiarrhythmic therapy in such conditions. Having previously demonstrated that I(K1) and I(Kr) can modulate cardiac conduction, we tested here the effects of pharmacological I(KATP) and I(Ks) activation on cardiac conduction and its dependence on the sodium current (I(Na)). Bath electrocardiograms (ECGs) recorded from Langendorff-perfused guinea pig ventricles revealed QRS prolongation during I(KATP) activation by pinacidil but not during I(Ks) activation by R-L3 relative to control. In contrast, when I(Na) was partially blocked by flecainide, R-L3 but not pinacidil prolonged the QRS relative to flecainide alone. Conduction velocity (θ) was quantified by optical mapping during epicardial pacing. Both longitudinal (θ(L)) and transverse (θ(T)) θ were reduced by pinacidil (by 10 ± 1 and 9 ± 3%, respectively) and R-L3 (by 11 ± 2% and 15 ± 4%, respectively). Flecainide decreased θ(L) by 33 ± 4% and θ(T) by 36 ± 5%. Whereas pinacidil did not further slow θ relative to flecainide alone, R-L3 decreased both θ(L) and θ(T). Pharmacological activation of I(KATP) and I(Ks) slows cardiac conduction; however, they demonstrate diverse effects on θ dependence on I(Na) blockade. These findings may have significant implications for the use of K(+) channel activators as antiarrhythmic drugs and for patients with Na(+) channel abnormalities or being treated with Na(+) channel blockers.

New observations on the “early repolarization syndrome”

They described a highprevalence of this electrocardiographic (ECG) pattern (de-fined as J-point elevation [JPE]) in idiopathic VF, thusseeming to confirm previous hypotheses. From a clinicalpoint of view, this new evidence forced us to look for thispattern in subjects classified until then as idiopathic VF. Atthe same time, it is necessary to establish the “reverseassociation”: that is, are healthy individuals with this pat-tern, without any other risk factor, at risk for sudden cardiacdeath (SCD)? This turns out to be a major clinical dilemmadue to the high prevalence of this pattern in the normalpopulation, and this was the subject of an excellent recentreview.

Effect of sodium-channel blockade on early repolarization in inferior/lateral leads in patients with idiopathic ventricular fibrillation and Brugada syndrome

A high incidence of early repolarization (ER) pattern in the inferolateral leads has been reported in patients with idiopathic ventricular fibrillation (IVF). Brugada syndrome (BS) is characterized by J-point or ST-segment elevation in the right precordial leads and ventricular fibrillation, and some patients with BS also have ER in the inferolateral leads. To compare the clinical characteristics and effects of sodium-channel blockade on ER between IVF patients with ER (early repolarization syndrome [ERS]) and BS patients with or without ER. Fourteen patients with ERS and 21 patients with BS were included in this study. ER was defined as an elevation of at least 0.1 mV from baseline in the QRS-T junction in the inferorolateral leads. Provocative tests with sodium-channel blockers were conducted in all patients with ERS to distinguish ERS from BS. In the ERS group, all patients were male and most patients experienced ventricular fibrillation during sleep or low activity (79%). ER was attenuated by sodium-channel blockers in most patients with ERS (13/14, 93%) and BS (5/5, 100%), whereas ST-segment elevation was augmented in the right precordial leads in the BS group. The rates of positive late potentials were significantly higher in the BS group (60%) than in the ERS group (7%) (P <.01). Some similarities were observed between ERS and BS, including gender, arrhythmia triggers, and response of ER to sodium-channel blockers. Unlike the ST segment in the right precordial leads in BS, ER was attenuated in patients with both ERS and BS, suggesting a differential mechanism between ER in the inferolateral leads and ST elevation in the right precordial leads.

Effects of sodium channel blockade on the cerebral processing of mechanical hyperalgesia: a fMRI study

Effects of sodium channel blockade on the cerebral processing of mechanical hyperalgesia: a fMRI study

Effect of Drugs on Defibrillation Capacity

Over 300,000 people die of sudden cardiac death (SCD) in the US annually. Implantable cardioverter-defibrillators (ICDs) have been shown to be more effective than antiarrhythmic drugs for the prevention of SCD in specific susceptible populations. Many patients in whom ICDs have been implanted receive concomitant therapy with antiarrhythmic drugs, for the purpose of reducing the frequency of appropriate and inappropriate defibrillation shocks. Drugs may influence defibrillation capacity and therefore influence the function of ICDs. The objective of this article is to review and update the literature regarding the effects of drugs on defibrillation capacity.A literature search was performed using PubMed (1966 to December 2007) to identify clinical studies, case reports and animal studies describing the effects of drugs on defibrillation capacity. Search terms included: antiarrhythmic drugs; cardiovascular drugs; amiodarone; sotalol; flecainide; propafenone; dofetilide; ibutilide; beta-blockers; lidocaine; procainamide; N-acetylprocainamide; mexiletine; disopyramide; moricizine; calcium channel blockers; defibrillation threshold; defibrillation energy requirements; defibrillation energy changes; defibrillation efficacy; implantable cardioverter defibrillators; and external defibrillators. Evidence from clinical studies indicates that amiodarone may increase defibrillation threshold (DFT). In addition, some data indicate that drugs including lidocaine, mexiletine, moracizine (moricizine), verapamil, venlafaxine and anaesthetic agents may increase DFT. In contrast, agents including sotalol, dofetilide and beta-adrenergic receptor antagonists (beta-blockers) may reduce DFT. Propafenone and procainamide appear to have minimal effect on DFT. For those antiarrhythmic drugs with both sodium and potassium channel blockade (e.g. amiodarone), the effect of sodium channel blockade predominates, resulting in an increase in DFT. Numerous drugs may affect defibrillation capacity. These effects must be considered when managing patients who have an ICD and require concomitant pharmacotherapy.

Effects of AMPA-receptor and voltage-sensitive sodium channel blockade on high potassium-induced glutamate release and neuronal death in vivo

High extracellular potassium induces spreading depression-like depolarizations and elevations of extracellular glutamate. Both occur in the penumbra of a focal ischemic infarct, and may be responsible for the spread of cell death from the infarct core to the penumbra. We have modeled this situation with microdialysis of an isotonic high-potassium solution into the normal rat amygdala for 70 min. This elevates extracellular glutamate up to 8-fold or more and produces irreversibly damaged, acidophilic neurons. NMDA-receptor blockade protects neurons and reduces the elevation of extracellular glutamate. Here we investigated the effects of sodium channel blockade with the voltage-sensitive sodium channel blocker tetrodotoxin and the AMPA receptor antagonist 2,3-dihydroxy-6-nitro-1,2,3,4-tetrahydrobenzo(f)quinoxaline-7-sulfonamide disodium (NBQX disodium) on high potassium-induced neuronal death and extracellular glutamate elevations. The acidophilic neurons produced are necrotic by ultrastructural examination. Tetrodotoxin, at dialysate concentrations of 33, 330 and 3300 μM (only a small fraction is extracted by tissue), markedly reduced the elevations of glutamate in rat amygdala at nearly all time points during high-potassium perfusion, but it reduced tissue edema only at the highest concentration, and it was neuroprotective only if dialyzed prior to high-potassium microdialysis (at 330 μM concentration). Although both 250 μM (6.2% is extracted by tissue) and 500 μM NBQX reduced elevations of glutamate, neither was neuroprotective, and neuropil edema was not reduced by either concentration. Our results suggest that in vivo, sodium influx through voltage-sensitive sodium channels but not through ligand-gated AMPA receptor channels contributes to high potassium-induced neuronal necrosis.

Molecular biology of the long QT syndrome: impact on management.

The long QT syndrome (LQTS) is a familial disease characterized by prolonged ventricular repolarization and high incidence of malignant ventricular tachyarrhythmias often occurring in conditions of adrenergic activation. Recently, the genes for the LQTS inked to chromosomes 3 (LQT3), 7 (LQT2), and 11 (LQT1) were identified as SCN5A, the cardiac sodium channel gene and as HERG and KvLQT1 potassium channel genes. These discoveries have paved the way for the development of gene-specific therapy for these three forms of LQTS. In order to test specific interventions potentially beneficial in the molecular variants of LQTS, we developed a cellular model to mimic the electrophysiological abnormalities of LQT3 and LQT2. Isolated guinea pig ventricular myocytes were exposed to anthopleurin and dofetilide in order to mimic LQT3 and LQT2, respectively. This model has been used to study the effect of sodium channel blockade and of rapid pacing showing a pronounced action potential shortening in response to Na+ channel blockade with mexiletine and during rapid pacing only in anthopleurin-treated cells but not in dofetilide-treated cells. Based on these results we tested the hypothesis that QT interval would shorten more in LQT3 patients in response to mexiletine and to increases in heart rate. Mexiletine shortened significantly the QT interval among LQT3 patients but not among LQT2 patients. LQT3 patients shortened their QT interval in response to increases in heart rate much more than LQT2 patients and healthy controls. These findings suggest that LQT3 patients are more likely to benefit from Na+ channel blockers and from cardiac pacing because they are at higher arrhythmic risk at slow heart rates. Conversely, LQT2 patients are at higher risk to develop syncope under stressful conditions, because of the combined arrhythmogenic effect of catecholamines with the insufficient adaptation of their QT interval. Along the same line of development of gene-specific therapy, recent data demonstrated that an increase in the extracellular concentration of potassium shortens the QT interval in LQT2 patients suggesting that intervention aimed at increasing potassium plasma levels may represent a specific treatment for LQT2. The molecular findings on LQTS suggest the possibility of developing therapeutic interventions targeted to specific genetic defects. Until definitive data become available, antiadrenergic therapy remains the mainstay in the management of LQTS patients, however it may be soon worth considering the addition of a Na+ channel blocker such as mexiletine for LQT3 patients and of interventions such as K+ channel openers or increases in the extracellular concentration of potassium for LQT1 and LQT2 patients.

Electrophysiologic effects of sodium channel blockade on anisotropic conduction and conduction block in canine myocardium: preferential slowing of longitudinal conduction by flecainide versus disopyramide or lidocaine.

The purpose of this study was to determine the effects of sodium channel blockade on anisotropic excitation propagation in the intact canine left ventricle. Anisotropic ventricular conduction- electric conductivity dependent on the myocardial fiber direction-is one of the important mechanisms of ventricular arrhythmia. However, the effects of sodium channel blockade, especially the differential effect of a subclass of this agent, on the anisotropic properties remain unknown. In 28 anesthetized, open chest dogs, a small cannula was inserted into the left anterior descending coronary artery. Saline (control), disopyramide, lidocaine or flecainide was infused selectively into the cannula. An array of 64 epicardial electrodes was placed on the anterior surface of the ventricle. Activation time (AT) was measured along the longitudinal (L) and transverse (T) directions. High dose flecainide (100 microg/kg body weight per min) delayed the AT along the L direction markedly (mean [+/-SE] 227 +/- 38%, p < 0.02) and mildly (121 +/- 10%, p < 0.02) along the T direction in regular beats (p < 0.007, L vs. T). Lidocaine and disopyramide did not show direction-dependent prolongation of the AT on regular beats. When examined on premature beats, AT was delayed, depending on the coupling interval and the fiber direction when saline, flecainide or lidocaine was infused. The conduction blocks along the L direction were observed in three of seven dogs on regular beats after flecainide and ventricular fibrillation ensued in two of these three dogs. A peculiar slowing of L conduction by flecainide may relate to the character of proarrhythmia.

A simple technique for production of chronic complete heart block in dogs.

A simple technique for production of chronic complete heart block in dogs.