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

Abstract

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.

Protective effect of flunarizine on blood-brain barrier permeability alterations in acutely hypertensive rats.

“…25 This is supported by the findings of the present study in which a fall of 8 mm Hg was observed for periods varying from 10 to 60 seconds so that the blood pressure of animals was restored to resting levels about 2 minutes before the induction of hypertension. The reduction in endothelial permeability produced by flunarizine in this study cannot be attributed to its blood pressure lowering effect since the mean blood pressures of the hypertensive group and the three drug-treated hypertensive groups were not statistically different.…”

Flunarizine reduces cerebral infarct size after photochemically induced thrombosis in spontaneously hypertensive rats.

“…Direct protection of the endothelial membrane offers a more reasonable explanation for the beneficial action of flunarizine in the present stroke model. In previous studies it has been shown that flunarizine protects against endothelial damage induced by citrate, CaCl 2 , or lactate in rats, 19 against microvascular permeability increase in rat skin, 20 against atherosclerotic plaque formation in electrically stimulated rabbit carotid artery, 21 and against arachidonic acid-induced damage of the pulmonary endothelium and subsequent platelet thrombosis in mice. 22 The…”

Temporal sequence of morphological alterations in artery walls during experimental atherogenesis — occurrence of leukocytes

“…In a previous publication [2] it was demonstrated in our model of experimental arteriosclerosis that one of the earliest events in plaque development is an in-creased endothelial permeability to macromolecules which lasts for some hours after short-time electrical stimulation. As presented in this report, the first cellular responses of the carotid artery to DC impulses are an enhanced attachment of leukocytes to the endothelial surface as well as an accumulation of these cells in the SES.…”

“…As described previously [2,4], in this experimental model the endothelium is maintained as a continuous lining. However, the endothelial permeability to macromolecules is enhanced for some hours after the first stimulation period, mainly beneath the anode.…”