pyrimidinones and pilsicainide

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

Antiarrhythmic drugs may induce cellular apoptosis in the heart. By using representatives of 5 different categories of antiarrhythmic drugs, that is, pilsicainide, propranolol, nifekalant, verapamil, and amiodarone, we investigated whether these ion channel blockers or beta-antagonists affect cardiac apoptosis in cell cultures. Cultured H9c2 cells were treated with the drugs at varying concentrations. To determine the degree of apoptosis, the percentage of hypodiploid cells, mitochondrial transmembrane potential (DeltaPsi(m)), and activities of caspases were measured quantitatively. At 24 h after administration, only amiodarone induced apoptosis in the H9c2 cells. Amiodarone at a concentration of 14.8 microM or higher decreased DeltaPsi(m) and activated caspase-2 within 3 h of administration, and it caused the appearance of hypodiploid cells and activation of caspases-3 and -9 at 6 h or later. Thus, amiodarone, but none of the other antiarrhythmic drugs tested, possesses a pro-apoptotic effect, mainly via the mitochondrial pathway, suggesting that this effect is distinct from the blocking action of Na+, K+, and Ca2+ channels or the beta-adrenergic receptor. Furthermore, induction of apoptosis in a dose-dependent manner by amiodarone indicates the importance of monitoring the serum concentration in order to avoid its adverse effects.

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Apoptosis; Caspases; Cell Line; Clone Cells; Diploidy; DNA Fragmentation; Dose-Response Relationship, Drug; Lidocaine; Membrane Potentials; Mitochondrial Membranes; Propranolol; Pyrimidinones; Signal Transduction; Time Factors; Verapamil

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