pyrimidinones and Atrial-Fibrillation

Acute coronary syndrome causes several types of arrhythmia because of its electrical instability and ischemia. The most important arrhythmia is ventricular tachycardia which degenerates to ventricular fibrillation. Prompt direct current cardioversion will be needed and prevention of ventricular tachyarrhythmia by potassium channel blocker became more popular in Japan. Nifekalant or amiodarone should be selected. Atrial fibrillation also occurred in the patients with acute coronary syndrome, and it may deteriorate hemodynamics condition. Therefore, termination and prevention of atrial fibrillation is another important issue in acute coronary syndrome. Aprindine, amiodarone, or bepridil will be the choice to prevent recurrent atrial fibrillation after direct current cardioversion.

Topics: Amiodarone; Angina, Unstable; Anti-Asthmatic Agents; Aprindine; Atrial Fibrillation; Bepridil; Electric Countershock; Humans; Myocardial Infarction; Potassium Channel Blockers; Pyrimidinones; Recurrence; Syndrome; Tachycardia, Ventricular; Ventricular Fibrillation

Nifekalant has been used in the treatment of atrial arrhythmia recently. However, there is no consensus on the preferable nifekalant dose to treat atrial fibrillation (AF). The purpose of this study was to explore efficacy and safety of different doses of nifekalant in the cardioversion of persistent AF. The study was a single-centre, randomized controlled trial. All subjects received nifekalant or placebo intravenously, and the nifekalant was given at the dosage of 0.3, 0.4 or 0.5 mg/kg. Primary efficacy end-point: compared with 0.3 mg group, the rate of cardioversion to sinus rhythm from AF in 0.4 and 0.5 mg group was higher. The 0.4 and 0.5 mg/kg doses were associated with a similar magnitude of efficacy (P > .05). Secondary efficacy end-point: termination rates of AF in the group of 0.4 mg and 0.5 mg were higher than 0.3 mg. Primary safety end-point: the rate of Torsades de Pointes or ventricular fibrillation was numerically lower in the 0.4 mg group than 0.5 mg group (P = .02). Secondary safety end-point: The rates of the majority of other common drug-related adverse events in the group of 0.5 and 0.4 mg were higher than the 0.3 mg group. A 0.4 mg/kg dose of intravenous nifekalant may be recommended during the radiofrequency ablation for persistent AF considering the benefit-risk profile.

Topics: Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Electric Countershock; Electrocardiography; Female; Humans; Male; Middle Aged; Pyrimidinones; Radiofrequency Ablation

Additional ablation of complex fractionated atrial electrograms (CFAE) after pulmonary vein isolation (PVI) has been shown to improve the success of ablation of persistent atrial fibrillation (AF). However, extensive ablation is often necessary to eliminate all CFAE or to terminate AF. We assessed the usefulness of the administration of an antiarrhythmic drug (AAD) before CFAE ablation.. One-hundred and ten patients with persistent AF first underwent PVI, roof and floor linear ablation (box isolation). One hundred patients who remained in AF after box isolation were then randomized to either receive (AAD group, n=50) or not receive (no-AAD group, n=50) intravenous nifekalant (0.3mg/kg) followed by a CFAE ablation. In the AAD group, nifekalant terminated AF in 19 (38%) patients and ablation of localized CFAE was performed in 31 patients who remained in AF after nifekalant, and terminated AF in 11 (35%) patients. In the no-AAD group, ablation of CFAE terminated AF in 13 (26%) patients. The AAD group had a significantly lesser number of radio frequency applications at CFAE sites (18 ± 12 versus 36 ± 10, p<0.0001) and shorter procedure time (162 ± 34 versus 197 ± 29 min, p<0.0001) compared with the no-AAD group. However, there was no significant difference in success rate at 12 months after a single ablation procedure between the two groups (AAD group, 74% versus no-AAD group, 76%).. An approach to ablation using nifekalant may be useful in localizing areas of CFAE, reducing the number of applications at CFAE sites and procedure time. Ablation of only CFAE localized with nifekalant may be sufficient for clinical outcome.

Topics: Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Catheter Ablation; Combined Modality Therapy; Electrocardiography; Female; Humans; Male; Middle Aged; Prospective Studies; Pyrimidinones; Treatment Outcome

Antiarrhythmic agents are considered to have significant effects on the defibrillation energy requirement, so this study investigated the effects of nifekalant on defibrillation.. Forty-two patients with persistent atrial fibrillation (AF) underwent electrical cardioversion via intracardiac electrode catheters prior to and after the intravenous administration of nifekalant. The success rate of the defibrillation and change in the defibrillation threshold using sequential incremental defibrillation energy deliveries was investigated. In addition, the parameters that could predict the beneficial effects of nifekalant were also assessed. Nifekalant significantly decreased the defibrillation energy requirement in 13 of the 42 cases, and nifekalant also converted AF to sinus rhythm with an identical energy to that of the last unsuccessful defibrillation in 21 of 42 cases. The success of defibrillation seemed to be dependent on significant prolongation of the intracardiac atrial electrogram intervals during AF by the nifekalant.. Intravenous nifekalant significantly improved the electrical defibrillation efficacy in patients with persistent AF that was resistant to defibrillation, without any serious adverse effects.

Topics: Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Combined Modality Therapy; Electric Countershock; Female; Humans; Male; Middle Aged; Pyrimidinones; Treatment Outcome

Nifekalant for shock-resistant atrial fibrillation.. In severely ill patients, the development of atrial fibrillation (AF) may provoke lethal hemodynamic instability requiring immediate electrical defibrillation, which often is unsuccessful. Using the novel potassium channel blocking agent nifekalant, we prospectively assessed the hypothesis that class III antiarrhythmic drugs facilitate electrical cardioversion and suppress the immediate recurrence of hemodynamically deleterious AF.. Among 1896 adults admitted to the intensive care unit for cardiovascular diseases, hemodynamically destabilizing new-onset AF (systolic blood pressure<90 mm Hg) resistant to conventional electrical cardioversion occurred in 27 patients, and of these, 24 patients (70+/-12 years) were enrolled. Twenty-one patients had congestive heart failure and 11 patients had been mechanically ventilated. After three failed transthoracic cardioversions due to failure of conversion to SR (11 patients) or immediate reinitiation (13 patients), nifekalant (0.25+/-0.04 mg/kg) was administered intravenously, and electrical defibrillation was reattempted. In 18 patients (75%), sinus rhythm was restored and maintained after nifekalant infusion (6 patients) or subsequent transthoracic cardioversion (12 patients). Nifekalant administration significantly decreased the heart rate and increased systolic blood pressure during AF (P<0.001), and successful cardioversion rapidly further ameliorated these parameters (P<0.001). Logistic regression analysis showed that atrial defibrillation failure (relative risk [RR] 19.34, P=0.05) and age of >75 years (RR 15.25, P=0.03) were independent predictors of in-hospital death.. Nifekalant renders electrical defibrillation and the prevention of the early recurrence of hemodynamically unstable AF more successful without deteriorating hemodynamics, and successful defibrillation is associated with a more favorable patient outcome. Pretreatment with other class III drugs, e.g., ibutilide or dofetilide, would also be efficacious in patients with failed urgent electrical cardioversion.

Topics: Aged; Aging; Anti-Arrhythmia Agents; Atrial Fibrillation; Electric Countershock; Female; Hemodynamics; Hospital Mortality; Humans; Male; Middle Aged; Premedication; Prognosis; Pyrimidinones; Secondary Prevention; Treatment Failure; Treatment Outcome

The aim of this study was to prospectively assess the efficacy, safety, and predictive effect of intravenous nifekalant administration for persistent atrial fibrillation (PerAF) after pulmonary vein isolation (PVI) with second-generation cryoballoon ablation (CBA) on 1-year atrial tachyarrhythmia (ATa) -free survival by examining the pharmacological conversion rate.One hundred and two drug-refractory, consecutive PerAF patients undergoing PVI were enrolled in this prospective observational study. After PVI, nifekalant (50 mg) was given followed by 30 minutes of observation and no further intervention. PerAF was successfully converted to sinus rhythm (SR) in 60 patients (58.8%) after a median time of 7.75 (4.13-12) minutes (group N). In the remaining 42 patients (41.2%) (group C), PerAF was successfully converted to SR by external electrical cardioversion. Nonsustained ventricular tachycardia occurred in 1 patient in group N. The left atrial volume (LAV) in group C was larger than that in group N (128.2 ± 28.2 versus 111.8 ± 24.5 mL, P = 0.002). Phrenic nerve injury occurred in 4 of 102 patients (3.9%). No other complications occurred during the procedure or within the 1-year follow-up period. At the 1-year follow-up, after a 3-month blanking period (BP), ATa-free survival during 1-year follow-up in group C was significantly lower than that in group N (50.0% versus 71.7%, P = 0.026), and the overall ATa-free survival rate was 62.7%. Two patients in group C and 4 patients in group N underwent a second procedure with radiofrequency catheter ablation. Multivariate Cox regression analysis demonstrated that unsuccessful conversion to SR (P = 0.025), ATa relapse during the BP (P = 0.000), and larger LAV (P = 0.016) were independent predictors of ATa recurrence at the 1-year follow-up.In conclusion, at the 1-year follow-up, the ATa-free survival rate after PVI with CBA for PerAF patients was 62.7%, and successful conversion to SR with nifekalant could serve as a clinical predictor of reduced ATa recurrence.

Topics: Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Cryosurgery; Electric Countershock; Female; Heart Atria; Humans; Infusions, Intravenous; Intraoperative Care; Intraoperative Complications; Male; Middle Aged; Organ Size; Peripheral Nerve Injuries; Phrenic Nerve; Progression-Free Survival; Prospective Studies; Pulmonary Veins; Pyrimidinones; Recurrence; Tachycardia, Ventricular; Treatment Outcome

Background The efficacy of nifekalant in preexcited atrial fibrillation ( AF ) has not been assessed. Methods and Results The study populations consisted of patients with sustained preexcited AF (n=51), paroxysmal supraventricular tachycardia (n=201), and persistent AF (n=87). Effects of intravenous infusion of nifekalant were assessed on electrophysiological and clinical parameters. Nifekalant prolonged the shortest preexcited R-R, the average preexcited R-R, and the average R-R intervals from 290±35 to 333±44 ms, 353±49 to 443±64 ms, and 356±53 to 467±75 ms, respectively, in patients with preexcited AF (all P<0.001). Nifekalant also decreased the percentage of preexcited QRS complexes, heart rate, and increased systolic pressure (all P<0.001). Nifekalant terminated AF in 33 of 51 patients (65%). Similar effects were also observed in a subgroup of 12 patients with preexcited AF and impaired left ventricular function. In patients with paroxysmal supraventricular tachycardia, nifekalant significantly prolonged the effective refractory period, the block cycle length of the antegrade accessory pathway, and the atrial effective refractory period (all P<0.001). Nifekalant had no effect on the effective refractory period of the antegrade atrioventricular node. Finally, in patients with persistent AF without an accessory pathway, nifekalant did not significantly decrease the ventricular rate of AF . One patient developed Torsades de Pointes. No other adverse effects were observed. Conclusions Nifekalant prolongs the effective refractory period of the antegrade accessory pathway and atrium without blocking antegrade conduction through the atrioventricular node, leading to slowing and/or to termination of preexcited AF . Thus, nifekalant might be an effective and a relatively safe drug in patients with preexcited AF .

Topics: Accessory Atrioventricular Bundle; Adult; Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Female; Humans; Male; Middle Aged; Pyrimidinones; Tachycardia, Supraventricular; Ventricular Dysfunction, Left; Wolff-Parkinson-White Syndrome

Topics: Aged; Atrial Fibrillation; Biopsy, Needle; Crystallization; Follow-Up Studies; Foot; Granuloma; Hand; Humans; Immunohistochemistry; Infusions, Intravenous; Male; Pyrimidinones; Rare Diseases; Risk Assessment

Persistent atrial fibrillation (AF) is characterized by electrical remodeling, ie, marked decreases in the atrial effective refractory period (ERP), ERP rate adaptation, and atrial conduction velocity. Little information is available on the effects of class III antiarrhythmic drugs on the remodeled atrium. We studied the effects of the class III antiarrhythmic drugs nifekalant, ibutilide, and amiodarone on rate-dependent changes in atrial action potential duration in patients with persistent AF. Right atrial (RA) monophasic action potential duration (MAPD) and intra-atrial conduction time (IACT) were measured at pacing cycle lengths (CLs) of 800, 700, 600, 500, 400, 350, 300, and 250 ms before and after administration of nifekalant (0.4 mg/kg + 0.3 mg/kg/hr, iv), amiodarone (5 mg/kg, iv), or ibutilide (0.01 mg/kg, iv) in 31 patients after successful internal cardioversion of chronic AF of > 2 months duration. Nifekalant and ibutilide significantly increased RA MAPD and the ERP at each CL in a reverse rate-dependent manner. Amiodarone did not affect RA MAPD. Nifekalant did not affect IACT, whereas amiodarone increased IACT at each CL in a rate-dependent manner, and ibutilide increased IACT at CLs ≤ 350 ms. The atrial electrophysiologic effects of the class III antiarrhythmic drugs nifekalant, amiodarone, and ibutilide differ, depending on the degree of electrical and structural remodeling and the effects of the drugs on the depolarizing and repolarizing currents.

Topics: Action Potentials; Adult; Aged; Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Cardiac Pacing, Artificial; Female; Heart Atria; Heart Conduction System; Humans; Male; Middle Aged; Pyrimidinones; Sulfonamides

Venous blood draining from the left atrium (LA) flows into the coronary sinus (CS) through the Marshall vein which has no valvular apparatus, thus allowing LA retroperfusion if reflow in the right atrium is hindered. We investigated pharmacologic atrial defibrillation via the CS in dogs with chronic atrial fibrillation (AF). Chronic AF was induced by rapid atrial pacing for 4-16 weeks in 6 mongrel dogs. A 7F occlusion balloon catheter was introduced into the proximal CS. Boluses of low doses of the class Ic antiarrhythmic drug, pilsicainide (2, 4, 6, and 8 mg as needed) or class III antiarrhythmic drug, nifekalant (0.5, 1, 2, and 4 mg) were infused directly within 3-4 seconds at 10 minute intervals into the temporarily balloon occluded CS near its orifice. In 4 of the 5 dogs (balloon catheter could not be placed in the CS in 1 dog), the cumulative dose of 11.5 ± 7.4 mg of pilsicainide was effective in restoring sinus rhythm; the venous concentration of pilsicainide was 1.23 ± 0.79 µg/mL. A cumulative dose of 7.5 mg nifekalant restored sinus rhythm in only 1 of the 6 dogs. Our results in dogs with sustained AF indicate that delivery of a class Ic or III antiarrhythmic drug near the CS ostium via the temporarily occluded CS is feasible and effective for pharmacologic atrial defibrillation; however, the effect may be related to the elevation of the serum concentration of the drug to the therapeutic range rather than to the delivery method itself.

Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Balloon Occlusion; Cardiac Pacing, Artificial; Chronic Disease; Coronary Sinus; Dogs; Drug Delivery Systems; Injections, Intravenous; Lidocaine; Pyrimidinones; Treatment Outcome

We assessed several pharmacological effects on electrocardiogram parameters and effective refractory period (ERP) in a patient with a short QT syndrome (SQTS). Pharmacological challenge tests revealed that disopyramide and selective I(kr) blocker, nifekalant normalized QT interval, and ERP of the atrial and ventricular myocardium. This study suggested that disopyramide and nifekalant should be feasible for the drug treatment of the SQTS. Moreover, QT interval was paradoxically prolonged at higher heart rates induced with isoproterenol infusion or an exercise test, although the mechanism of this QT prolongation remains to be investigated.

Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Body Surface Potential Mapping; Disopyramide; Humans; Male; Pyrimidinones; Syndrome; Tachycardia, Ventricular; Treatment Outcome; Young Adult

Chronic atrial fibrillation (AF) is characterized by a marked decrease in the atrial effective refractory period (ERP) and in the ERP adaptation to rate as well as a decrease in the atrial conduction velocity. Little information is available about the ionic mechanisms underlying AF in humans.. We studied the effect of IKr blocker nifekalant on the rate-dependent changes in atrial action potential duration in 11 patients after successful internal cardioversion of chronic AF of >2 months duration and in 7 patients without AF. In AF patients, right atrial (RA) monophasic action potential (MAP) was recorded at pacing cycle lengths (CLs) of 800-250 ms before and after administration of nifekalant. In control patients, RAMAP was recorded at CLs of 600 and 350 ms before and after administration of nifekalant.. Nifekalant significantly increased RAMAPD at 90% repolarization (RAMAPD90) at CLs of 800-300 ms in the AF patients. The increase in RAMAPD90 by nifekalant became significantly smaller at shorter CLs (42.5 +/- 12.4 ms at a CL of 600 ms vs 32.8 +/- 14.5 ms at a CL of 350 ms, P < 0.05). Effect of nifekalant on RAPMAPD was attenuated at CL of 600 ms in AF patients in comparison to control patients (increase in RAMAPD in control; 73.0 +/- 36.6 ms vs increase in RAMAPD in AF; 42.5 +/- 12.4 ms, P < 0.05); however, it was similar at a CL of 350 ms between control and AF patients.. Electrophysiological effects of nifekalant are significantly attenuated in the chronically remodeled human atrium at slower heart rates, but the beneficial effect of RAMAPD prolongation by IKr blocker was well-preserved even at shorter CLs after chronic AF.

Topics: Action Potentials; Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Chronic Disease; Electric Countershock; Female; Heart Atria; Heart Rate; Humans; Male; Middle Aged; Pyrimidinones; Refractory Period, Electrophysiological

Nifekalant, a class III antiarrhythmic drug, has been shown to suppress ventricular tachyarrhythmias, but its effects on AF are unclear. The aim of this study was to clarify the effects of nifekalant on the atrial vulnerability parameters in patients with paroxysmal AF. The study included 18 patients with paroxysmal AF who underwent electrophysiological study before and after intravenous infusion of nifekalant. The atrial electrophysiological parameters including the atrial effective refractory period (AERP), maximum intraatrial conduction delay, and wavelength index, calculated as the ratio of AERP to the maximum conduction delay, were quantitatively measured at baseline and during nifekalant infusion. The mean AERP was significantly prolonged from 214 +/- 27 ms at baseline to 242 +/- 39 ms after nifekalant (P < 0.001). Although earlier studies have shown that nifekalant does not affect the atrial conduction time, the mean maximum conduction delay of the study patients was significantly prolonged from 59 +/- 19 ms at baseline to 72 +/- 28 ms after nifekalant (P = 0.015). There was no significant difference in the wavelength index at baseline (4.1 +/- 1.7) and after nifekalant (4.1 +/- 2.5). However, when the differences of AERP and wavelength index were defined as each parameter during nifekalant infusion minus that at baseline, the difference of AERP showed a direct positive correlation with that of the wavelength index (P = 0.013). In conclusion, nifekalant may be effective in the prevention of AF due to prolongation of the AERP. However, in those patients who have a lesser degree of prolongation of the AERP by nifekalant, the wavelength index tended to be decreased, suggesting that the drug might augment the propensity for AF.

Topics: Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Atrial Appendage; Atrial Fibrillation; Atrial Function; Bundle of His; Coronary Vessels; Electrocardiography; Electrophysiology; Female; Heart Ventricles; Humans; Infusions, Intravenous; Linear Models; Male; Matched-Pair Analysis; Middle Aged; Pyrimidinones; Refractory Period, Electrophysiological; Time Factors

Topics: Adult; Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Combined Modality Therapy; Defibrillators, Implantable; Electric Countershock; Female; Humans; Male; Potassium Channel Blockers; Pyrimidinones

Nifekalant is a class III antiarrhythmic drug, which prolongs the refractory period of the atrial and ventricular myocardium, without negative inotropic action. Intravenous nifekalant was administered in four patients with atrial tachyarrhythmia and severe heart failure to terminate or prevent atrial tachyarrhythmia.. Two of three episodes of atrial tachyarrhythmia were terminated by intravenous nifekalant (0.22 to 0.30 mg/kg) administration. Continuous intravenous infusion of nifekalant (0.15 to 0.40 mg/kg/hr) during six episodes to maintain the sinus rhythm, prevented recurrence of atrial tachyarrhythmia in five episodes in which prolongation of the QTc interval was observed to more than 450 msec. None of the patients showed worsening of the hemodynamics during treatment. One patient developed polymorphic ventricular tachycardia, which deteriorated into ventricular fibrillation.. Nifekalant may be effective for treating atrial tachyarrhythmia in patients with severe heart failure. Further clinical studies are needed to confirm these findings.

Topics: Adult; Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Female; Heart Failure; Humans; Infusions, Intravenous; Male; Middle Aged; Pyrimidinones; Tachycardia

To compare the effects of class Ic and III antiarrhythmic agents on the termination and prevention of atrial fibrillation, the present study investigated the use-dependent electrophysiological effects of flecainide, nifekalant and d,l-sotalol on the human atrium. Flecainide significantly prolonged effective refractory period (ERP), intra-atrial conduction time (IACT) and monophasic action potential duration (MAPD), and its effects on ERP and IACT were use-dependent. Nifekalalant significantly prolonged ERP and MAPD, and these effects were reverse use-dependent; however, there was no significant change in IACT. d,l-Sotalol significantly prolonged MAPD and the effect was reverse use-dependent. It significantly prolonged ERP, but the effect was not reverse use-dependent. d,l-Sotalol increased IACT in a use-dependent manner. Thus, for atrial fibrillation, class Ic antiarrhythmic agents might be more effective in termination and class III antiarrhythmic agents might be more effective in prevention.

Topics: Action Potentials; Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Function; Cohort Studies; Drug Evaluation; Electrophysiologic Techniques, Cardiac; Flecainide; Heart Atria; Humans; Middle Aged; Pyrimidinones; Sotalol

Effects of class Ic drug pilsicainide and class III drug MS-551 were determined in the canine model of atrial fibrillation (AF) induced under vagal stimulation. Pilsicainide injected intravenously at a dose of 1.0 mg/kg over 3 min terminated AF in six of six dogs. After pilsicainide injection, the effective refractory period (ERP) of the right atrium (RA) increased (104 +/- 22 to 122 +/- 31 ms; p < 0.05), and intraatrial conduction time (CT) increased (24%; p < 0.05) in the RA during vagal stimulation. Wavelength index (WLI; ERP/CT), an estimate of the wavelength for reentry, was decreased slightly but significantly (-2%; p < 0.05) in the RA after pilsicainide. MS-551 injected intravenously at a dose of 0.5 mg/kg over a 3-min period terminated AF in three of eight dogs. An additional dose of 0.5 mg/kg of MS-551 terminated AF in three of the remaining five dogs. After MS-551 injection, ERP increased (100 +/- 30 to 143 +/- 28 ms; p < 0.05), but CT remained unchanged in the RA, and therefore WLI was increased significantly (48%; p < 0.01). Immediately before termination of AF with test drugs, mean AF intervals (FF intervals) increased, whereas the standard deviation of FF intervals did not change significantly. In conclusion, both pilsicainide and MS-551 effectively terminated vagotonic AF after an increase in FF intervals. However, changes in WLI were different between the two test drugs. Vagotonic AF could, therefore, be terminated either by prolongation of ERP or suppression of conduction with antiarrhythmic drugs.

Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Function; Dogs; Electric Stimulation; Female; Lidocaine; Male; Pyrimidinones; Vagus Nerve

It is well known that vagal stimulation increases the vulnerability to atrial fibrillation via muscarinic receptor-mediated shortening of refractory period. Recently it has been reported that some class III antiarrhythmic drugs effectively terminate or prevent atrial flutter and fibrillation by prolonging atrial effective refractory period. However, effects of class III antiarrhythmic drugs on the muscarinic acetylcholine receptor-operated K+ current (IK.ACh), which is important for the repolarization phase of the action potential in atrial cells, have not been thoroughly examined.. Effects of three class III antiarrhythmic drugs, d,l-sotalol, E-4031, and MS-551, on the carbachol (1 mumol/L)-induced action potential shortening and outward K+ current were examined in guinea pig atrial cells by conventional microelectrode and patch clamp techniques. In isolated left atria, d,l-sotalol (100 mumol/L), E-4031 (3 mumol/L), and MS-551 (30 mumol/L) partially reversed the carbachol-induced action potential shortening. In isolated single atrial cells, IK.ACh was activated by extracellular application of carbachol (1 mumol/L) or adenosine (10 mumol/L) or by intracellular loading of GTP gamma S (100 mumol/L). Sotalol (3 to 1000 mumol/L), E-4031 (1 to 100 mumol/L), and MS-551 (1 to 100 mumol/L) inhibited the carbachol-induced IK.ACh in a concentration-dependent manner, and their IC50 (half-maximal inhibition) values were 35.5, 7.8, and 11.4 mumol/L, respectively. However, the GTP gamma S-induced and adenosine-induced IK.ACh were inhibited by high concentrations of E-4031 and MS-551 but not by sotalol.. Sotalol may inhibit IK.ACh by the blockade of the atrial muscarinic receptors, whereas E-4031 and MS-551 may inhibit the current not only by blocking the muscarinic receptors but also by depressing the function of the K+ channel itself and/or G proteins. These drugs may potentially be useful for the prevention and termination of atrial flutter and fibrillation through their inhibitory action on IK.ACh.

Topics: Acetylcholine; Action Potentials; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Atrial Function, Left; Cells, Cultured; Guinea Pigs; Heart Atria; In Vitro Techniques; Myocardial Contraction; Patch-Clamp Techniques; Piperidines; Potassium Channels; Pyridines; Pyrimidinones; Receptors, Muscarinic; Sotalol

To investigate the clinical effects of MS-551, a Class III antiarrhythmic agent, 11 patients underwent electrophysiological study. MS-551 was given intravenously as an initial dose of 0.2 or 0.3 mg/kg for 5 minutes followed by the continuous infusion at 0.2 or 0.3 mg/kg for 30 minutes, respectively, in all patients. The rate corrected QT interval increased significantly from 3 minutes after the beginning of MS-551 infusion. The sinus heart rate decreased significantly by 8% at 10 minutes after the drug administration (P < 0.025). Mean PR and QRS intervals, and blood pressure were not significantly affected by the drug. Mean PA, AH, and HV intervals during sinus rhythm were also not affected. The effective refractory periods (ERPs) of the atrium and ventricle were significantly prolonged by 13% from 202 +/- 24 ms to 231 +/- 26 ms (P < 0.0005), and by 7% from 238 +/- 11 ms to 257 +/- 13 ms (P < 0.002), respectively, by MS-551. The ERP of the atrioventricular node and sinoatrial nodal recovery time were not changed significantly by the drug. This is a report of the effects of MS-551 in humans. This agent could be useful for treatment of tachyarrhythmias by prolongation of ERPs of the atrium and ventricle without significant variations of blood pressure and intracardiac conduction times. It is noteworthy that MS-551 slightly but significantly decreased heart rate.

Topics: Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrioventricular Node; Blood Pressure; Bundle of His; Electrocardiography; Electrophysiology; Female; Heart Atria; Heart Rate; Heart Ventricles; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Middle Aged; Pyrimidinones; Refractory Period, Electrophysiological; Sinoatrial Node; Tachycardia