Effects of Flunarizine on the Distribution of Calcium in Vascular Smooth Muscle

Borgers, M.; Ghoos, E; Thoné, Fred; Nueten, J. M. Van

doi:10.1159/000158243

Cited by 10 publications

(7 citation statements)

References 11 publications

(15 reference statements)

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“…In the preparations in which only the smooth muscle was exposed to the drug, inhibition of hypoxic facilitation by flunarizine is probably mediated through the inhibition of calcium influx in the vascular smooth muscle cells at the level of the plasma membrane (Godfraind & Miller, 1982;Borgers et al, 1980;.…”

Section: Discussionmentioning

confidence: 99%

Flunarizine inhibits endothelium‐dependent hypoxic facilitation in canine coronary arteries through an action on vascular smooth muscle

Iqbal¹,

Vanhoutte²

1988

British J Pharmacology

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1 Hypoxia augments contractile responses to several vasoactive agents in canine isolated coronary arteries with intact endothelium. Calcium antagonists inhibit the further increases in tension caused by hypoxia. The present experiments were designed to determine whether the calcium-antagonist flunarizine would inhibit hypoxic contractions in isolated blood vessels through an action on the endothelium or on the vascular smooth muscle. 2 Rings of canine coronary arteries, with or without endothelium, were suspended at optimal length for isometric tension recording in organ chambers filled with modified Krebs-Ringer bicarbonate solution.3 Hypoxia (95% N2 and 5% C02) augmented contractile responses to prostaglandin F2.(2 x 106 M); removal of the endothelium abolished this hypoxic facilitation. 4 Flunarizine (5 x 10-5-5 x 10-7M) exerted a long-lasting inhibition of the hypoxic facilitation in a concentration-dependent manner. Flunarizine did not inhibit the response to prostaglandin F2,. 5 To differentiate between the response of smooth muscle and the endothelium, strips of coronary arteries without endothelium were layered with strips with or without endothelium. Hypoxia augmented contractions only in layered preparations with endothelium. Flunarizine prevented the hypoxic contractions in layered preparations in which only the smooth muscle was treated with flunarizine. In contrast, when only the endothelium was treated, no or minimal inhibition of the hypoxic contraction occurred with flunarizine (10' and 5 x 10-5M, respectively).6 These experiments indicate that the calcium antagonist flunarizine inhibits endotheliumdependent hypoxic facilitation in canine coronary arteries primarily through its action on vascular smooth muscle.

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Section: Discussionmentioning

confidence: 99%

Flunarizine inhibits endothelium‐dependent hypoxic facilitation in canine coronary arteries through an action on vascular smooth muscle

Iqbal¹,

Vanhoutte²

1988

British J Pharmacology

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“…Flunarizine [(E)-l-bis(4-fluorophenyl)methyl-4-(3-phenyl-2-propenyl)-piperazine dihydrochloride], a selective calcium entry blocker [55,16,57], causes selective inhibition of SMC contractions [54] and of intracellular Ca 2+ deposition [8].…”

Section: The Drugmentioning

confidence: 99%

Inhibition of smooth muscle cell proliferation and endothelial permeability with flunarizine in vitro and in experimental atheromas

1985

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Repeated weak electrical stimulations of rabbit carotid artery walls with implanted electrodes cause intimal proliferations of smooth muscle cells (SMC) and lead to fibromuscular plaques beneath the anode. If the animals receive a cholesterol-enriched diet the plaques become typical atheromas. The endothelial lining is maintained. The procedure for the production of an atheroma with 11 +/- 4 layers of SMC lasts 4 weeks. Addition of the calcium antagonist Flunarizine to the food during the stimulation periods inhibits the growth of the plaque. The inhibition is dose-dependent. Whether the drug inhibits atherogenesis by direct action on SMC or via an effect on permeation of macromolecules through the endothelium has been studied by measurement of (1) peroxidase (MW 40,000 dalton) permeability through the stimulated endothelium of the artery and (2) the inhibitory effects of Flunarizine on cultures of arterial SMC. Endothelial permeability increases for some hours after stimulation mainly beneath the anode. Flunarizine inhibits the permeation of peroxidase through the endothelial lining for the most part by its action on intercellular transport. The drug also inhibits the growth of SMC in mass cultures and clone cultures. The inhibition of proliferation is not specific for SMC. Skin fibroblasts obtained from the same animals as the artery smooth muscle cells are also inhibited in mass cultures and clone cultures. From the results it can be concluded that Flunarizine exerts its inhibitory action not only by its effect on the permeation through the endothelial lining but by a combined action on permeability and proliferation of cells in the artery wall.

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“…This method rather specifically demonstrates calcium. 2,3,5,7 This assumption is supported by the observation that after EGTA treatment the precipitate was entirely lost.' '6 A direct correlation was seen between the degree of contraction and the amount of electron-dense precipitate over the contractile apparatus.…”

Section: Discussionmentioning

confidence: 87%

The Prevention of Ca2+ Overload in Vascular Smooth Muscle by Flunarizine as Detected by Laser Microprobe Mass Analysis (LAMMA)

et al. 1985

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In vitro exposure of depolarized caudal artery preparations of the rat to a high calcium concentration resulted in a strong contraction of the smooth muscle cells. This muscle contraction was suppressed by flunarizine. It was shown cytochemically, using the combined oxalate-pyroantimonate method for the localization of calcium, that a considerable amount of electron-dense precipitate was seen over the depolarized muscle cells after incubation in a calcium containing medium. On the other hand this precipitate was not present on the smooth muscle cells when flunarizine was added to this incubation medium. The reaction product was only present in the extracellular space. These results were controlled by Laser Microprobe Mass Analysis. By evaporating and ionizing small parts of the smooth muscle cells (+/- 1 micron), it was confirmed that the cytochemical method indeed demonstrated calcium, with negligible interference of other cations.

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Effects of Flunarizine on the Distribution of Calcium in Vascular Smooth Muscle

Cited by 10 publications

References 11 publications

Flunarizine inhibits endothelium‐dependent hypoxic facilitation in canine coronary arteries through an action on vascular smooth muscle

Flunarizine inhibits endothelium‐dependent hypoxic facilitation in canine coronary arteries through an action on vascular smooth muscle

Inhibition of smooth muscle cell proliferation and endothelial permeability with flunarizine in vitro and in experimental atheromas

The Prevention of Ca2+ Overload in Vascular Smooth Muscle by Flunarizine as Detected by Laser Microprobe Mass Analysis (LAMMA)

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