Electrophysiological effects of Org 7797 in the closed-chest anaesthetized dog.

1. The intravenous electrophysiological effects of a new antifibrillatory agent, Org 7797, were studied in closed chest anaesthetized dogs. Effects of fast sodium and slow calcium-mediated action potentials were also examined in guinea-pig isolated papillary muscle. 2. The major effects of a known antifibrillatory dose of Org 7797 (0.5 mg kg-1) were a protracted slowing of AV nodal conduction (for at least 20 min) and prolongation of the AV nodal functional refractory period. Conduction in the atria and His-Purkinje system (reflected by the St-A and HV intervals) were not significantly modified whilst ventricular conduction (reflected by the QRS interval) and the ventricular functional refractory period were only transiently prolonged. No other electrophysiological changes were seen. 3. A higher dose of Org 7797 (1.5 mg kg-1) slowed conduction at all levels of the myocardium (as evidenced by increases in the St-A, AH, HV and QRS intervals), slightly shortened cardiac repolarization (as assessed from JTc) and decreased Wenckebach rate. Atrial refractory periods were increased whereas effects on ventricular refractory periods were modest. 4. Neither heart rate nor sinus node recovery time were modified by either dose of Org 7797. 5. Org 7797, at a concentration (20 microM) which reduced Vmax of fast sodium-mediated action potentials in isolated papillary muscle by 83%, did not modify Vmax of slow calcium-mediated action potentials. It prolonged duration of the latter but did not modify that of the former. However, the plateau phase of both the 'fast' and especially the 'slow' action potentials was prolonged. 6. It is concluded that the main electrophysiological effects of a known antifibrillatory dose of Org 7797 in dogs with normal cardiac function are seen at the level of the AV node, actions which are unlikely to be explained by calcium channel block. Higher doses display a class Ic profile. This preferential action on the AV node may contribute to the control of ventricular rate during atrial fibrillation in the absence of infra-nodal conduction disturbances.7. These results contrast with those previously obtained in infarcted dogs and might further suggest that myocardial infarction enhances the Class I action of Org 7797.

Comparative antidysrhythmic profiles of bepridil, amiodarone and disopyramide in the guinea-pig and dog.

The antiarrhythmic effects of a novel antianginal agent, bepridil, were compared with four reference products. Bepridil increased the effective refractory period in isolated guinea-pig atria slightly more than hydroquinidine, and much more than disopyramide and lidocaine. Amiodarone was without effect. The doses of bepridil necessary for correcting atrial fibrillation induced by local application of aconitine, were similar for hydroquinidine, higher than for lidocaine and disopyramide but lower than for amiodarone. Bepridil depressed the tachycardia and ventricular fibrillation induced by perfusing aconitine in anesthetized guinea-pigs at doses of the same order of magnitude as for disopyramide and hydroquinidine. Lidocaine only exerted weak activity in this system, while amiodarone was without effect. Bepridil was less active than the four reference products, particularly disopyramide, on rhythm disorders induced by coronary artery ligation.

[Prolongation of the effective refractory period on isolated guinea pig atria by some anti-arrhythmia agents: relevance in a comparison of their potentialities]. / Prolongation de la période réfractaire effective de l'oreillette isolée de cobaye par quelques antidysrythmiques: intérêt d'une comparaison de leurs potentialités.

The effects of bepridil, nifedipine, verapamil, lignocaïne and amiodarone on the atrial effective refractory period were investigated in the guinea-pig. The observed results permitted elucidation of a remarkable activity by both nifedipine and verapamil, and by bepridil and lignocaïne. In contrast, in the experimental conditions, no activity was detected with amiodarone up to concentrations of 10(-4) M. The efficacity rating of the test compounds is not reflected by their anti-arrhythmic efficacity as demonstrated in vivo in the animal, nor by their therapeutic anti-arrhythmic efficacity as reported in the clinical literature. However, this efficacity rating may be related to the interaction of the compounds with the transmembrane sodium or calcium movements.

[Morphine self-administration added to food conditioning: methodological variant in rats]. / Auto-injections morphiniques substituées au conditionnement alimentaire: étude chez le rat d'une variante méthodologique.

Rats with permanent intra-jugular cannula are submitted to an alimentary operant reinforcement schedule with fixed ratio type FR 1, FR5, then FR 20. As a result, the animals are self administering (together with the alimentary inducer) a slow (about 5 sec) intravenous infusion of morphine (0.05 mg/kg). 20 per cent only of the experimental population exhibit a psychogenic dependance afterward. On the other hand, the animals for which morphine self-administration has been substituted to the alimentary reinforcement without respecting a transitory period combining both types of reinforcement have never shown any tendancy toward morphine self-administration. The lack of positive results could be related to the marked duration of the self-injection.

[Creation, in the dog, of a denervated antral pouche, associated with a Heindenhain's pouche: technical considerations relative to surgical time and postoperative complications]. / Création, chez le chien, d'une poche antrale énervée associée à une poche de Heidenhain: considérations techniques relatives au temps chirurgical et aux suites post-opératoires

Overall assessment following the creation of denervated antral and fundic pouches, in 64 mongrel dogs, leads to the recommendation of certain important technical options: surgical intervention carried out in 1 stage; respecting of precise operative timetable; reestablishement of digestive continuity by gastro-jejunostomy with large anastomosis mouth; inutility of scraping the walls of vessels irrigating the pouches.