Mibefradil prevents neointima formation after vascular injury in rats. Possible role of the blockade of the T-type voltage-operated calcium channel.
Mibefradil is a novel calcium antagonist that is selective for the T-type voltage-operated calcium channel rather than the L type. Because T-type calcium channels are present on rapidly proliferating cells and mediate the increase of intracellular calcium induced by some growth factors, such as platelet-derived growth factor, we hypothesized that the blockade of T channels could prevent the excessive smooth muscle cell proliferation that occurs in conditions such as vascular injury. To test this hypothesis, we evaluated in rats the effects of mibefradil (which blocks both L- and T-type channels) on neointima formation after vascular injury, and we compared them with those of equihypotensive doses of amlodipine and verapamil (which block only L-type channels). Mibefradil (30 mg/kg) decreased the area of neointima formed 14 days after balloon injury by 54% (P < .001). In contrast, neither verapamil nor amlodipine had an effect despite a blood pressure reduction at least equal to that of mibefradil. The in vivo effect of mibefradil was indeed an inhibition of smooth muscle cell proliferation, as shown by thymidine incorporation experiments. This antiproliferative effect of mibefradil was also observed in vitro in smooth muscle cells stimulated by fetal calf serum. In this condition also, verapamil was ineffective. We conclude that in rats mibefradil has a potent antiproliferative effect on smooth muscle cells after vascular injury. This effect might be due to blockade of voltage-operated T channels.
Schmitt
R
R
Pharma Division, Preclinical Research, Clinical Research and Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Clozel
J P
JP
Iberg
N
N
Bühler
F R
FR
D017311:Amlodipine / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020212:Carotid Artery Injuries; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials; D020748:Mibefradil; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D051381:Rats; D017208:Rats, Wistar; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D017539:Tunica Intima / Q000166:cytology / Q000187:drug effects*; D014700:Verapamil / Q000494:pharmacology
D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D013764:Tetrahydronaphthalenes; D017311:Amlodipine; D020748:Mibefradil; D014700:Verapamil