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J Leboeuf

Publications and source records attributed to J Leboeuf.

7 recordsLinked to original sources
PubMed1997

In vitro calcium antagonistic and antioxidant effects of Org 13061 and its enantiomers, new potential antiatherosclerotic compounds.

The calcium antagonistic and antioxidant properties of a new potential antiatherosclerotic agent, Org 13061 were compared with those of its (-) and (+) enantiomers (Org 13471 and Org 13581) In vitro and with appropriate reference drugs. Org 13061 antagonized contractions induced by potassium in rabbit aortic rings with an IC50 value of 0.50 microM and reduced the maximum rate of phase 0 depolarization (Vmax) of the 'slow' calcium-mediated transmembrane action potentials in cardiac tissue (IC25 = 0.82 microM). Similarly to reference drugs, Org 13061 was more selective in reducing vascular compared to cardiac contraction. In concentrations overlapping those exerting vasorelaxant actions, Org 13061 inhibited copper ion-induced human low density lipoprotein (LDL) peroxidation (0.1-1 microM) and inhibited lipid accumulation by rat aortic smooth muscle cells in culture (1-3 microM). Higher concentrations (3 microM) modestly inhibited proliferation of these cells. The (-) enantiomer was ten times more potent than the (+) enantiomer as a vasorelaxant but was equipotent in inhibiting lipid accumulation and LDL peroxidation (eg, lag phase of conjugated dienes formation increased by 29 and 61 min and by 22 and 56 min in response to 0.3 and 1 microM (-) and (+) enantiomers, respectively). The antioxidant probucol was approximately three times more potent than Org 13061 in inhibiting lipid accumulation but was 30 times less potent in antagonizing LDL peroxidation. The classical calcium channel blocking agents were totally ineffective on lipid accumulation (1-10 microM), whereas human LDL peroxidation was slightly reduced by nifedipine (0.1-3 microM) but unaltered by diltiazem (0.1-30 microM) and verapamil (0.1-3 microM). In conclusion, the racemic Org 13061 selectively blocks voltage-operated calcium channels (VOCs) in concentrations that also exert marked antioxidant activity. The (-) enantiomer is largely responsible for calcium channel block but as antioxidants, the enantiomers are equipotent. This mixed pharmacological profile of Org 13061, not shared by known calcium channel blocking agents, may be potentially useful in the treatment of atherosclerosis.

Animals↗
PubMed1993

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.

Action Potentials↗
PubMed1992

Protective effect of bepridil against veratrine-induced contracture in rat atria.

In isolated stimulated rat atria, superfusion with veratrine caused a marked contracture (VIC) which was absent in calcium-free medium and which was inhibited by tetrodotoxin (IC50VIC of 1.38 microM). Lowering the extracellular calcium concentration from 2.5 to 0.5 or 0.1 mM reduced the veratrine-induced contracture and delayed its onset. Superfusion of bepridil (1-10 microM) for 60 min before and during veratrine exposure markedly slowed the onset of contracture, reduced the maximum response (IC50VIC = 2.11 microM) and facilitated recovery upon washout of the alkaloid. The direct negative inotropic effect (NIE) of bepridil (IC50NIE = 10.96 microM) resulted in an VIC/NIE ratio of 5.19 for this drug. The protective effects of bepridil were rate-independent and were not modified by the presence of atropine (1.4 microM) and propranolol (0.3 microM) in the medium. Diltiazem, verapamil and nifedipine only reduced veratrine-induced contracture at concentrations much higher than those producing a negative inotropic effect, giving them negative NIE/VIC ratios of 0.31, 0.08 and 0.08 respectively. Like bepridil, flunarizine had a positive NIE/VIC ratio (15.87, IC50VIC = 3.71 microM). The lack of effect of the quaternary derivative of bepridil CERM 11888 indicated that intracellular sites of action may be involved in the activity of bepridil on veratrine-induced contracture. Given that veratrine-induced changes may mimic some of the pathological changes occurring in ischaemia, the results suggest that bepridil and flunarizine may be more effective than L-type, slow calcium ion-channel blockers in protecting against calcium overload during ischaemia and reperfusion injury.

Animals↗
PubMed1989

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.

Anesthesia↗
PubMed1989

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.

Animals↗
PubMed1982

Studies on the bradycardia induced by bepridil.

Bepridil, a novel active compound for prophylactic treatment of anginal attacks, induced persistent bradycardia and a non-specific anti-tachycardial effect, the mechanisms of which were investigated in vitro and in vivo. In vitro perfusion of bepridil in the life-support medium for isolated sino-atrial tissue from rabbit heart, caused a reduction in action potential (AP) spike frequency (recorded by KCl microelectrodes) starting at doses of 5 X 10(-6) M. This effect was dose-dependent up to concentrations of 5 X 10(-5) M, whereupon blockade of sinus activity set in. Bepridil at a dose of 5 X 10(-6) M, induced a concomitant reduction in AP amplitude (falling from 71 +/- 8 mV to 47 +/- 6 mV), maximum systolic depolarization velocity (phase 0) which fell from 1.85 +/- 0.35 V/s to 0.84 +/- 0.28 V/s, together with maximum diastolic depolarization velocity (phase 4) which fell from 38 +/- 3 mV/s to 24 +/- 5 mV/s. In vivo injection of bepridil at a dose of 5 mg/kg (i.v.) into 6 anaesthetized dogs which had undergone ablation of all the extrinsic cardiac afferent nerve supply, together with a bilateral medullo-adrenalectomy, caused a marked reduction in heart rate which fell from 98.7 +/- 4.2 beats/min to 76 +/- 5.3 beats/min sustained for more than 45 min. It is concluded that bepridil reduces heart rate by acting directly on the sinus node. This effect, which results in a flattening of the phase 0 and phase 4 slope, together with a longer AP duration, may be due to an increase in the time constants of slow inward ionic currents (already demonstrated elsewhere), but also to an increased time constant for deactivation of the outward potassium current (Ip).

Action Potentials↗