Abstract
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.
Highlights
Atrial fibrillation (AF), characterized by rapid and irregular electrical activation of the atria, reduced cardiac output, poor response to exercise, and fatigue, is the most commonly occurring clinical arrhythmia.[1]
INa from atrial myocytes activated at more negative voltages than ventricular INa, with measurable inward currents being evident from voltages of 260 mV and positive and reaching a maximum at approximately 240 mV in atrial cells, whereas INa in ventricular myocytes were activated from 250 mV and reached a maximum at w230 mV (Figure 1C)
The current density–voltage relations of each cell type were fitted by a modified Boltzmann relation (Supplemental Equation 1) and the more negative voltage dependence of activation of atrial INa was reflected in a mean half-maximal voltage of activation (Vhalf,act) approximately 7 mV more negative than that of ventricular INa (P, .0001; Supplemental Table 1)
Summary
Atrial fibrillation (AF), characterized by rapid and irregular electrical activation of the atria, reduced cardiac output, poor response to exercise, and fatigue, is the most commonly occurring clinical arrhythmia.[1] AF is associated with significant morbidity and mortality, principally through an elevated risk of thromboembolism and ischemic stroke owing to inadequate emptying of the atria, the elevated ventricular rate can contribute to tachycardia-induced cardiomyopathy and decompensated heart failure.[1] The condition tends to be progressive, with paroxysms of AF leading with time to persistent and permanent AF.[1] The progressive nature of AF is thought to arise through the elevated rate causing electrical and structural remodeling that stabilizes the arrhythmia.[1] Early intervention to prevent and/or control the arrhythmia is highly desirable.[1,2]. Class 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 Na1 channel blocker but the mechanisms underlying its atrialselective action remain unclear
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