Anti-proliferative effects of benidipine hydrochloride in porcine cultured vascular smooth muscle cells and in rats subjected to balloon catheter-induced endothelial denudation.
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.
Ide
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Department of Pharmacology, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Kondoh
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Satoh
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Karasawa
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D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002404:Catheterization / Q000009:adverse effects*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004095:Dihydropyridines / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000502:physiology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D013936:Thymidine / Q000378:metabolism
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C061004:benidipine; D004247:DNA; D013936:Thymidine