Mechanisms of Vasodilatation and Antivasoconstriction

Nueten, J. M. Van; Wellens, D

doi:10.1177/000331977903000702

Cited by 28 publications

(10 citation statements)

References 9 publications

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“…The present experiments thus support previous hyptheses that this drug exerts its antivasocon strictor activity (17,18) at the cellular level by inhibiting stimulated calcium influx (19). The differences in intensity and distribution of the precipitated calcium between control (nondepolarized) and depolarized smooth muscle cells indicates on the one hand that increased entry of calcium is causally related to the sustained contraction.…”

Section: Discussionsupporting

confidence: 90%

“…Flunarizine causes a long-lasting inhibition of the contrac tions induced in the depolarized vascular smooth muscle by calcium (17,18). Hence, it has been suggested by Van Nueten and Wellens (19) that it exerts its effect on the peripheral vascular smooth muscle through its ability to decrease the rate of stimulated calcium influx, thereby inhibiting vasoconstriction and thus im proving peripheral blood flow.…”

Section: Introductionmentioning

confidence: 99%

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

Borgers¹,

Ghoos²,

Thoné³

et al. 1980

J Vasc Res

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Exposure of depolarized caudal artery preparations of the rat to various calcium concentrations evoked sustained contractions of the smooth muscle in a dose-dependent way. Flunarizine was shown to suppress this sustained muscle contraction. Experiments were undertaken to determine the subcellular site where flunarizine interferes with the calcium-induced contractile process. The subcellular distribution of calcium was assessed by electron microscopy, using a combined oxalate-pyroantimonate method. In depolarized strips precipitated calcium was mainly distributed over the contractile elements and the microvesicles lining the cell membrane. When flunarizine was added to the preparation, the precipitate was predominantly confined to the extracellular space, whereas only spotty precipitates were seen in mitochondria and sarcoplasmic reticulum. The myofibrils were almost free of deposits. Without previous depolarization, the smooth muscle cells demonstrated a moderate amount of precipitate over the mitochondria, nuclei, sarcoplasmic vesicles, plasmalemmal microvesicles and myofibrils. In these conditions neither the amount nor the intracellular distribution of the precipitate was influenced by the addition of flunarizine. These observations suggest that flunarizine interferes with the entry of calcium at the plasma membrane level, but only in conditions where the influx of the ion is stimulated.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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

Borgers¹,

Ghoos²,

Thoné³

et al. 1980

J Vasc Res

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“…In addition, it specifi¬ cally blocks Ca2+ channels activated by vasocon¬ strictor agents and does not affect the increase in Ca2+ influx due to intrinsic myogenic changes in membrane permeability. These selective actions of flunarizine appear not to be found with other putative inhibitors of Ca2+ flux such as verapamil (Van Nueten & Wellens 1979). The mechanism of action of flunarizine in vascular smooth muscle is unknown: it has been found to bind specifically to plasma membranes of vascular smooth muscle cells to block Ca2+ influx, with no effect on intracellular Ca2+ (Godfriand 1981).…”

Section: Discussionmentioning

confidence: 93%

Flunarizine, a calcium influx blocker, inhibits TRH- but not potassium-stimulated prolactin secretion

Merritt

Tomlinson

Brown

1984

Acta Endocrinologica

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The effect of flunarizine on the secretion of prolactin from monolayer cultures of normal rat pituitary cells has been determined. Both basal and TRHstimulated secretion were found to be significantly inhibited by micromolar concentrations of flunarizine, whereas depolarization (high K+)-stimulated secretion was virtually unaffected. These results indicate that TRH-stimulated prolactin secretion probably involves calcium influx and that flunarizine may be useful as a probe for particular Ca2+ channels.

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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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Mechanisms of Vasodilatation and Antivasoconstriction

Cited by 28 publications

References 9 publications

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

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

Flunarizine, a calcium influx blocker, inhibits TRH- but not potassium-stimulated prolactin secretion

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

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