Electrophysiological Effects of Ranolazine, a Novel Antianginal Agent With Antiarrhythmic Properties

doi:10.1161/01.CIR.0000139333.83620.5D

Paper

Electrophysiological Effects of Ranolazine, a Novel Antianginal Agent With Antiarrhythmic Properties

Published Aug 24, 2004 · C. Antzelevitch, L. Belardinelli, A. Zygmunt

Circulation

Q1 SJR score

671

Citations

28

Influential Citations

Full textSemantic Scholar

Abstract

Background—Ranolazine is a novel antianginal agent capable of producing antiischemic effects at plasma concentrations of 2 to 6 &mgr;mol/L without reducing heart rate or blood pressure. The present study examines its electrophysiological effects in isolated canine ventricular myocytes, tissues, and arterially perfused left ventricular wedge preparations. Methods and Results—Transmembrane action potentials (APs) from epicardial and midmyocardial (M) regions and a pseudo-ECG were recorded simultaneously from wedge preparations. APs were also recorded from epicardial and M tissues. Whole-cell currents were recorded from epicardial and M myocytes. Ranolazine inhibited IKr (IC50=11.5 &mgr;mol/L), late INa, late ICa, peak ICa, and INa-Ca (IC50=5.9, 50, 296, and 91 &mgr;mol/L, respectively) and IKs (17% at 30 &mgr;mol/L), but caused little or no inhibition of Ito or IK1. In tissues and wedge preparations, ranolazine produced a concentration-dependent prolongation of AP duration of epicardial but abbreviation of that of M cells, leading to reduction or no change in transmural dispersion of repolarization (TDR). At [K+]o=4 mmol/L, 10 &mgr;mol/L ranolazine prolonged QT interval by 20 ms but did not increase TDR. Extrasystolic activity and spontaneous torsade de pointes (TdP) were never observed, and stimulation-induced TdP could not be induced at any concentration of ranolazine, either in normal or low [K+]o. Ranolazine (5 to 20 &mgr;mol/L) suppressed early afterdepolarizations (EADs) and reduced the increase in TDR induced by the selective IKr blocker d-sotalol. Conclusions—Ranolazine produces ion channel effects similar to those observed after chronic amiodarone (reduced IKr, IKs, late INa, and ICa). The actions of ranolazine to suppress EADs and reduce TDR suggest that, in addition to its antianginal actions, the drug may possess antiarrhythmic activity.

In Vitro Study

Highly Cited

Study Snapshot

Ranolazine, a novel antianginal agent, also shows potential antiarrhythmic properties, suppressing early afterdepolarizations and reducing transmural dispersion of repolarization.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Sign up to use Study Snapshot

Consensus is limited without an account. Create an account or sign in to get more searches and use the Study Snapshot.

Create an account

Paper

Electrophysiological Effects of Ranolazine, a Novel Antianginal Agent With Antiarrhythmic Properties

Sign up to use Study Snapshot

References

Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial.

Ranolazine combined with beta-blockers or calcium antagonists improves exercise tolerance and reduces angina attacks in patients with severe chronic angina.

Assessing predictors of drug-induced torsade de pointes.

Drugs that prolong action potential duration, induce early afterdepolarizations, and ectopic beats are likely to cause torsades de pointes, but the exact relationship between these events and TdP development remains unclear.

Transmural Electrophysiological Heterogeneities Underlying Arrhythmogenesis in Heart Failure

Selective prolongation of action potential duration within midmyocardial cells contributes to heart failure phenotype, including QT-interval prolongation, transmural heterogeneity of repolarization, and susceptibility to conduction block and reentrant PVT.

Cisapride-Induced Transmural Dispersion of Repolarization and Torsade de Pointes in the Canine Left Ventricular Wedge Preparation During Epicardial Stimulation

Cisapride induces long-QT syndrome and TdP at low concentrations, with epicardial activation of the left ventricle facilitating the development of TdP under long-QT conditions.

Short-Term Treatment With Ranolazine Improves Mechanical Efficiency in Dogs With Chronic Heart Failure

Short-term treatment with ranolazine improves left ventricular function without increasing myocardial oxygen consumption in dogs with chronic heart failure.

Citations

Effects of Eleclazine (GS6615) on the proarrhythmic electrophysiological changes induced by myocardial stretch

Eleclazine (GS6615) reduces proarrhythmic electrophysiological changes and simplifies activation patterns during ventricular fibrillation in an experimental model.

Ranolazine Unveiled: Rediscovering an Old Solution in a New Light

Ranolazine shows promising results in treating atrial fibrillation and ventricular arrhythmias when combined with other medications.

Effects of ranolazine on the arrhythmic substrate in hypertrophic cardiomyopathy

Ranolazine's antiarrhythmic efficacy and safety in hypertrophic cardiomyopathy depend on the degree of repolarization impairment, with optimal benefits in models with maximum JTc interval 370 ms.

Underlying mechanism of atrial fibrillation associated Nppa-I137T mutation and cardiac effect of potential drug therapy.

The Nppa (p.I137T) variant causes atrial fibrillation through structural remodeling and electrical remodeling, which can be treated with late sodium current blockers and Na v 1.8 blockers.

Mexiletine: Antiarrhythmic mechanisms, emerging clinical applications and mortality

Mexiletine is a vital therapeutic option for patients with ventricular arrhythmias, long QT syndrome, and other heart rhythm disorders, offering antiarrhythmic effects and addressing potential risks.

Mechanism of Ion Channel Impairment in the Occurrence of Arrhythmia in Patients with Hypertrophic Cardiomyopathy.

Ion channel abnormalities may play a significant role in the early stages of hypertrophic cardiomyopathy, leading to sudden cardiac death.

Ranolazine improved left ventricular diastolic functions and ventricular repolarization indexes in patients with coronary slow flow

Ranolazine improves left ventricular diastolic functions and ventricular repolarization parameters in patients with coronary slow flow.

Overview of Cardiac Arrhythmias and Treatment Strategies

Cardiac arrhythmias can cause severe morbidity and mortality, and understanding their molecular and cellular aspects is crucial for developing novel treatments and managing their consequences.