Electrophysiological effects of bepridil and its quaternary derivative CERM 11888 in closed chest anaesthetized dogs: a comparison with verapamil and diltiazem.

1. The electrophysiological effects of bepridil, its quaternary derivative, CERM 11888 (methylpyrrolidinium bromide) (both 2.5 mg kg-1 i.v.) and those of verapamil and diltiazem (0.2 mg kg-1 i.v.) were studied in closed chest anaesthetized dogs at doses used in clinical studies. 2. The four drugs caused a bradycardia with the following order of potency: bepridil greater than CERM 11888 greater than diltiazem greater than verapamil. 3. All the compounds slowed conduction in the AV node, increased the refractory period (RP) and decreased Wenckebach rates with the following order: verapamil much greater than diltiazem greater than bepridil greater than CERM 11888. 4. Verapamil and diltiazem did not affect conduction or the RP in atria while bepridil weakly slowed the former and markedly increased the latter. CERM 11888 caused a lengthening of RP but this was a delayed effect. 5. In the ventricle, bepridil and CERM 11888 caused a small increase in the QRS and a more pronounced increase in the RP. Both compounds increased QTc but did not modify HV. Verapamil and diltiazem had no significant effects at the ventricular level. 6. Our results confirm that the main sites of action of calcium antagonists are the SA and AV nodes. Bepridil has a broader spectrum of activity and also acts at the atrial and ventricular levels. A comparison of the effects of bepridil with those of its quaternary derivative suggests the involvement of an intracellular action in the electrophysiological effects of bepridil.

Comparative effects of bepridil, its quaternary derivative CERM 11888 and verapamil on caffeine-induced contracture in ferret hearts.

1. The effects of bepridil, its quaternary derivative: CERM 11888 (methyl-pyrrolidinium bromide) (10(-7)-10(-5) M), and verapamil (10(-7)-10(-6) M) were compared on caffeine-induced contracture of isolated ventricular trabeculae of the ferret. 2. Bepridil diminished the amplitude of contracture in a concentration-dependent fashion, and this effect was significantly different from that of CERM 11888 which, like verapamil, only reduced the amplitude at the highest concentration used. 3. Bepridil (10(-6) M) significantly shortened the time to peak tension and accelerated the relaxation phase of contracture. This latter effect was different from that of CERM 11888. Verapamil (10(-6) M) also tended to accelerate the relaxation phase. At 10(-5) M these actions of bepridil on the time to peak and relaxation tended to reverse. 4. At all concentrations bepridil and verapamil reduced the rate of repriming of contracture and this effect of bedpridil was significantly different from that of its quaternary derivative which only showed a significant effect at 10(-5) M. 5. These results demonstrate a clear intracellular effect of bepridil in the ferret heart. Verapamil and CERM 11888 had only weak intracellular effects even at high concentrations. 6. Analysis of the results suggests that the main sites of action of bepridil in this model are the sarcoplasmic reticulum and one or two calcium compartments in the sarcolemma.

[(Arylpiperazino-4-butyryl)-6 benzoxazolinones and reduction products: chemistry and pharmacodynamic study]. / (Arylpipérazino-4 butyrl)-6 benzoxazolinones et preduits de réduction: étude chimique et pharmacodynamique.

The synthesis of various 6-(4-arylpiperazino-butyryl)-3-methyl-benzoxazolinones and their reduction products, 6-(4-arylpiperazino-1-hydroxy-butyl)-3-methyl-benzoxazolinones and 6-(4-arylpiperazino-butyl)-3 methyl-benzoxzolinones, is described. These compounds were tested for psychotropic and analgesic activities.

Electrophysiological effects of the new cardioactive drug CERM 4205: a comparative study in an animal model and in man.

The cardiac electrophysiological effects of CERM 4205, a new cardioactive agent, were studied by means of intracardiac electrodes in man and in anaesthetized dogs. The results show that CERM 4205 is a cardioactive drug with a main inhibitory effect on slow-response structures (sinus and atrioventricular node) with an associated effect on fast-response structures (atrial, His-Purkinje and ventricular tissues). No qualitative differences were observed between the effects observed in man and dogs. In conclusion, the present study confirms that CERM 4205 is a compound with combined class IV and class I electrophysiological effects in dogs and man. The anaesthetized dog appears to be a satisfactory model for the evaluation of the electrophysiological effects of cardioactive drugs.

Comparative effects of bepridil, diltiazem, nifedipine and verapamil on haemodynamic parameters and myocardial oxygen consumption in anaesthetized dogs.

The haemodynamic effects of 4 calcium antagonists, bepridil (1.25 to 5 mg/kg i.v.), diltiazem (0.1 to 0.3 mg/kg i.v.), nifedipine (0.01 to 0.03 mg/kg i.v.) and verapamil (0.1 to 0.3 mg/kg i.v.) were compared in anaesthetized open-chest dogs. The following parameters were measured: sinusal coronary blood flow (SCBF), total coronary vascular resistance (TCVR), aortic blood pressure, heart rate, left dP/dt max, amplitude of right ventricular contraction, double product, myocardial oxygen consumption (MVO2) and arterial and coronary venous blood gases (pO2 and pCO2) and pH. All 4 substances increased SCBF and decreased TCVR. The greatest effects, taking into account relative dose size, were obtained with nifedipine and verapamil. These 2 substances also had the greatest effect on systemic vasodilatation, as reflected by hypotension. The 4 substances had a direct negative chronotropic effect on the myocardium, an effect which was masked by reflex sympathetic stimulation and decreased vagal tone secondary to a drop in blood pressure. The most marked negative chronotropic effects were seen with diltiazem, verapamil and bepridil in that order. Nifedipine and verapamil produced the greatest negative inotropic effects, whereas diltiazem had very little effect on this parameter. The direct consequence of these haemodynamic effects of the 4 substances was to improve oxygenation of the myocardium. The most durable effect on PvO2 was seen with nifedipine and verapamil. The findings demonstrate not only the heterogeneous action of the 4 calcium antagonists, but also the influence of the experimental conditions on the effects obtained with these substances.

Effect of methylated bepridil on slow action potentials in cardiac muscle and vascular smooth muscle.

The anti-anginal agent bepridil blocks slow Ca2+ channels in a variety of tissues. Since bepridil accumulates inside cells, the possibility exists that bepridil acts, at least partially, from inside the cell. To test this possibility, we examined the effects of a quaternary ammonium analog of bepridil, methylated bepridil, which presumably would enter the cells less readily, on the Ca2+-dependent slow action potentials of guinea pig papillary muscles (in 25 mM [K+]0) and rabbit pulmonary arteries (in tetraethylammonium chloride). In cardiac muscle, methylated bepridil had little effect on the slow action potentials at low stimulation frequencies (0.5 Hz), but at higher frequencies (1.0 and 2.0 Hz) the slow action potentials were depressed and/or the muscle was unable to follow each stimulation. These effects are similar to those obtained with bepridil, but bepridil was more potent than methylated bepridil. In vascular smooth muscle cells, methylated bepridil inhibited the slow action potentials at a somewhat lower dose than bepridil. We conclude that, in cardiac muscle, bepridil probably has two sites of action, one outside the cell (presumably on or associated with the slow Ca2+ channel) and a second site inside the cell. On the other hand, in vascular smooth muscle cells, bepridil may act only on an external site.

Effects of bepridil and of its quaternary derivative on rat tail artery.

The effects of bepridil and its quaternary ammonium derivative (BN+) were compared, showing that: (i) both drugs inhibited K+-induced contractions with similar time courses and potencies, (ii) bepridil blocked the tonic but not the phasic component of contractions elicited by noradrenaline, whereas BN+ had no effect on noradrenaline-elicited contractions. These results, and the relative insensitivity of skinned taenia caeci to bepridil, suggest that this drug and BN+ do not act directly on contractile proteins but affect K+- and noradrenaline-induced calcium channel activities differentially.

[Benzoxazolinone phenylethanolamine antagonists of adrenergic receptors. A chemical and pharmacodynamic study]. / Phényléthanolamines benzoxazolinoniques antagonistes des récepteurs adrénergiques. Etude chimique et pharmacodynamique.

Benzoxazolinone can be considered as a bioisosteric analogue of pyrocatechol. This concept has led to the synthesis of benzoxazolinonic phenylethanolamines. The pharmacological study shows that these compounds possess an affinity for adrenergic receptors. Compound (XXXIV), the most interesting, is a competitive alpha and beta adrenergic antagonist which has been studied for antihypertensive activity.

Effects of bepridil and nifedipine on regional myocardial contractility during ischaemia in anaesthetized dogs.

Subtotal reduction (60%-70%) of blood flow in the circumflex artery in anaesthetized open-chest dogs caused a long-lasting increase (222%) in coronary vascular resistance and stable changes in myocardial segmental contractility (% delta L), as measured by the method of piezoelectric crystals. % delta L increased by 31.2% in the healthy zone while hypokinesia occurred in the moderately ischaemic zone (-50.8%). In the severely ischaemic zone there was a paradoxical lengthening (bulge or dyskinesia) of 7.3% during systole. Bepridil (2.5 mg.kg-1, IV) decreased heart rate (-15.6%) and systolic (-20.8%) and diastolic (-31.6%) blood pressure, and increased total coronary blood flow (+40.7%). % delta L was increased in the healthy zone (+20.4%) and in the moderately ischaemic zone (+48.2%). Bepridil completely inhibited the bulge in the severely ischaemic zone. Nifedipine (0.02 mg.kg-1, IV) greatly reduced systolic (-31.3%) and diastolic (-40.7%) blood pressure as well as coronary blood flow (-30.4%), without changing heart rate. A delayed increase in % delta L occurred in the healthy zone (+8.4%) and in the moderately ischaemic zone (+38.5%). In the severely ischaemic zone, there was no improvement of the bulge. The observed differences in contractility between the two calcium antagonists are discussed in terms of their haemodynamic differences. Improvement of myocardial segmental contractility, if it occurred, may have been due to bradycardia, slight decrease in contractility, as measured by LV dP/dt max/P, increased total coronary blood flow, decreased afterload, so long as it was not too great, and anti-ischaemic properties of the compound.

[Synthesis and pharmacologic study of 6-(amino-2 ethyl) benzoxazolinones]. / Synthèse et étude pharmacologique d'(amino-2 éthyl)-6 benzoxazolinones.

Reaction of various amines on 6-(2-bromoethyl)benzoxazolinone or its N-methylated derivative provided eleven new 6-substituted aminoalkyl analogues. In a pharmacological evaluation, several compounds bearing an arylpiperazinic moiety were found to possess significant effects on arterial blood pressure and on the central nervous system; two of them showed interesting analgesic activity.