Using the [3H]
thymidine incorporation technique, the anti-proliferative effects of
benidipine, a long-acting
calcium antagonist, on porcine cultured vascular smooth muscle cells (VSMCs) were determined and compared with those of other
calcium antagonists.
Benidipine inhibited serum-stimulated [3H]
thymidine incorporation into VSMCs (IC50, 0.2 microM), and this inhibitory effect was significantly more potent than that of
nitrendipine,
felodipine,
nisoldipine,
manidipine,
amlodipine,
nifedipine,
verapamil and
diltiazem. When growth-arrested cells were stimulated with
platelet-derived growth factor followed by
insulin,
benidipine, administered with either stimulation, inhibited [3H]
thymidine incorporation into VSMCs. This suggests that it acts in both the G0/G1 and G1/S phases. In another series of experiments, the anti-proliferative effect in vivo was investigated using rats subjected to balloon
catheter-induced endothelial denudation of the aorta.
Benidipine (5 mg/kg, p.o., b.i.d.) significantly reduced the incorporation of [3H]
thymidine into aortic
DNA 48 h after balloon injury, whereas it did not affect incorporation into bone marrow, suggesting that it inhibits arterial
DNA synthesis. From our results,
benidipine was shown to exert antiproliferative effects on VSMCs in vivo as well as in vitro. The
drug may be useful for the treatment of vascular proliferative diseases such as restenosis following percutaneous transluminal angioplasty and
atherosclerosis.