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

Schaeffer, Paul; Baissat, J.; Dureng, G; Lamar, J.C.; Stoclet, Jean‐Claude

doi:10.1016/0014-2999(86)90699-0

Cited by 5 publications

(4 citation statements)

References 6 publications

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“…Recent results in rat, and especially in rabbit aorta, where bepridil has been compared with several "calcium antagonists," provide indirect evidence for an intracellular action of this drug ( an intracellular effect of bepridil were unsuccessful. Similar findings with bepridil on rat-tail artery and portal vein have also been described by Shaeffer et al [29,30]. Interestingly, the ratio fox" the calmodulin antagonist W-7 and the intracellularly acting, propylmethylene-dioxyindene IPrMDI, Rahwan 1261/was near unity.…”

Section: Vascular Smooth Musclesupporting

confidence: 86%

Berpidil: A pharmacological reappraisal of its potential beneficial effects in angina and tissue protection following ischemia

Massingham

Zwieten

1989

Cardiovasc Drug Ther

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In this review the pharmacologic properties of the calcium antagonist bepridil have been reexamined, particularly the evidence for an intracellular locus of action for the drug. Physicochemical properties of bepridil show it to be highly lipophylic, rapidly and extensively taken up, and accumulated in certain tissues. Combined electrophysiologic and mechanical studies have provided convincing, but indirect, evidence for an intracellular action of bepridil in cardiac muscle. Bepridil also fulfills, to a greater or lesser extent, certain important pharmacologic criteria necessary for evoking an intracellular action of a drug in cardiac and vascular smooth muscle: 1. Responses to agonists known to utilize intracellular calcium in the response are inhibited to a similar extent to depolarization-induced K+ responses. 2. Phasic and tonic responses to noradrenaline in vascular tissues are not, or are only to a minor extent, differentially antagonized. 3. Responses to the calcium ionophore A 23187 are antagonized. 4. Activity is retained following removal of the cell membrane by surfactants. 5. Isolated enzyme systems (e.g., calmodulin, myosin light-chain kinase) are affected by the drug at similar concentrations to those that are effective in whole cells or tissues. Finally results obtained with bepridil in ischemic myocardium have been reviewed to ascertain whether its broader pharmacologic spectrum over the calcium-entry blockers is associated with enhanced tissue protective properties. Positive results with bepridil in hypoxic myocytes and ischemic myocardium distinguishes this drug from the classical antianginal agents verapamil, nifedipine, and diltiazem. It is suggested that bepridil, because of its paucity of hemodynamic effects, may be of special therapeutic interest in the management of silent ischemia where cellular mechanisms leading to cytoprotection are more desirable than strong hemodynamic activity.

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Section: Vascular Smooth Musclesupporting

confidence: 86%

Berpidil: A pharmacological reappraisal of its potential beneficial effects in angina and tissue protection following ischemia

Massingham

Zwieten

1989

Cardiovasc Drug Ther

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“…These experiments have also shown that the quaternary ammonium derivative of bepridil, CERM 11888, has effects upon 'slow structures' but these were somewhat weaker, and more delayed in onset, than those induced by bepridil. In vitro experiments have shown that CERM 11888 has an equivalent calcium channel blocking potency to bepridil (Wahler et al, 1986;Schaeffer et al, 1986), although recent results have indicated that CERM 11888 is some 2-3 times less potent than bepridil at vascular calcium channels (John and Massingham, unpublished results). Further experiments are required to resolve this discrepancy.…”

Section: Discussionmentioning

confidence: 99%

“…CERM 11888 would be expected to penetrate into cells to a lesser extent or at a much reduced rate than the parent drug bepridil. CERM 11888 has been shown to have an approximately similar potency to bepridil on sarcolemmal calcium and sodium channels (Wahler et al, 1986;Schaeffer et al, 1986;Leboeuf et al, unpublished results). Thus in the present study the effects of bepridil and CERM 11888 were compared to those of two classical calcium antagonist drugs: verapamil and diltiazem (see Figure 1, Ponsonnaille et al, 1982;Beaughard et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

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

Leboeuf

Lamar

Massingham

et al. 1989

British J Pharmacology

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1 The electrophysiological effects of bepridil, its quaternary derivative, CERM 11888 (methylpyrrolidinium bromide) (both 2.5mgkg-1 i.v.) and those of verapamil and diltiazem (0.2mgkg-' 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 > CERM 11888 > diltiazem > 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 > diltiazem > bepridil > 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.

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“…The quaternary derivative of bepridil (CERM 11888), although having effects similar to bepridil on the slow inward calcium current and contractile responses dependent upon extracellular calcium, has little effect on phenomena that are dependent upon intracellular calcium ions. These results suggest that unlike bepridil, the pharmacological effects of CERM 11888 are due to effects of the drug uniquely at the cell membrane level (Schaeffer et al, 1986;Wahler et al, 1986). The reference calcium antagonist, verapamil, is also known mainly for its inhibitory action on calcium movements at the level of the cell membrane but may also, to a much lesser extent than bepridil, enter the cell (Pang & Sperelakis, 1983;.…”

Section: Introductionmentioning

confidence: 99%

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

Leboeuf¹,

Léoty

Lamar³

et al. 1989

British J Pharmacology

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1 The effects of bepridil, its quaternary derivative: CERM 11888 (methyl-pyrrolidinium bromide) (10-710-5M), and verapamil (10 7-1O-6M) 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 (10-6M) also tended to accelerate the relaxation phase. At 10 -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-s 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.

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

Cited by 5 publications

References 6 publications

Berpidil: A pharmacological reappraisal of its potential beneficial effects in angina and tissue protection following ischemia

Berpidil: A pharmacological reappraisal of its potential beneficial effects in angina and tissue protection following ischemia

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

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

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