Effects of a single local administration of cilostazol on neointimal formation in balloon-injured rat carotid artery

Abstract

To elucidate if locally administered cilostazol, an inhibitor of cyclic AMP phosphodiesterase III, suppresses neointimal formation in balloon-injured carotid artery of the rat, 20 mg of cilostazol was topically applied using pluronic gel at the time of balloon injury. Rats were sacrificed 14 days after balloon injury to measure the extent of neointimal formation. Plasma and tissue concentrations of cilostazol were also measured at 1, 3, 7 and 14 days after topical application. The 5-bromo-2'-deoxyuridine (BrdU, a thymidine analogue) was given intraperitoneally to detect proliferation of smooth muscle cells in the injured media at 3 days after balloon injury. At 1 day after injury, plasma and tissue concentrations were 0.147+/-0.043 microg/ml and 1380 microg/g tissue. Although the plasma concentration of cilostazol was undetectable ( < 0.02 microg/ml), a significant amount of cilostazol (46 microg/g tissue) was still detected in the tissue at the site of application even after 2 weeks. The intimal area of the injured carotid after 2 weeks was significantly smaller in the cilostazol-treated group than in the gel-treated control group (0.06+/-0.01 vs 0.15+/-0.02 mm2, P<0.001). BrdU-positive smooth muscle cells in the injured media after 3 days were also significantly fewer in the cilostazol-treated group than in the gel-treated control group (4.3+/-0.5 vs 9.1+/-0.9% of total cells, P < 0.001). These results suggest that local administration of cilostazol using pluronic gel maintains a high concentration of the drug at the application site, has an anti-proliferative effect on smooth muscle cells, and may have potential for clinical therapeutic use for the prevention of restenosis following arterial intervention.