flunarizine and Arrhythmias--Cardiac

Potassium (K(+)) channels are membrane proteins expressed in most living cells that selectively control the flow of K(+) ions. More than 80 genes encode the K(+) channel subunits in the human genome. The TWIK-related K(+) channel (TREK-1) belongs to the two-pore domain K(+) channels (K2P) and displays various properties including sensitivity to physical (membrane stretch, acidosis, temperature) and chemical stimuli (signaling lipids, volatile anesthetics). The distribution of TREK-1 in the central nervous system, coupled with the physiological consequences of its opening and closing, leads to the emergence of this channel as an attractive therapeutic target. We review the TREK-1 channel, its structural and functional properties, and the pharmacological agents (agonists and antagonists) able to modulate its gating.

Topics: Arrhythmias, Cardiac; Depression; Epilepsy; Humans; Inflammation; Models, Molecular; Molecular Structure; Neuroprotective Agents; Pain; Potassium Channels, Tandem Pore Domain; Structure-Activity Relationship

This is a brief review of agents that stabilize calcium release from the sarcoplasmic reticulum in cardiac muscle. An excess intracellular calcium concentration (calcium overload) is a common feature in a variety of cardiac cell injuries. Calcium overload elicits diastolic and systolic failure, and is involved in the genesis of arrhythmias. These abnormalities appear in part to be caused by the spontaneous release of calcium ions from the sarcoplasmic reticulum. Previous efforts to treat calcium overload were made with the intention to decrease the total intracellular content of calcium ions. However, such procedures would result in a decrease in contractility. Agents that stabilized calcium release from the sarcoplasmic reticulum may therefore be useful to correct abnormalities in calcium overload. In this review, after briefly describing intracellular calcium homeostasis, strategies against calcium overload, especially those involving magnesium ion, ryanodine, caffeine, dantrolene, phenytoin, R56865, KT361 and flunarizine will be discussed.

Topics: Animals; Anti-Arrhythmia Agents; Anticonvulsants; Arrhythmias, Cardiac; Benzothiazoles; Caffeine; Calcium; Calcium Channel Blockers; Dantrolene; Flunarizine; Homeostasis; Humans; Magnesium; Models, Cardiovascular; Muscle Relaxants, Central; Myocardial Contraction; Myocardium; Phenytoin; Piperidines; Ryanodine; Sarcoplasmic Reticulum; Thiazepines; Thiazoles

What is the central question of this study? Can successful electrical shock in combination with a delayed after-depolarization (DAD) blocker suppress early refibrillation episodes following long duration ventricular fibrillation (LDVF)? What is the main finding and its importance? Flunarizine significantly reduced the activation of LDVF and early ventricular fibrillation (VF) recurrence following LDVF, suggesting that DADs potentially contribute to refibrillation in prolonged VF. Thus, DAD inhibition can be used as an adjunctive therapy for electrical defibrillation to treat prolonged VF and suppress refibrillation following LDVF.. This study attempts to detect changes in the defibrillation threshold (DFT) at different stages of ventricular fibrillation (VF) (short duration VF, SDVF; long duration VF, LDVF) and during early refibrillation following successful defibrillation of LDVF by giving flunarizine, a blocker of delayed after-depolarizations (DADs). Twelve beagles were divided into two groups (the control group, n = 6; and the flunarizine group, n = 6). Two 64-electrode basket catheters were deployed into the left and the right ventricles for global endocardium mapping. The DFTs of SDVF and LDVF were determined at 20 s and 7 min, respectively, after VF induction in each group. Any refibrillation episodes were recorded within 15 min after the first successful defibrillation of LDVF. In the flunarizine group, the SDVF-DFT values before and after the drug were not significantly different. The 7 min LDVF-DFTs were markedly reduced by 26% (P < 0.05, the control group) and 38% (P < 0.01, the flunarizine group) compared to the 20 s SDVF-DFTs within each group. The difference between SDVF-DFT and LDVF-DFT after flunarizine was larger than that in the control group (213 ± 65 vs. 120 ± 84 V, P < 0.05). The number of refibrillation episodes per animal (1.3 ± 1.0) following successful defibrillation of LDVF after flunarizine was 48% of that in controls (2.7 ± 2.0, P < 0.05). The effect of flunarizine on SDVF-DFT and LDVF-DFT indicates that the role of DADs in the defibrillation mechanism may differ as VF continues. Flunarizine significantly reduced early VF recurrence following LDVF, suggesting that DADs potentially contribute to refibrillation in a canine model of prolonged VF.

Topics: Animals; Arrhythmias, Cardiac; Disease Models, Animal; Dogs; Electric Countershock; Endocardium; Female; Flunarizine; Heart Ventricles; Male; Time Factors; Ventricular Fibrillation

In conscious dogs with chronic atrioventricular (AV) block, we recently demonstrated that flunarizine is effective against ouabain-induced arrhythmias (triggered activity resulting from delayed afterdepolarizations, DADs) but fails to suppress spontaneous ventricular tachycardias (VT) occurring 24 h after left anterior descending coronary artery occlusion (abnormal automaticity). Neither does flunarizine affect normal automaticity, which suggests that flunarizine could be used as a clinical tool to recognize cardiac arrhythmias based on triggered activity. To elucidate further the arrhythmia mechanism-specific action of flunarizine, we investigated (a) its hemodynamic and electrophysiologic effects in 6 anesthetized dogs, (b) its ability to prevent pacing-induced VT 7 days after myocardial infarction (reentry) in 9 anesthetized animals, and (c) its effect on premature escape beats (PEBs) in 9 conscious dogs with chronic AV block. PEBs are probably caused by DADs. Flunarizine decreased systemic blood pressure (p less than 0.01), and left ventricular dP/dt (p less than 0.01), but did not affect AH or HV internal, QRS duration, QT time, or the effective refractory period of either AV node or right ventricle over a wide range of (paced) cycle lengths. Flunarizine decreased the inducibility of PEBs by 42% (p less than 0.01), but not that of the reentrant VT in any of the 6 inducible dogs. Therefore, we conclude that although flunarizine has no electrophysiologic effects in normal heart, it prevents induction of PEBs. The inability of flunarizine to prevent induction of reentrant VT confirms the mechanism-specific action of flunarizine against triggered activity.

Topics: Analysis of Variance; Animals; Arrhythmias, Cardiac; Blood Pressure; Cardiac Complexes, Premature; Dogs; Electric Stimulation; Electrocardiography; Female; Flunarizine; Male; Myocardial Infarction; Tachycardia

In male rats, anaesthetized with pentobarbitone, ligation of the main left coronary artery causes an early phase of ventricular arrhythmias which last about 30 min. In approximately 60% of control animals, ventricular fibrillation occurs but since spontaneous reversion to sinus rhythm may occur, mortality is of the order of 30%. When administered intravenously 15 min prior to ligation, verapamil (0.01 and 0.05 mg kg-1), prenylamine (0.5 mg kg-1), flunarizine (0.1, 0.25, 0.5 and 1.0 mg kg-1) and cinnarizine (0.25, 0.5 and 1.0 mg kg-1) protected against these arrhythmias. Higher doses of verapamil (0.1 and 0.5 mg kg-1), prenylamine (5 mg kg-1) and flunarizine (2.5 mg kg-1) did not afford a similar protection and mortality was increased to or above control values. Death was due in prenylamine-treated rats to atrioventricular block leading to asystole whereas in those administered verapamil or flunarizine it was a consequence of persistent ventricular fibrillation. Prior to ligation, a sustained fall in mean arterial blood pressure was observed only following the administration of the highest doses of prenylamine, flunarizine and cinnarizine. Heart rate was reduced by administration of only the highest dose of prenylamine. These studies show that although the four calcium antagonists studied, i.e. verapamil, prenylamine, flunarizine and cinnarizine do suppress ischaemia-induced arrhythmias, this protective effect may be limited to a narrow concentration range.

Topics: Anesthesia; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Calcium Channel Blockers; Cinnarizine; Coronary Disease; Flunarizine; Heart Rate; Male; Prenylamine; Rats; Rats, Inbred Strains; Verapamil