“… 10 , 11 , 12 , 13 On the other hand, in contrast to previous reports from rat and guinea pig cardiac myocytes, there was no significant difference between rabbit atrial and ventricular cells in the rate of recovery of I Na from inactivation in the present study. 10 , 12 Significant atrial-ventricular differences in block of I Na by ranolazine were also evident: (1) ranolazine caused a significantly greater negative shift in V half,inact in atrial cells than in ventricular cells, as has been reported previously in canine cardiac myocytes 11 ; (2) the recovery from inactivation of I Na was slowed by ranolazine to a greater extent in atrial myocytes than in ventricular cells; and (3) although there was little effect of HP on instantaneous block in ventricular cells, in atrial cells ranolazine produced an instantaneous block that showed marked voltage dependence, increasing from ∼16% block at an HP of −120 mV to ∼36% at −100 mV. The atrial-selective slowing of recovery from inactivation contrasts somewhat with a report showing little atrial-ventricular difference in the recovery from block in canine cardiac myocytes.…”
Section: Discussioncontrasting
confidence: 99%
“… 11 , 22 , 29 The mechanism underlying the more negative voltage dependence of I Na activation and inactivation in the present study compared with previous reports is unclear but, in principle, could reflect differences in recording conditions (eg, temperature, composition of solutions) and/or species differences in the biophysical properties of cardiac Na + channel isoforms. 10 , 11 , 12 , 13 , 22 , 29 Figure 8 The window current in atrial and ventricular myocytes. Data plotted against the left-hand axis are window current densities calculated from the parameters presented in Supplemental Table 1 for atrial ( solid black line ) and ventricular ( dashed black line ) myocytes.…”
Section: Discussionmentioning
confidence: 99%
“…Evidence from canine, guinea pig, rabbit, and rat cardiac myocytes supports the existence of atrial-ventricular differences in Na + channel function: compared with the voltage-gated Na + channel current ( I Na ) of ventricular myocytes, atrial I Na inactivates at more negative voltages, with more rapid onset, and recovers more slowly from inactivation. 10 , 11 , 12 , 13 …”
BackgroundClass 1 antiarrhythmic drugs are highly effective in restoring and maintaining sinus rhythm in atrial fibrillation patients but carry a risk of ventricular tachyarrhythmia. The antianginal agent ranolazine is a prototypic atrial-selective voltage-gated Na+ channel blocker but the mechanisms underlying its atrial-selective action remain unclear.ObjectiveThe present study examined the mechanisms underlying the atrial-selective action of ranolazine.MethodsWhole-cell voltage-gated Na+ currents (INa) were recorded at room temperature (∼22°C) from rabbit isolated left atrial and right ventricular myocytes.ResultsINa conductance density was ∼1.8-fold greater in atrial than in ventricular cells. Atrial INa was activated at command potentials ∼7 mV more negative and inactivated at conditioning potentials ∼11 mV more negative than ventricular INa. The onset of inactivation of INa was faster in atrial cells than in ventricular myocytes. Ranolazine (30 μM) inhibited INa in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated/inactivated state block. Ranolazine caused a significantly greater negative shift in voltage of half-maximal inactivation in atrial cells than in ventricular cells, the recovery from inactivation of INa was slowed by ranolazine to a greater extent in atrial myocytes than in ventricular cells, and ranolazine produced an instantaneous block that showed marked voltage dependence in atrial cells.ConclusionDifferences exist between rabbit atrial and ventricular myocytes in the biophysical properties of INa. The more negative voltage dependence of INa activation and inactivation, together with trapping of the drug in the inactivated channel, underlies an atrial-selective action of ranolazine.
“… 10 , 11 , 12 , 13 On the other hand, in contrast to previous reports from rat and guinea pig cardiac myocytes, there was no significant difference between rabbit atrial and ventricular cells in the rate of recovery of I Na from inactivation in the present study. 10 , 12 Significant atrial-ventricular differences in block of I Na by ranolazine were also evident: (1) ranolazine caused a significantly greater negative shift in V half,inact in atrial cells than in ventricular cells, as has been reported previously in canine cardiac myocytes 11 ; (2) the recovery from inactivation of I Na was slowed by ranolazine to a greater extent in atrial myocytes than in ventricular cells; and (3) although there was little effect of HP on instantaneous block in ventricular cells, in atrial cells ranolazine produced an instantaneous block that showed marked voltage dependence, increasing from ∼16% block at an HP of −120 mV to ∼36% at −100 mV. The atrial-selective slowing of recovery from inactivation contrasts somewhat with a report showing little atrial-ventricular difference in the recovery from block in canine cardiac myocytes.…”
Section: Discussioncontrasting
confidence: 99%
“… 11 , 22 , 29 The mechanism underlying the more negative voltage dependence of I Na activation and inactivation in the present study compared with previous reports is unclear but, in principle, could reflect differences in recording conditions (eg, temperature, composition of solutions) and/or species differences in the biophysical properties of cardiac Na + channel isoforms. 10 , 11 , 12 , 13 , 22 , 29 Figure 8 The window current in atrial and ventricular myocytes. Data plotted against the left-hand axis are window current densities calculated from the parameters presented in Supplemental Table 1 for atrial ( solid black line ) and ventricular ( dashed black line ) myocytes.…”
Section: Discussionmentioning
confidence: 99%
“…Evidence from canine, guinea pig, rabbit, and rat cardiac myocytes supports the existence of atrial-ventricular differences in Na + channel function: compared with the voltage-gated Na + channel current ( I Na ) of ventricular myocytes, atrial I Na inactivates at more negative voltages, with more rapid onset, and recovers more slowly from inactivation. 10 , 11 , 12 , 13 …”
BackgroundClass 1 antiarrhythmic drugs are highly effective in restoring and maintaining sinus rhythm in atrial fibrillation patients but carry a risk of ventricular tachyarrhythmia. The antianginal agent ranolazine is a prototypic atrial-selective voltage-gated Na+ channel blocker but the mechanisms underlying its atrial-selective action remain unclear.ObjectiveThe present study examined the mechanisms underlying the atrial-selective action of ranolazine.MethodsWhole-cell voltage-gated Na+ currents (INa) were recorded at room temperature (∼22°C) from rabbit isolated left atrial and right ventricular myocytes.ResultsINa conductance density was ∼1.8-fold greater in atrial than in ventricular cells. Atrial INa was activated at command potentials ∼7 mV more negative and inactivated at conditioning potentials ∼11 mV more negative than ventricular INa. The onset of inactivation of INa was faster in atrial cells than in ventricular myocytes. Ranolazine (30 μM) inhibited INa in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated/inactivated state block. Ranolazine caused a significantly greater negative shift in voltage of half-maximal inactivation in atrial cells than in ventricular cells, the recovery from inactivation of INa was slowed by ranolazine to a greater extent in atrial myocytes than in ventricular cells, and ranolazine produced an instantaneous block that showed marked voltage dependence in atrial cells.ConclusionDifferences exist between rabbit atrial and ventricular myocytes in the biophysical properties of INa. The more negative voltage dependence of INa activation and inactivation, together with trapping of the drug in the inactivated channel, underlies an atrial-selective action of ranolazine.
“…A recent study showed that the molecular mechanism responsible for differences in I Na in atria versus ventricular rat cells could be attributed to lower Na v β 2 and Na v β 4 expression in atria compared to that in ventricle (Chen et al. ). The authors speculate the lower expression of these beta subunits is responsible for the distinct biophysical properties of I Na in atria, namely, a more negative steady‐state inactivation, and a faster activation and inactivation.…”
Brugada syndrome (BrS) is an inherited disease associated with ST elevation in the right precordial leads, polymorphic ventricular tachycardia (PVT), and sudden cardiac death in adults. Mutations in the cardiac sodium channel account for a large fraction of BrS cases. BrS manifests in the right ventricle (RV), which led us to examine the biophysical and molecular properties of sodium channel in myocytes isolated from the left (LV) and right ventricle. Patch clamp was used to record sodium current (I
Na) in single canine RV and LV epicardial (epi) and endocardial (endo) myocytes. Action potentials were recorded from multicellular preparations and single cells. mRNA and proteins were determined using quantitative RT‐PCR and Western blot. Although LV wedge preparations were thicker than RV wedges, transmural ECG recordings showed no difference in the width of the QRS complex or transmural conduction time. Action potential characteristics showed RV epi and endo had a lower V
max compared with LV epi and endo cells. Peak I
Na density was significantly lower in epi and endo RV cells compared with epi and endo LV cells. Recovery from inactivation of I
Na in RV cells was slightly faster and half maximal steady‐state inactivation was more positive. β2 and β4 mRNA was detected at very low levels in both ventricles, which was confirmed at the protein level. Our observations demonstrate that V
max and Na+ current are smaller in RV, presumably due to differential Nav1.5/β subunit expression. These results provide a potential mechanism for the right ventricular manifestation of BrS.
“…An atrial-ventricular difference in the properties of I Na , especially in the voltage dependence of steady-state inactivation, has been reported (Li et al, 2002 ; Burashnikov et al, 2007 ; Chen et al, 2016 ; Fan et al, 2016 ; Caves et al, 2017 ). In these studies, the voltage dependent steady-state inactivation curves for I Na were found to be negatively shifted (by 5–16 mV) in atrium as compared to the ventricular parameters.…”
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Developing effective and safe anti-AF drugs remains an unmet challenge. Simultaneous block of both atrial-specific ultra-rapid delayed rectifier potassium (K+) current (IKur) and the Na+ current (INa) has been hypothesized to be anti-AF, without inducing significant QT prolongation and ventricular side effects. However, the antiarrhythmic advantage of simultaneously blocking these two channels vs. individual block in the setting of AF-induced electrical remodeling remains to be documented. Furthermore, many IKur blockers such as acacetin and AVE0118, partially inhibit other K+ currents in the atria. Whether this multi-K+-block produces greater anti-AF effects compared with selective IKur-block has not been fully understood. The aim of this study was to use computer models to (i) assess the impact of multi-K+-block as exhibited by many IKur blokers, and (ii) evaluate the antiarrhythmic effect of blocking IKur and INa, either alone or in combination, on atrial and ventricular electrical excitation and recovery in the setting of AF-induced electrical-remodeling. Contemporary mathematical models of human atrial and ventricular cells were modified to incorporate dose-dependent actions of acacetin (a multichannel blocker primarily inhibiting IKur while less potently blocking Ito, IKr, and IKs). Rate- and atrial-selective inhibition of INa was also incorporated into the models. These single myocyte models were then incorporated into multicellular two-dimensional (2D) and three-dimensional (3D) anatomical models of the human atria. As expected, application of IKur blocker produced pronounced action potential duration (APD) prolongation in atrial myocytes. Furthermore, combined multiple K+-channel block that mimicked the effects of acacetin exhibited synergistic APD prolongations. Synergistically anti-AF effects following inhibition of INa and combined IKur/K+-channels were also observed. The attainable maximal AF-selectivity of INa inhibition was greatly augmented by blocking IKur or multiple K+-currents in the atrial myocytes. This enhanced anti-arrhythmic effects of combined block of Na+- and K+-channels were also seen in 2D and 3D simulations; specially, there was an enhanced efficacy in terminating re-entrant excitation waves, exerting improved antiarrhythmic effects in the human atria as compared to a single-channel block. However, in the human ventricular myocytes and tissue, cellular repolarization and computed QT intervals were modestly affected in the presence of actions of acacetin and INa blockers (either alone or in combination). In conclusion, this study demonstrates synergistic antiarrhythmic benefits of combined block of IKur and INa, as well as those of INa and combined multi K+-current block of acacetin, without significant alterations of ventricular repolarization and QT intervals. This approach may be a valuable strategy for the treatment of AF.
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