piperidines and Ventricular-Fibrillation

Topics: Adrenergic beta-Antagonists; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Disopyramide; Electric Countershock; Electric Stimulation; Electrocardiography; Exercise Test; Flecainide; Heart Ventricles; Humans; Lidocaine; Phenytoin; Piperidines; Procainamide; Quinidine; Risk; Tachycardia; Tocainide; United States; Ventricular Fibrillation; Verapamil

Topics: Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Coronary Disease; Encainide; Flecainide; Heart Ventricles; Humans; Lidocaine; Mexiletine; Myocardial Infarction; Piperidines; Tachycardia; Tocainide; Ventricular Fibrillation

The effectiveness of perhexiline maleate in the suppression of ventricular ectopic activity has been studied in 10 patients after myocardial infarction. Before treatment all patients exhibited frequent ectopic beats, i.e. more than 8 per hour. Numerous Holter magnetic tape recordings were made over a 9 - 10-month period of treatment. During the entire period of monitoring significant suppression of ectopic activity was observed in 5 patients and transient suppression in 4, of whom 3 subsequently showed a transient increase. The drug was discontinued in 1 patient because of nausea, anorexia and weight loss. No other adverse effects were encountered.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Trials as Topic; Humans; Male; Middle Aged; Myocardial Infarction; Perhexiline; Piperidines; Ventricular Fibrillation

Topics: Antineoplastic Agents; Carbazoles; Defibrillators, Implantable; Humans; Male; Middle Aged; Piperidines; Ventricular Fibrillation

Ibrutinib is an oral inhibitor of Bruton tyrosine kinase approved for the treatment of chronic lymphocytic leukaemia, mantle cell lymphoma and refractory Waldenstrom's disease. It increases progression-free survival, overall survival, response rate. The most frequent adverse reactions, are increased risk in of bleeding and atrial fibrillation, but several reports of more dangerous rhythm disturbances have been recently reported in literature. A case of a patient with refractory Waldenstrom's disease, who developed ventricular fibrillation while taking ibrutinib, is reported, along with a concise literature review.

Topics: Adenine; Death, Sudden, Cardiac; Electrocardiography; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Ventricular Fibrillation; Waldenstrom Macroglobulinemia

Atrial fibrillation is a side effect of ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase used for treatment of B-cell lymphoproliferative disorders. We determined if single (2 or 10 mg/kg), or chronic (14 days) oral ibrutinib followed by 24-hour washout conferred susceptibility to electrically induced arrhythmias in 1-month-old male C57BL/6 mice. A single higher dose of ibrutinib increased arrhythmia inducibility. There was no inducibility difference after chronic dosing with washout. This suggests that high serum drug levels might be responsible for the proarrhythmic effect of ibrutinib and that an altered dosing strategy might mitigate the side effects.

Topics: Adenine; Animals; Atrial Fibrillation; Disease Models, Animal; Disease Susceptibility; Dose-Response Relationship, Drug; Electrocardiography; Male; Mice; Mice, Inbred C57BL; Piperidines; Pulse Therapy, Drug; Pyrazoles; Pyrimidines; Random Allocation; Reference Values; Risk Assessment; Ventricular Fibrillation

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Cohort Studies; Female; Follow-Up Studies; Humans; Lymphoma; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Ventricular Fibrillation

Topics: Action Potentials; Aged; Antineoplastic Agents; Electrocardiography, Ambulatory; Heart Conduction System; Heart Rate; Humans; Male; Piperidines; Protein Kinase Inhibitors; Quinazolines; Risk Factors; Time Factors; Torsades de Pointes; Ventricular Fibrillation

The Tako-Tsubo syndrome (or transient left ventricular apical balloning) is a new clinical entity, very similar to acute myocardial infarction, but different by its excellent short-term prognosis. It has been reported after a physical or an emotional stress, and it is diagnosed by a coronary angiogram and a left ventriculography. We report here a case of Tako-Tsubo syndrome related to an anaphylactic shock caused by succinylcholine during general anaesthesia of a female patient, wearing an unadjustable gastric band.

Topics: Anaphylaxis; Anesthesia, General; Anesthesia, Intravenous; Diabetes Mellitus, Type 2; Female; Gastroplasty; Heart Arrest; Humans; Intraoperative Complications; Laparoscopy; Middle Aged; Neuromuscular Depolarizing Agents; Obesity; Pelvic Floor; Piperidines; Postoperative Complications; Propofol; Pulmonary Edema; Remifentanil; Succinylcholine; Takotsubo Cardiomyopathy; Ventricular Fibrillation

The role of K(ATP) channels in the antiarrhythmic effect of Escherichia coli endotoxin-induced nitric oxide synthase (iNOS) was examined in an anesthetised rat model of myocardial ischemia and reperfusion arrhythmia by using glibenclamide (1 mg kg(-1)), nateglinide (10 mg kg(-1)) and repaglinide (0.5 mg kg(-1)). Endotoxin (1 mg kg(-1)) was administered intraperitoneally 4 h before the occlusion of the left coronary artery and glibenclamide, nateglinide or repaglinide was administered 30 min before coronary artery occlusion. We also evaluated the effects of K(ATP) channel blockers and nonselective K(+) channel blocker tetraethylammonium (TEA) on cardiac action potential configuration in the atria obtained from endotoxemic rats. The mean arterial blood pressure of rats receiving endotoxin was lower during both the occlusion and reperfusion periods. Endotoxin significantly reduced the total number of ectopic beats and the duration of ventricular tachycardia. Glibenclamide, but not nateglinide and repaglinide, prevented the hypotension and antiarrhythmic effects of endotoxin. Atria obtained from endotoxin-treated rats had prolonged action potential duration. This effect was abolished with pretreatment of iNOS inhibitors, l-canavanine and dexamethasone and perfusion of glibenclamide, but not with TEA and non-sulfonylurea drug, nateglinide. We demonstrated that glibenclamide inhibits the antiarrhythmic effect of endotoxin and this effect does not appear to involve K(ATP) channels.

Topics: Action Potentials; Adenosine Triphosphate; Animals; Arrhythmias, Cardiac; Blood Pressure; Carbamates; Cyclohexanes; Disease Models, Animal; Drug Interactions; Endotoxemia; Glyburide; Heart Atria; Heart Conduction System; Lipopolysaccharides; Male; Myocardial Ischemia; Nateglinide; Phenylalanine; Piperidines; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Sprague-Dawley; Tachycardia, Ventricular; Tetraethylammonium; Time Factors; Ventricular Fibrillation; Ventricular Premature Complexes

The aims of this study were to determine if endothelin-1 (ET-1) under normal and ischaemic conditions exhibits a direct arrhythmogenic effect that is independent of its ability to cause coronary vasoconstriction, and to determine the contribution of the ET(A) and ET(B) receptor subtype. ET(A/B) (with ET-1) and ET(A) (ET-1 in the presence of BQ-788) receptor activation resulted in a significant reduction in both epi- and endocardial monophasic action potential duration (MAPD(90)). ET(A) receptor activation reduced both epi- and endocardial effective refractory period (ERP). This MAPD(90) and ERP shortening were associated with a reduction in coronary flow, myocardial contractility and induction of ventricular fibrillation (VF) during ERP measurement. The ET(B) agonist sarafotoxin (S6c) had no marked, or concentration-dependent, effect on MAPD(90), ERP, myocardial contractility or induction of arrhythmias. Neither ET-1 nor S6c, given prior to coronary artery occlusion, significantly changed the ischaemia-induced dispersion of MAPD(90), ERP or the % incidence of VF. In conclusion, neither ET(A) nor ET(B) receptor stimulation has a direct arrhythmogenic effect in isolated rabbit hearts under normal or ischaemic conditions. The ET-1-induced arrhythmogenic effect observed in nonischaemic hearts is likely to be the result of the associated coronary vasoconstriction caused by ET(A) receptor stimulation resulting in myocardial ischaemia.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Circulation; Disease Models, Animal; Endocardium; Endothelin B Receptor Antagonists; Endothelin-1; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Ischemia; Oligopeptides; Pericardium; Piperidines; Rabbits; Receptor, Endothelin A; Receptor, Endothelin B; Ventricular Fibrillation; Viper Venoms

Topics: Animals; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Electrophysiologic Techniques, Cardiac; Heart Conduction System; Heart Ventricles; Humans; Long QT Syndrome; Piperidines; Pyridines; Ventricular Fibrillation

The area of vulnerability (AOV) to ventricular fibrillation (VF) induction by high-voltage shocks has been proposed as a measure of vulnerability to VF. Biphasic shocks spanning the T wave and ranging between 50 V and the upper limit of vulnerability (ULV) to VF were delivered before and after terikalant (1 mg/kg) and barium (1.1 mg/kg load followed by 0.05-0.10 mg/kg/min maintenance) or vehicle in dogs. The AOV decreased by 34% and 28% (p < 0.01) after terikalant and barium (n = 8 dogs each), respectively. Mean ULV, defibrillation threshold (DFT), and ventricular vulnerability period (VVP) decreased by 16%, 23%, and 31% (p < 0.01), respectively, after terikalant, and by 25%, 17% (p < 0.01), and 13% (p = 0.08), respectively, after barium. Vehicle (n = 14) did not significantly alter any of these variables. The ULV was correlated with the DFT before and after terikalant (r = 0.78, p < 0.01) and barium (r = 0.83, p < 0.01). Potassium channel blockers of the current reduce the ability to induce VF; this effect may be related to the anti-fibrillatory action of class III anti-arrhythmic drugs and their ability to decrease DFT.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Barium Compounds; Chlorides; Chromans; Dogs; Electric Countershock; Electrocardiography; Female; Infusions, Intravenous; Male; Piperidines; Ventricular Fibrillation; Ventricular Function

The spatial and dynamic properties of ventricular fibrillation (VF) may be random or related to cellular electrical properties of the normal heart. Local activation intervals (AIs) in VF may depend on the local refractory period (RP), and sustained VF may require a steep action potential (AP) restitution curve. In guinea pig hearts, AP durations (APDs) and RPs on the epicardium are shorter at the apex and progressively longer toward the base, producing gradients of RPs that may influence the spatial organization of VF. In the present study, the influence of APDs on VF dynamics is investigated in perfused guinea pig hearts stained with a voltage-sensitive dye by comparing APD gradients to the dynamics of VF elicited by burst pacing. In VF, AIs had no clear periodicity, but average AIs were shorter at the apex (57.5+/-8.1 ms) than the base (76.1+/-1.5 ms, n=6, P<0.05) and had gradients similar to APD gradients (correlation coefficient 0.71+/-0.04). Analysis of local velocity vectors showed no preferential directions, and fast Fourier transform (FFT) power spectra were broad (10 to 24 Hz) with multiple peaks (n=6). However, the selective inhibition of delayed K(+) rectifying currents, I(Kr) (E4031; 0.5 micromol/L, n=3), shifted FFT spectra from complex to a lower dominant frequency (10 Hz) and altered repolarization but retained the correlation between mean AIs and RPs. Thus, VF dynamics are consistent with a multiple wave-make and wave-break mechanism, and the local RP influences VF dynamics by limiting the range of VF frequencies and AIs at each site. The full text of this article is available at http://www.circresaha.org.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Female; Guinea Pigs; Heart Conduction System; Heart Ventricles; Piperidines; Pyridines; Ventricular Fibrillation

The 4-aminopyridine (4-AP)-sensitive transient outward current (Ito) has been reported to play an important role in the ischemia- or high [Ca2+]o-induced reentrant ventricular arrhythmias. However, the role of 4-AP sensitive Ito in reperfusion arrhythmia remains unknown. Rat hearts were perfused with Tyrode solution (control), and treated with 0.5 micromol/L verapamil, 1 micromol/L glibenclamide, 10 micromol/L E-4031 or 2 mmol/L 4-AP. After a 10-min perfusion, hearts were subjected to 30-min global ischemia followed by 10-min reperfusion. The effects of the ion-channel blockers on the incidence of ventricular tachycardia (VT), torsades de pointes (Tdp) and ventricular fibrillation (VF) during the reperfusion period were investigated. Verapamil and 4-AP abolished VF and Tdp. The incidence of VT was also attenuated by verapamil, but not by 4-AP. Glibenclamide and E-4031 (a blocker of a rapidly activating component of delayed rectifier K+ current) did not affect the incidence of those tachyarrhythmias. Accordingly, (1) the underlying mechanism of VF or Tdp is different from that of VT, and (2) 4-AP sensitive Ito is required for the occurrence of reperfusion Tdp or VF in the present model.

Topics: 4-Aminopyridine; Animals; Anti-Arrhythmia Agents; Blood Flow Velocity; Glyburide; Heart; Heart Rate; In Vitro Techniques; Male; Myocardial Reperfusion; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Tachycardia, Ventricular; Torsades de Pointes; Ventricular Fibrillation; Verapamil

The electrical alternans shown on an ST segment, ST alternans, is known as one of the most important predictors of ventricular fibrillation (VF). It has also been reported that sodium channel inhibition changes action potential configuration, especially on the repolarization phase. Thus, the sodium channel blocker may produce ST alternans and trigger reentrant arrhythmia.. A sodium channel blocker (disopyramide, lidocaine, or flecainide) was infused selectively into the left anterior descending coronary artery in anesthetized, open-chest dogs. Sixty unipolar electrograms were simultaneously recorded from the entire cardiac surface of the heart. The amplitude of ST alternans (STa) was determined as the difference in the ST-segment magnitude between 2 consecutive electrograms. We accepted the greatest STa among 60 leads for evaluation. High-dose flecainide (100 microg. kg-1. min-1) increased STa and evoked a spontaneous VF. The STa in high-dose flecainide loading (8.7+/-3.4 mV; mean+/-SEM) was significantly greater than that in disopyramide or lidocaine (0. 9+/-0.4 and 0.8+/-0.2 mV, P<0.05). Treatment of 4-aminopyridine (4-AP) suppressed the increase in STa and the occurrence of VF evoked by flecainide, while E4031 or verapamil did not inhibit those.. Flecainide caused the ST alternans that was closely correlated to the occurrence of VF. Because the ST alternans was suppressed by 4-AP treatment, a 4-AP-sensitive current such as Ito or Isus may play an important role on this phenomenon.

Topics: 4-Aminopyridine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Vessels; Disopyramide; Dogs; Electrocardiography; Flecainide; Injections; Lidocaine; Piperidines; Pyridines; Sodium Channels; Ventricular Fibrillation; Verapamil

The effects of the extremely selective mu-opioid receptor agonist, [D-Arg2,Lys4]-dermorphin-(1-4)-amide (DALDA), the mu-opioid receptor agonist morphine, the mu/delta agonist D-Ala2, Leu5, Arg6-enkephalin (dalargin), the kappa-opioid receptor agonist spiradoline, and the sigma1-receptor antagonist DuP 734 on ventricular fibrillation threshold (VFT) was investigated in an experimental post-infarction cardiosclerosis model and an immobilization stress-induced model in rats. Both models produced a significant decrease in VFT. The postinfarction cardiosclerosis-induced decrease in VFT was significantly reversed by intravenous administration of dalargin (0.1 mg/kg), DALDA (0.1 mg/kg), or morphine HCl (1.5 mg/kg). Pretreatment with naloxone (0.2 mg/kg) completely eliminated the increase in cardiac electrical stability produced by DALDA. Both spiradoline (8 mg/kg, i.p.) and DuP 734 (1 mg/kg, i.p.) produced a significant increase in VFT in rats with post-infarction cardiosclerosis. This effect of spiradoline was blocked by nor-binaltorphimine. The immobilization stress-induced decrease in VFT was significantly reversed by administration of either DALDA, spiradoline or DuP 734. In conclusion, activation of either mu- or kappa1-opioid receptors or blockade of sigma1-receptors reversed the decrease in VFT in both cardiac compromised models. Since DALDA and dalargin essentially do not cross blood brain barriers, their effects on VFT may be mediated through peripheral mu-opioid receptors.

Topics: Animals; Anti-Arrhythmia Agents; beta-Endorphin; Disease Models, Animal; Dynorphins; Enkephalin, Leucine-2-Alanine; Heart; Immobilization; Ligands; Morphine; Myocardial Infarction; Myocardium; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Piperidines; Pyrrolidines; Rats; Receptors, Opioid; Receptors, Opioid, delta; Stress, Physiological; Ventricular Fibrillation

This study was designed to test whether the refractory state of nondepolarized myocardium is a major determinant of electrical defibrillation.. Postshock recovery interval (PSRI) was estimated by measuring the residual refractory period after an appropriately timed field stimulus (1 to 16 V). The PSRI and transcardiac defibrillation threshold (DFT) were compared before and during the administration of E-4031, a new Class III antiarrhythmic drug (group 1, n = 10), or between monophasic and biphasic shocks (group 2, n = 14) in anesthetized open chest dogs. Group 1: E-4031 reduced the DFT from 2.6 +/- 0.6 J to 1.8 +/- 0.6 J (P < 0.01). The PSRI increased with the increase of the applied voltage and was almost always greater during E-4031 infusion than at baseline. There was an inverse correlation between the changes of DFT and PSRI measured with a 14-V stimulus (r = -0.80, P < 0.01) and a 16-V stimulus (r = -0.80, P < 0.01). Group 2: Mean DFTs were not statistically different between the two waveforms (3.3 +/- 1.0 J vs 2.9 +/- 1.4 J). However, there also was an inverse correlation between the differences in individual PSRIs and DFTs of the two waveforms (10-V stimulus: r = -0.62, P < 0.05; 16-V stimulus: r = -0.75, P < 0.01).. Modulation of defibrillation efficiency by E-4031 infusion or by changes of the shock waveform was related to the effect of these interventions on PSRI. These results suggest an independent role for the refractoriness of nondepolarized myocardium in the mechanism of defibrillation.

Topics: Animals; Anti-Arrhythmia Agents; Dogs; Electric Countershock; Electric Stimulation; Heart; Piperidines; Pyridines; Refractory Period, Electrophysiological; Ventricular Fibrillation

Topics: Anesthetics, Local; Animals; Anti-Arrhythmia Agents; Cats; Dogs; Electrocardiography; Female; In Vitro Techniques; Lidocaine; Male; Piperidines; Rabbits; Rana ridibunda; Rats; Rats, Wistar; Ventricular Fibrillation

Arrhythmias induced by coronary artery ligation in cats, by CaCl2 and epinephrine in rats, and by ouabain in guinea-pigs were used as experimental models for studying the effects of a new calcium antagonist AR-1 ([1,2,5-trimethyl-4-phenyl-4-beta-(N-cyanoethyl-N-4'-methoxybenzyl) -ethylamino]piperidine, calcium channel blocker and calmodulin antagonist) on ventricular arrhythmias. Coronary ligation caused 90% lethality (ventricular fibrillation) with 12.5 min in untreated control cats, which was prevented by administration of AR-1 (4 mg/kg body weight (b.w.) before or after arrhythmia induction. Pretreatment with AR-1 afforded protection in a dose-related fashion. A dose of 1.5 mg/KG b.w. increased survival to 45%, and all cats dosed with 3 to 5 mg/Kg b.w. survived. CaCl2 (180 mg/Kg b.w., i.v.) induced ventricular fibrillation and 100% lethality. These effects were completely prevented by an anti-arrhythmic dose of AR-1 (3 mg/kg b.w.). Epinephrine-induced ventricular arrhythmias were also prevented by the same dose of AR-1. AR-1 (5 mg/kg b.w.) did not prevent ouabain (0.5 mg/kg b.w.)-induced arrhythmias that caused death within 17 +/- 3.7 min, but displayed protective effects during 67 +/- 7.7 min. The results from these animal studies, in conjunction with previously studies demonstrating coronarodilatory and anti-platelet efficacy of this compound, collectively suggest that AR-1 has a potential to become a useful antianginal and antiarrhythmic therapeutic agent.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channel Blockers; Calcium Chloride; Cardiovascular Agents; Coronary Vessels; Electrocardiography; Epinephrine; Male; Ouabain; Piperidines; Rats; Rats, Wistar; Tachycardia, Ventricular; Ventricular Fibrillation

We investigated the antiarrhythmic effects of bidisomide (SC-40230), a new class I antiarrhythmic drug, in early-phase ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats. The effects of bidisomide were compared with those of mexiletine (MXT) and disopyramide (DSP), established class I antiarrhythmic drugs. Drugs were administered intravenously, 5 min before induction of coronary occlusion. Bidisomide (5 mg/kg) reduced the number of premature ventricular complexes and the incidence of ventricular tachycardia and ventricular fibrillation similarly to MXT and DSP in rats with ventricular arrhythmias induced by coronary artery occlusion. In rats with ventricular arrhythmias induced by coronary artery reperfusion following a 5-min coronary occlusion, the antiarrhythmic effects of 5 mg/kg of bidisomide were similar to those of the same doses of MXT and DSP. All three drugs significantly slowed the heart rate. Our results suggest that bidisomide may effectively reduce the severity of life-threatening ventricular arrhythmias that occur during acute coronary syndrome.

Topics: Animals; Anti-Arrhythmia Agents; Blood Pressure; Cardiac Complexes, Premature; Coronary Disease; Disopyramide; Heart Rate; Male; Mexiletine; Myocardial Reperfusion Injury; Piperidines; Rats; Rats, Sprague-Dawley; Tachycardia, Ventricular; Ventricular Fibrillation

We compared the effects of class I-IV antiarrhythmic agents on the ventricular fibrillation threshold (VFT) induced by electrical stimulation directly on the myocardium in anesthetized, open-chest guinea pigs. VFT was assessed by determining the intensity (mA) of electrical current required to induce ventricular fibrillation (VF) and is expressed as a percentage change of the baseline premedication value. The following antiarrhythmic agents or their solvent were administered intravenously (i.v.) to pentobarbital-anesthetized animals (n = 6-12 per group): class I antiarrhythmic agent encainide (1.5 mg/kg); class II antiarrhythmic agents atenolol (2.5 mg/kg), metoprolol (2.5 mg/kg), and nebivolol (2.5 mg/kg); class III antiarrhythmic agents dofetilide (0.08 mg/kg), terikalant (0.04 mg/kg), and DL-sotalolol (10 mg/kg); and class IV antiarrhythmic agent verapamil (0.16 mg/kg). The antiarrhythmic compounds or their solvents resulted in the following changes in the VFT at 15 min after treatment: saline control, 1 +/- 14% (mean +/- SEM) from its baseline value; 10% hydroxypropyl-beta-cyclodextrine (CD), 4 +/- 13%; encainide, 183 +/- 46% (p < 0.05 vs. saline); atenolol, 66 +/- 23% (p > 0.05 vs. saline); metoprolol, 89 +/- 25% (p > 0.05 vs. saline); nebivolol, 224 +/- 58% (p < 0.05 vs. 10% CD); DL-sotalol, 485 +/- 119% (p < 0.05 vs. saline); dofetilide, 357 +/- 69% (p < 0.05 vs. saline); terikalant, 487 +/- 183% (p < 0.05 vs. saline), and verapamil, -17 +/- 21% (p > 0.05 vs. saline). At the doses used, all compounds significantly reduced heart rate (HR).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Atenolol; Benzopyrans; Chromans; Disease Models, Animal; Electric Stimulation; Electrocardiography; Encainide; Ethanolamines; Guinea Pigs; Heart; Heart Conduction System; Injections, Intravenous; Male; Metoprolol; Nebivolol; Phenethylamines; Piperidines; Sotalol; Sulfonamides; Ventricular Fibrillation; Verapamil

The cardioprotective effect of R56865, an Na(+)- and Ca(2+)-overload inhibitor, was studied in 20 regionally ischemic reperfused (I/R) porcine hearts. Ten pigs were treated with a single intravenous (i.v.) injection of 0.4 mg/kg 15 min before occlusion of the distal left anterior descending coronary artery (LAD) for 45 min. Ten other animals served as controls. Infarct size (IS) was determined as percentage of infarcted (tetrazolium method) to ischemic (dye technique) myocardium after 24-h reperfusion. Regional systolic shortening (SS) was determined by sonomicrometry. Fifteen minutes after i.v. administration of R56865, a significant decrease in heart rate (HR) (from 83 +/- 15 to 74 +/- 16 beats/min), dP/dtmax (from 2,033 +/- 604 to 1,822 +/- 524 mm Hg/s), LAD blood flow (BF, from 17 +/- 7 to 14 +/- 7 ml/min), and calculated global myocardial O2 consumption (MVO2) (from 5.9 +/- 0.9 to 5.4 +/- 0.9 ml O2/min x 100 g) was observed. Although this investigational drug attenuated the increase in HR during early reperfusion, the incidence of ventricular fibrillation (VF) was not affected during either ischemia or reperfusion. R56865 reduced IS by 24% from 67.1 +/- 16% (control group) to 50.8 +/- 13%. In addition, this treatment improved systolic shortening after 24-h reperfusion from 6 +/- 8% (control group) to 15 +/- 9%. Our results support the concept that inhibition of intracellular Na(+)- and Ca(2+)-overload is a promising new principle in treatment of myocardial I/R.

Topics: Animals; Benzothiazoles; Blood Pressure; Calcium; Calcium Channel Blockers; Coronary Circulation; Female; Heart Rate; Injections, Intravenous; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Oxygen Consumption; Piperidines; Sodium; Sodium Channel Blockers; Swine; Thiazoles; Ventricular Fibrillation

RP58866 (1-[-2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4- (3,4-dimethoxyphenyl)-piperidine), a specific blocker of the inwardly rectifying K+ current (IK1), is an extremely effective antiarrhythmic agent in rat, rabbit and primate (marmoset) isolated hearts in the settings of acute ischaemia and reperfusion (Rees and Curtis, 1993a). In the present study we further examined the mechanism of action of RP58866. We used the new dual coronary perfusion cannula that allows left and right sides of the heart to be perfused independently. The model has not previously been used for pharmacological investigations. Isolated rat hearts (n = 112) were randomized to one of four groups: perfusion of the left and right coronary beds with drug-free solution (n = 28), perfusion of the left coronary bed with 3 mumol/l RP58866 (n = 28), perfusion of the right coronary bed with 3 mumol/l RP58866 (n = 28) or perfusion of left and right coronary beds with 3 mumol/l RP58866 (n = 28). After 5 min perfusion, left regional ischaemia was induced and maintained for 30 min. Regional coronary flow was measured by in-line flowmeters. Epicardial monophasic action potentials (MAP) were recorded from the left (n = 15/group) and right (n = 13/group) perfusion regions using a suction electrode. Delivery of RP58866 to the uninvolved zone (right perfusion bed) suppressed ischaemia-induced ventricular fibrillation (VF): incidences (%) of VF were 80, 60, 33 (P < 0.05) and 27% (P < 0.05) in groups with no drug, with RP58866 delivered to the left bed, with RP58866 to the right bed and with RP58866 to the left plus right beds, respectively. Protection correlated with widening of MAP duration in the uninvolved zone which at 100% repolarization was 130.6 +/- 8.0, 129.1 +/- 7.0, 155.8 +/- 6.5 (P < 0.05 versus control) and 155.3 +/- 8.7 (P < 0.05) in the four groups, respectively after 5 min of ischaemia (just prior to the onset of ventricular arrhythmias). Corresponding values recorded from the involved zone (left perfusion bed) were 102.6 +/- 7.8, 131.2 +/- 11.1 (P < 0.05), 138.2 +/- 11.6 (P < 0.05) and 147.1 +/- 8.9 ms (P < 0.05), suggesting that RP58866 may gain access to ischaemic tissue via collatoral flow from the right perfusion bed. In order to suppress ischaemia-induced VF, it appears that the IK1 blocker RP58866 must widen APD in uninvolved tissue. APD widening activity restricted to the involved tissue alone is insufficient to prevent VF. However, caution should be exercised when using the

Topics: Animals; Anti-Arrhythmia Agents; Chromans; Coronary Circulation; Male; Myocardial Ischemia; Perfusion; Piperidines; Potassium; Potassium Channels; Rats; Rats, Wistar; Ventricular Fibrillation

The electrophysiologic and antifibrillatory properties of NE-10064 were studied in vivo in a conscious canine model of sudden cardiac death. Purpose bred male mongrel dogs weighing 14.5-21.5 kg were anesthetized, and surgical anterior myocardial infarction (MI) was induced by a 2-h occlusion, with reperfusion, of the left anterior descending coronary artery (LAD). Three to 5 days after induction of anterior wall MI, animals were subjected to testing by programmed electrical stimulation (PES). As compared with predrug incidence (12 of 12), NE-10064 (10 mg/kg intravenously, i.v.) reduced (p < 0.05) the incidence (8 of 12) of PES-induced ventricular tachycardia (VT). All but 1 control animal remained inducible after vehicle (5% dextrose in water). The cycle length of induced VT was not prolonged by NE-10064 (0.245 +/- 0.046 s predrug vs. 0.301 +/- 0.060 s postdrug). NE-10064 increased ventricular effective refractory period (VERP 166 +/- 5 ms predrug vs. 194 +/- 13 ms postdrug, p = 0.013), prolonged QTc interval (310 +/- 12 ms predrug vs. 350 +/- 16 ms postdrug, p = 0.004) and prolonged the effective refractory period (ERP) of noninfarcted myocardium (p = 0.045). The drug did not affect ECG-indexes of conduction velocity: QRS and P-R intervals were not affected, nor were activation delay and conduction time of noninfarcted and infarcted myocardium. In the sudden cardiac death protocol, NE-10064 protected (p = 0.018) against ischemia-induced ventricular fibrillation (VF, 75% survival with drug vs. 25% survival without drug). NE-10064 afforded protection (p = 0.040) throughout 14 h posterolateral ischemia in the presence of the previous anterior infarct.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Arrhythmia Agents; Death, Sudden, Cardiac; Disease Models, Animal; Dogs; Electric Stimulation; Electrocardiography; Electrophysiology; Heart Rate; Hydantoins; Imidazoles; Imidazolidines; Male; Myocardial Infarction; Piperazines; Piperidines; Tachycardia, Ventricular; Ventricular Fibrillation

We investigated the effects of the ATP-dependent K+ channel antagonist glyburide and the ATP-dependent K+ channel agonist pinacidil in a Langendorff-perfused rabbit isolated heart subjected to a period of global hypoxia. A class III antiarrhythmic drug, E-4031, also was studied in this model. These studies aimed to define the mechanism of action of putative profibrillatory actions of pinacidil and the mechanism for the antifibrillatory effect of the class III antiarrhythmic drug, E-4031, in the hypoxic heart. After stabilization and determination of baseline functional parameters under normoxic perfusion conditions (95% O2/5% CO2), hearts were subjected to global hypoxia by switching to a 95% N2/5% CO2 saturated perfusion medium for a period of 12 min. After the hypoxic period, normoxia was re-established by switching to the oxygen-carbon dioxide saturated buffer medium for a period of 40 min. The oxygen tension of the perfusion buffer was reduced from approximately 400 mm Hg to below 50 mm Hg during the hypoxic period. All hearts subjected to hypoxia had reduced function: the left ventricular developed pressure and +/- dP/dt were reduced significantly. Myocardial tissue ATP concentrations were reduced (> 50%) in hearts subjected to hypoxia. Under conditions of hypoxic/reoxygenation and in the presence of a low (2.5 mM) potassium concentration ([K+]0), pinacidil (1.25 microM) facilitated the induction of ventricular fibrillation (80% fibrillation in the presence of pinacidil vs. 20% in the absence of pinacidil). Glyburide (10 microM) and E-4031 (1 and 10 microM) significantly reduced the incidence of ventricular fibrillation associated with pinacidil (20% fibrillation in the presence of hypoxia, pinacidil, and glyburide or 10 microM E-4031). Opening of the ATP-dependent K+ channel by pinacidil under normoxia and low K+ also facilitated the induction of ventricular fibrillation (60% ventricular fibrillation). Pinacidil failed to induce ventricular fibrillation under either normoxic or conditions of hypoxic/reoxygenation when the [K+]0 was increased to 5.1 mM. The results of this study demonstrate that K+ channel activators facilitate the induction of ventricular fibrillation under both normoxic conditions and conditions of hypoxic/reoxygenation when the perfusion buffer K+ concentration is reduced.

Topics: Adenosine Triphosphate; Animals; Anti-Arrhythmia Agents; Antihypertensive Agents; Blood Pressure; Guanidines; Heart; Hemodynamics; In Vitro Techniques; Myocardial Contraction; Myocardium; Oxygen Consumption; Pinacidil; Piperidines; Potassium; Potassium Channels; Pyridines; Rabbits; Ventricular Fibrillation

Bidisomide is a Class Ia/Ib antiarrhythmic agent with activity against ventricular and supraventricular arrhythmias. The potential for bidisomide to increase defibrillation threshold (DFT) was tested in anesthetized dogs with healed left ventricular infarcts (> or = 10 days). Defibrillation patches were attached to each ventricle and shocks were delivered via an external cardioverter/defibrillator. Three groups were studied: placebo (saline), canine therapeutic bidisomide (TB, 2-5 micrograms/mL plasma concentration) and supratherapeutic bidisomide (STB, 6-14 micrograms/mL). Each animal received only one treatment. An abbreviated DFT curve was determined before and after treatment. Heart rate, blood pressure, PR, QRS, infarct size, and hematocrit were also measured before and after treatment. DFT was significantly increased (average +3 to +5 joules [J], P < 0.05) by TB and STB. TB (5/5) did not increase DFT beyond 40 J. In 6/7 experiments, STB did not increase DFT beyond 40 J. Placebo (n = 6) had no significant effect on DFT. Infarct size (mean = 11% of the left ventricle) was not significantly different between groups. Heart rate and QRS were not significantly altered but blood pressure was significantly decreased (16%-31% systolic, 29%-45% diastolic) and hematocrit was significantly increased (19% to 25%) in all groups. PR was significantly increased by STB only.. therapeutic and supratherapeutic doses of bidisomide slightly but significantly increased DFT (3-5 J) in a canine infarcted heart model.

Topics: Animals; Anti-Arrhythmia Agents; Blood Pressure; Dogs; Electric Countershock; Electrocardiography; Heart Rate; Myocardial Infarction; Piperidines; Ventricular Fibrillation

The antifibrillatory effects of flecainide 1 mg/kg + 0.05 mg/kg/min intravenously (i.v.), bretylium 6 mg/kg i.v., D-sotalol 2 mg/kg + 0.1 mg/kg/min i.v., and E-4031, a new class III drug, 50 micrograms/kg + 5 micrograms/kg/min i.v. were compared with three different methods of determining ventricular fibrillation threshold (VFT) in anesthetized open-chest dogs. In protocol 1, VFT was determined with 2-S, 50-Hz continuous pulses. Flecainide (n = 7) prolonged intraventricular conduction time (CT) and ventricular effective refractory period (ERP) and increased VFT significantly. Bretylium (n = 6) prolonged ERP slightly, but did not increase VFT significantly. Both D-sotalol (n = 6) and E-4031 (n = 6) prolonged ERP and increased VFT. In protocol 2, VFT was determined with the extrastimulus technique in dogs, with localized ventricular necrosis produced with protease. Flecainide (n = 10), D-sotalol (n = 8), and E-4031 (n = 8) restored VFT, which had been decreased by protease injection, to the baseline level, whereas bretylium (n = 8) did not. In protocol 3, the train pulse method with 100-Hz train pulses covering the vulnerable period was used in the same dogs used for protocol 2. Flecainide, bretylium, and D-sotalol increased VFT, but E-4031 did not. The antifibrillatory effects of class III drugs differ depending on the method of VFT determination. The present data suggest that the antifibrillatory effects of antiarrhythmic drugs should be assessed by different methods of VFT determination.

Topics: Analysis of Variance; Animals; Anti-Arrhythmia Agents; Bretylium Compounds; Dogs; Electric Stimulation; Flecainide; Heart Conduction System; Piperidines; Pyridines; Sotalol; Ventricular Fibrillation

The effectiveness of blockade of the inwardly rectifying K+ current (IK1) in prevention of arrhythmias is unknown. We have examined the antiarrhythmic potential of a new selective IK1 blocker, RP58866, in rat, rabbit, and primate (marmoset) isolated hearts in the settings of acute ischemia and reperfusion.. In concentration-response studies (n = 12 per group), the drug reduced ischemia-induced ventricular fibrillation (VF) in rat from control incidence of 100 to 50%, 17% (p < 0.05), and 0% (p < 0.05) at 1, 3, and 10 mumol/L, respectively. RP58866 produced significant bradycardia at the 3- and 10-mumol/L concentrations and significant QT interval widening at all three concentrations (p < 0.05). When rat hearts (n = 12 per group) were paced (5 Hz) via the left atrium to prevent bradycardia, the antiarrhythmic effects of 10-mumol/L RP58866 were unmodified (ischemia-induced VF incidence was reduced by drug from 83% in control hearts to 8%; p < 0.05). Similarly, pacing did not prevent the drug's QT-widening activity at 90% repolarization (QT90 was 64 +/- 3 msec in control hearts versus 128 +/- 17 msec in the presence of 10 mumol/L of drug after 10 minutes of ischemia; p < 0.05). These values are similar to equivalent values in unpaced hearts (65 +/- 3 msec in control hearts versus 159 +/- 15 msec with 10 mumol/L of drug; p < 0.05). In separate groups of rat hearts (n = 10 per group) subjected to 10 minutes of ischemia, reperfusion-induced VF incidence was reduced from 90% in control hearts to 10% (p < 0.05), 0% (p < 0.05), and 0% (p < 0.05) by 1-, 3-, and 10-mumol/L RP58866. To examine whether drug actions were species-specific, we performed further studies in rabbit and primate using the middle concentration of RP58866 (3 mumol/L). Ischemia-induced VF incidence was too low in these species to assess the effects of the drug. However, RP58866 widened QT interval (p < 0.05), slowed heart rate (p < 0.05), and reduced the incidence of reperfusion-induced VF from 67% to 8% (p < 0.05) in rabbit. Furthermore, in the more clinically relevant primate species (marmoset; n = 9-12 per group), RP58866 (3 mumol/L) abolished ischemia-induced VT (36% incidence in control hearts; p < 0.05) and significantly reduced the incidence of ischemia-induced ventricular premature beats from 91% to 33% (p < 0.05). The drug was also effective against reperfusion VF in primates (incidence reduced from 64% in control hearts to 11%; p < 0.05). As in rat and rabbit, RP58866 significantly widened QT interval in primate and caused bradycardia before and during ischemia. RP58866 had no significant influence on coronary flow in any species. Finally, in further studies on rat, QT widening by RP58866 was found to persist relatively unmodified in nonischemic hearts perfused with solution containing K+. RP58866, a selective IK1 blocker, is a potent and efficacious new antiarrhythmic drug in ischemia and reperfusion in rat, rabbit, and primate. When tested in rat, pharmacological activity was undiminished by cardiac pacing or elevation of extracellular K+.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Callithrix; Cardiac Pacing, Artificial; Chromans; Electrocardiography; Heart; Male; Myocardial Reperfusion Injury; Piperidines; Potassium Channels; Rabbits; Rats; Rats, Wistar; Tachycardia, Ventricular; Ventricular Fibrillation

Previous studies in isolated ventricular myocytes showed that WAY-123,398 is a selective blocker of the delayed rectifier K+ current (IK). In this report, we studied the electrophysiological and hemodynamic effects of WAY-123,398 in open-chest anesthetized dogs. WAY-123,398 prolonged atrial and ventricular refractoriness without affecting conduction; WAY-123,398 was as effective as UK-68798, E-4031, and dl-sotalol, but less potent than UK-68798 and E-4031. The increase in atrial refractoriness was approximately twice as large as the ventricular increase with all compounds. The hemodynamic effects of WAY-123,398 were similar to those of UK-68798; at the ED20 for increasing ventricular refractoriness, WAY-123,398 did not affect the mean arterial pressure and decreased the heart rate by 20%. In a different series of experiments, all four compounds produced large and comparable increases in the ventricular fibrillation threshold in anesthetized dogs; WAY-123,398 and UK-68798 induced defibrillation and restoration of sinus rhythm in two of six dogs each and E-4031 in one of six dogs. No episodes of drug-induced restoration to sinus rhythm were observed in dogs treated with sotalol or vehicle. In conclusion, WAY-123,398 is an effective Class III agent without Class I actions and with a favorable hemodynamic profile.

Topics: Anesthesia; Animals; Anti-Arrhythmia Agents; Atrioventricular Node; Benzimidazoles; Dogs; Electrocardiography; Electrophysiology; Female; Heart; Heart Conduction System; Hemodynamics; In Vitro Techniques; Male; Phenethylamines; Piperidines; Purkinje Fibers; Pyridines; Refractory Period, Electrophysiological; Sotalol; Sulfanilamides; Sulfonamides; Ventricular Fibrillation

Class III antiarrhythmic agents such as E-4031 have demonstrated efficacy in preventing and/or terminating malignant ventricular arrhythmias in experimental models. It has recently been suggested that Class III agents might possess additional antiischemic properties that may translate into a reduction in the frequency or severity of arrhythmia. The potential for the Class III antiarrhythmic agent E-4031 to limit the extent of developing myocardial infarction was assessed in a barbiturate-anesthetized canine model of ischemic-reperfusion injury. Untreated control (n = 13) and E-4031-treated animals (n = 8, 300 micrograms/kg, i.v., immediately preceding myocardial ischemia) were subjected to a 90-min period of left circumflex coronary artery occlusion followed by a 5-h period of reperfusion. The predominant hemodynamic effect displayed by E-4031 was a reduction in heart rate throughout the period of coronary artery occlusion and early reperfusion. Areas at risk of infarction, expressed as percentages of left ventricle, were equivalent in the control and E-4031 treatment groups (38.5 +/- 1.0 and 34.6 +/- 1.9%, respectively). Posterolateral myocardial infarct sizes, expressed either as percentages of risk area or of total left ventricle, were reduced slightly but not significantly in the E-4031 treatment group compared to the control group (35.2 +/- 5.6 and 45.4 +/- 3.0% of risk area, respectively; 12.7 +/- 2.4 and 17.6 +/- 1.4% of left ventricle, respectively). Regional myocardial blood flows in nonischemic and central ischemic zones of myocardium did not differ significantly between the control and E-4031 treatment groups before and during the period of coronary artery occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Arrhythmia Agents; Coronary Circulation; Dogs; Female; Hemodynamics; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Piperidines; Pyridines; Ventricular Fibrillation

In a perfused guinea-pig heart model of myocardial ischaemia, reducing coronary flow by 95% for four successive 6 min periods caused a reproducible net loss of K+ into the coronary perfusate. This was reduced in a concentration-dependent manner by ATP dependent K+ channel blockers (glibenclamide and glipizide) and calcium channel blockers (verapamil and nifedipine). Other K+ channel blockers (UK-66,914, 4-aminopyridine, R56865 and phentolamine) and beta 1-adrenoceptor and beta 2-adrenoceptor antagonists (betaxolol and ICI118551) did not reduce this loss significantly. A single 30 min low-flow period reliably induced K+ release and ventricular fibrillation in control hearts. Glibenclamide, glipizide and phentolamine suppressed ventricular fibrillation but not ischaemic K+ loss in this model. R56865 and 4-aminopyridine and coadministration of betaxolol and ICI118551 yielded similar results while UK-66,914 suppressed neither. In our model, modulation of ischemic K+ loss and suppression of ventricular fibrillation were not closely associated and appeared to occur via separate mechanisms.

Topics: 4-Aminopyridine; Animals; Anti-Arrhythmia Agents; Benzothiazoles; Calcium Channel Blockers; Disease Models, Animal; Glipizide; Glyburide; Guinea Pigs; In Vitro Techniques; Male; Myocardial Ischemia; Piperidines; Potassium; Potassium Channels; Pyrazines; Pyridines; Sympatholytics; Thiazoles; Ventricular Fibrillation

The threshold dose of ouabain necessary to induce ventricular fibrillation is decreased in sensitized guinea-pigs signalizing an enhanced arrhythmogenicity. Esculetine or WEB 2170 antagonists of histamine and PAF, respectively and especially a combination of both can increase the threshold dose of ouabain-induced fibrillation demonstrating an antiarrhythmic effect. BN 52256 a substance with multi-antagonistic properties shows antiarrhythmic effect in this method, too. WEB 2170 and BN 52256 decrease the incidence of ventricular fibrillation after coronary ligation in rats.

Topics: Anesthesia; Animals; Anti-Arrhythmia Agents; Azepines; Clemastine; Coronary Disease; Coronary Vessels; Guinea Pigs; Organoselenium Compounds; Ouabain; Piperidines; Platelet Activating Factor; Propranolol; Rats; Triazoles; Umbelliferones; Ventricular Fibrillation

The Class III agent E-4031 was evaluated for its antiarrhythmic and antifibrillatory actions in conscious dogs 3-5 days after anterior myocardial infarction that were responsive to the induction of tachyarrhythmia by programmed electrical stimulation. The administration of E-4031 as an intravenous loading dose (100 micrograms/kg) followed by an infusion for 90 min (10 micrograms/kg/min) suppressed the induction of ventricular tachycardia by programmed electrical stimulation in 6 of 12 dogs and prolonged the cycle length of the induced arrhythmia in 5 of the 6 remaining animals. Continued administration of E-4031 in a dose regimen of 1,000 microgram/kg every 2 h provided significant protection (8 of 10 dogs) against the development of ventricular fibrillation (sudden coronary death) within the first hour after the onset of myocardial ischemia in a region of the ventricle remote from the infarct-related vessel. The incidence of sudden coronary death was 80% in a comparable control group of electrically inducible postinfarcted dogs. Increases in ventricular myocardial refractoriness in the paced QT and QTc intervals suggest that Class III electrophysiologic actions contribute to the antiarrhythmic and antifibrillatory actions of E-4031. The findings suggest that E-4031 may be of clinical utility in the prevention of life-threatening arrhythmias in the setting of myocardial ischemia in the postinfarcted heart.

Topics: Animals; Anti-Arrhythmia Agents; Coronary Disease; Death, Sudden; Dogs; Electric Stimulation; Electrocardiography; Electrophysiology; Heart Rate; Male; Piperidines; Pyridines; Ventricular Fibrillation

MDL 11,939 (alpha-phenyl-1-[2-phenylethyl]-4-piperidine-methanol) is a new class III antiarrhythmic agent that was evaluated for antiarrhythmic activity in anesthetized dogs. Intravenous (i.v.) administration of MDL 11,939 (1, 3, and 10 mg/kg) increased left ventricular effective refractory periods. Q-T interval, and Q-Tc in a dose-related way. The effects of MDL 11,939 on ventricular refractoriness were similar to those observed with administration of identical doses of d-sotalol, with the exception that those produced by MDL 11,939 lasted longer. Intraduodenal administration of 10 mg/kg MDL 11,939 also increased left ventricular effective refractory period (LV ERP). The increase in left ventricular refractoriness produced by MDL 11,939 occurred without a significant increase in QRS duration. MDL 11,939 (10 mg/kg i.v.) also protected against induction of ventricular tachycardia (VT) and ventricular fibrillation (VF) induced with programmed electrical stimulation (PES) in anesthetized dogs with chronic 4- to 7-day myocardial infarctions. In comparison, antiarrhythmic effects of bretylium (10 mg/kg i.v.) against PES-induced ventricular arrhythmias were dependent on additional administration of propranolol (0.1 mg/kg i.v.), whereas propranolol alone (0.1 mg/kg i.v.) was ineffective. The results observed with MDL 11,939 are consistent with its in vitro class III antiarrhythmic action and suggest utility for this agent in treatment of VT and VF.

Topics: Animals; Anti-Arrhythmia Agents; Bretylium Compounds; Dogs; Drug Therapy, Combination; Electrocardiography; Electrophysiology; Female; Heart; Heart Ventricles; Male; Piperidines; Propranolol; Tachycardia; Ventricular Fibrillation

A 32-year-old woman with prolapsed mitral valve was treated with flecainide because of an episode of primary ventricular fibrillation. The drug was chosen because several hundred short runs of ventricular tachycardia unrelated to exercise were observed during 24-hour monitoring. Oral medication at a dose of 200 mg twice daily suppressed all repetitive ventricular ectopy. Eighteen months later, however, a further 24-hour recording showed a ventricular arrhythmia which was provoked early in the morning by exercise. Because the tablets were taken late in the evening and early in the morning it was suspected that toxic levels of flecainide may have produced the arrhythmia. Measurement confirmed this suspicion. Reducing the dosage abolished the arrhythmia.

Topics: Adult; Anti-Arrhythmia Agents; Electrocardiography; Female; Flecainide; Heart Ventricles; Humans; Mitral Valve Prolapse; Physical Exertion; Piperidines; Tachycardia; Ventricular Fibrillation

The antiarrhythmic agent flecainide acetate was resolved by fractional crystallization of its diastereomeric alpha-bromocamphor-pi-sulfonate salts. Optical purity of the two enantiomers was shown to be greater than 99% by an NMR technique using the chiral shift reagent Eu(hfbc)3. Antiarrhythmic effects of flecainide and its enantiomers were assessed in two different animal models, chloroform-induced ventricular fibrillation in mice and ouabain-induced ventricular tachycardia in dogs. The two enantiomers were highly effective in suppressing both of these experimental arrhythmias and appeared to be essentially equipotent. No significant differences were found either between the two enantiomers or between the enantiomers and racemic flecainide.

Topics: Animals; Anti-Arrhythmia Agents; Chloroform; Dogs; Female; Flecainide; Magnetic Resonance Spectroscopy; Mice; Ouabain; Piperidines; Stereoisomerism; Tachycardia; Ventricular Fibrillation

Fifty patients with drug-refractory (failed 7 +/- 2 other drug trials) sustained ventricular tachycardia or fibrillation were treated with oral lorcainide. Twenty-three patients underwent programmed stimulation both before and after oral lorcainide, and all 23 remained inducible, although ventricular tachycardia cycle length was prolonged and mean arterial pressure was higher. Lorcainide was discontinued in 23 patients prior to hospital discharge because of death in four patients, side effects in five patients, spontaneous clinical arrhythmia recurrence in six patients, and ventricular tachyarrhythmias induced at electrophysiologic study in eight patients. Twenty-seven patients were discharged on an average dose of 169 +/- 56 mg twice a day, including 15 in whom ventricular tachycardia remained inducible. During long-term follow-up the drug was discontinued in 15 patients; three because of side effects, three because of clinical nonfatal arrhythmia recurrence, two who selected other alternative therapy, and seven patients who died suddenly due to ventricular tachyarrhythmias. Twelve patients remain on long-term lorcainide. The actuarial 1-year chance of being arrhythmia free was 38.9%, and 1-year cardiovascular and arrhythmia survival rates were 56.8% and 60.4%, respectively. Based on our data we conclude that: In this extremely drug-resistant patient population the clinical efficacy of lorcainide is low; lorcainide should not be used empirically in such highly drug-resistant patients; persistent ventricular tachyarrhythmia inducibility at electrophysiologic study implies a poor prognosis in patients treated with oral lorcainide; the incidence of becoming noninducible during oral lorcainide therapy in highly drug-resistant patients appears low; and for patients in whom the drug seems partially beneficial it could be used in conjunction with a backup automatic implantable cardioverter/defibrillator.

Topics: Administration, Oral; Benzeneacetamides; Cardiac Pacing, Artificial; Humans; Male; Middle Aged; Piperidines; Tachycardia; Ventricular Fibrillation

Twenty-two patients with coronary artery disease and spontaneous ventricular tachycardia (VT) or ventricular fibrillation (VF) underwent intracardiac electrophysiologic evaluation and, when possible, ambulatory monitoring before and after therapy with flecainide (mean dose 418 +/- 87 mg [mean +/- standard deviation]). An average of 4 antiarrhythmic agents were used and were unsuccessful before therapy with flecainide was begun. During 64 +/- 16 hours of control Holter monitoring in 16 patients, all had 1 or more salvos of VT, as well as ventricular premature complexes (VPCs). Programmed stimulation during the control period induced VT in 17 of 22 patients. After flecainide therapy, Holter monitoring showed elimination of all forms of VT in all but 1 patient, as well as significant reduction of paired VPCs by 95% (p less than 0.03) and single VPCs by 70% (p less than 0.005). Electrophysiologic study during flecainide therapy showed significant increases in AH, HV, PR, QRS and QTc intervals, and the ventricular effective refractory period. Programmed stimulation in 17 patients taking flecainide, with a mean plasma level of 1,075 +/- 521 ng/ml, showed ablation of inducible VT in only 2 patients, a worsening in 5 and continued VT inducibility in 10. Adverse effects that required drug withdrawal were infrequent and encountered in patients who received higher drug levels: 1 patient with congestive heart failure and 1 with severe sinus bradycardia. Thus, although flecainide suppresses complex ventricular arrhythmias on Holter recordings, it rarely alters the response to programmed stimulation. Caution is recommended in its use for recurrent sustained VT or VF and in the interpretation of electrophysiologic studies until the predictive value of programmed stimulation with flecainide therapy is established.

Topics: Adult; Aged; Ambulatory Care; Anti-Arrhythmia Agents; Coronary Disease; Electrocardiography; Female; Flecainide; Follow-Up Studies; Heart Ventricles; Humans; Male; Middle Aged; Monitoring, Physiologic; Piperidines; Tachycardia; Ventricular Fibrillation

Lorcainide, a new antiarrhythmic agent with local anesthetic or membrane-stabilizing properties similar to those of quinidine, was tested in 76 patients with diverse types of heart disease and recurrent ventricular tachycardia or ventricular fibrillation. Lorcainide was administered for 72 to 96 hours in a dose ranging from 200 to 400 mg daily. Evaluation of drug efficacy involved ambulatory monitoring and exercise stress testing in 60 patients who had high grade ventricular arrhythmia. Invasive electrophysiologic testing was carried out in the remaining 16 patients who exhibited infrequent ventricular ectopic activity during control studies. Lorcainide was effective in 21 (38%) of 56 patients evaluated for suppression of ventricular ectopic activity and in 6 (40%) of 15 who had invasive testing. In five patients, the drug was discontinued because of toxic reactions. Thus, 27 (38%) of the 71 patients who completed the drug study responded to lorcainide. Side effects, reported by 42 patients (55.3%), consisted primarily of insomnia and gastrointestinal symptoms; 7 experienced aggravation of arrhythmia. Fifteen patients were discharged while receiving lorcainide therapy, but in four the treatment was discontinued after 2 months because of side effects. Three patients died, one suddenly. It is concluded that lorcainide is of value in a small subset of patients with life-threatening ventricular arrhythmias who have proven refractory to conventional drugs. Its usefulness is limited by the high frequency of insomnia.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Benzeneacetamides; Exercise Test; Female; Humans; Male; Middle Aged; Piperidines; Tachycardia; Ventricular Fibrillation

The effect of flécaïnide (new class I antiarrhythmic) on ventricular rhythm troubles was studied in 24 patients using Holter's method. The following results were obtained. For ventricular tachycardia, two cases of suppression, three cases of distinct reduction in the number and duration of attack and one failure were recorded. For single ventricular extrasystoles, doublets and triplets, nine very good results (80 to 100 per cent reduction of arrhythmia) and four 50 to 80 per cent reductions in ventricular prematurity were obtained. Results were uncertain in two patients as the disappearance of extra-systoles was not followed by relapse after termination of treatment. There were three failures. A twenty-fifth patient was treated with flécaïnide IV followed by oral administration with uncertain results. Undesirable effects are infrequent and are often characterized by sinusal bradycardia. Blurred vision and paraesthesia were encountered. The principal biological parameters remained unchanged.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Female; Flecainide; Humans; Male; Middle Aged; Piperidines; Tachycardia; Ventricular Fibrillation

Repetitive extrasystole and fibrillation thresholds were assessed by various methods of programmed atrial and ventricular stimulation using intracavitary bipolar electrode catheters and a microcomputer based 3-channel stimulator as previously described. "2nd Phase" ventricular arrhythmias were produced by ligation of the left descending coronary artery. 2,5-Bis-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide acetate (flecainide, R 818, Tambocor) caused a significant increase of the atrial and ventricular fibrillation thresholds. The antifibrillatory action was similar in atrial and ventricular tissues. "2nd Phase" ventricular arrhythmias were dose-dependently reduced or abolished completely. Similar doses were required to suppress spontaneous arrhythmic activity and to increase the fibrillation thresholds. Thus, flecainide proved to be a powerful antiarrhythmic agent with strong antifibrillatory properties in therapeutic doses. It may be a promising drug for the treatment of atrial and ventricular reentrant arrhythmias.

Topics: Animals; Anti-Arrhythmia Agents; Cardiac Complexes, Premature; Dogs; Electric Stimulation; Female; Flecainide; Heart; Male; Myocardial Infarction; Piperidines; Ventricular Fibrillation

The effect of a dopamine agonist, bromocriptine, on ventricular fibrillation (VF) threshold was studied in anaesthetised dogs. Bromocriptine produced an increase of 50% in VFT. Pretreatment with the dopamine antagonist haloperidol abolished the effects of bromocriptine on VF threshold as did pretreatment with the peripheral dopamine antagonist, domperidone. It is concluded that bromocriptine reduces vulnerability of the nonischaemic canine ventricle to fibrillation. This effect is most probably mediated by peripheral presynaptic stimulation of dopaminergic receptors, thereby inhibiting noradrenaline release.

Topics: Animals; Benzimidazoles; Bromocriptine; Dogs; Domperidone; Dopamine Antagonists; Female; Haloperidol; Male; Piperidines; Ventricular Fibrillation

11 patients (mean age 52 +/- 16.3 years) with recurrent ventricular tachycardia (VT), in whom VT could be initiated by programmed ventricular stimulation, were studied before and after lorcainide, a new antiarrhythmic agent. Lorcainide was either injected intravenously at a dose of 2 mg/kg within five to ten minutes (n = 3) or infused at a rate of 0.1 mg/kg/min up to the same total dose. After intravenous administration, there was no change in inducibility of VT in three patients, whereas in seven patients VT was either more difficult to induce requiring two instead of one premature beat (n = 2) or a higher rate of basic pacing (n = 2) or VT was no longer inducible (n = 3). In one case, VT was easier to induce. In patients with still inducible VT, the rate of VT decreased from 220 +/- 33 b.p.m. to 186 +/- 49.1 b.p.m. (non-significant). The echo zone for initiation of VT did not show any consistent change. The coupling interval between the last stimulated complex and the first beat of VT increased from 327 +/- 66.8 ms to 390 +/- 98.6 ms (p less than 0.05). The effective refractory period of the right ventricle increased slightly though not significantly. In three cases paradoxical side effects, probably due to lorcainide, were observed. The blood level of lorcainide at the end of injection or infusion immediately before right ventricular stimulation was 0.69 +/- 0.48 micrograms/ml (range 0.11 to 1.74 micrograms/ml). No N-dealkylated metabolite of lorcainide was detected after intravenous injection. Thus far, lorcainide is effective in preventing initiation of VT in some patients making it more difficult to induce in others. However, long-term efficacy and tolerance to the drug cannot be predicted from the data of this study though the data suggest that the drug might be effective on the long-term run against ventricular tachyarrhythmias.

Topics: Benzeneacetamides; Cardiac Pacing, Artificial; Coronary Disease; Heart Failure; Heart Rate; Piperidines; Tachycardia; Ventricular Fibrillation

Topics: Aconitine; Action Potentials; Administration, Oral; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Disease; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Epinephrine; Female; Heart Conduction System; Hemodynamics; Male; Ouabain; Piperidines; Time Factors; Ventricular Fibrillation

The long-term anti-arrhythmic efficacy of lorcainide (R15 889) was studied in 20 ambulatory postmyocardial infarction patients. Lorcainide reduced the frequency of ventricular ectopic beats by more than 70% and 90% in 17 and 11 of the patients respectively. The anti-arrhythmic response improved with long-term administration of the drug. Fourteen patients complained of insomnia during the early stages of the study, but this side-effect waned later on. On electrocardiographic examination, the P-R interval, QTc interval and QRS duration were prolonged, and T-wave changes were noted while the patients were receiving lorcainide. Lorcainide seems to be a useful addition to the available anti-arrhythmic agents, and should form part of the armamentarium against ventricular ectopic activity.

Topics: Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Electrocardiography; Humans; Male; Middle Aged; Myocardial Infarction; Piperidines; Ventricular Fibrillation

Topics: Alkylation; Amides; Animals; Arrhythmias, Cardiac; Diethylamines; Dimethylamines; Disopyramide; Heterocyclic Compounds; Hydantoins; Isomerism; Mice; Piperidines; Quinidine; Structure-Activity Relationship; Urea; Ventricular Fibrillation

Topics: Adrenergic alpha-Antagonists; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzamides; Blood Pressure; Cats; Cell Membrane; Electric Stimulation; Electrocardiography; Female; Hypothermia, Induced; Indoles; Male; Piperidines; Ventricular Fibrillation

Topics: Alkenes; Allyl Compounds; Animals; Anti-Arrhythmia Agents; Anura; Benzyl Compounds; Calcium Chloride; Depression, Chemical; Drug Antagonism; Guinea Pigs; Heart; Heart Atria; Heart Rate; In Vitro Techniques; Isoproterenol; Lethal Dose 50; Lidocaine; Neuromuscular Junction; Norepinephrine; Ouabain; Piperidines; Sciatic Nerve; Ventricular Fibrillation

Topics: Amides; Anesthetics, Local; Animals; Arrhythmia, Sinus; Arrhythmias, Cardiac; Blood Pressure; Cats; Epinephrine; Female; Guinea Pigs; Halothane; Ileum; In Vitro Techniques; Indoles; Lidocaine; Male; Muscle Contraction; Nicotine; Ouabain; Piperidines; Procaine; Propranolol; Quinidine; Tachycardia; Ventricular Fibrillation

Topics: Androstanes; Animals; Bromides; Dogs; Epinephrine; Halothane; Neuromuscular Depolarizing Agents; Piperidines; Ventricular Fibrillation