Title

Inhibition of neointimal formation in balloon-injured rat carotid arteries following administration of cilostazol

Date of Completion

January 2003

Keywords

Health Sciences, Pharmacology

Degree

Ph.D.

Abstract

Neointimal formation is suggested to play a very important role in the mechanism for restenosis. Cilostazol is a PDE3 isozyme-selective inhibitor and its pharmacological actions are thought to be the result of elevated intracellular CAMP levels. ^ Fourteen days after balloon injury (fifteen days after first drug administration), thick neointima composed mainly of SMCs appeared at the lesion site of rat left common carotid artery. Neointimal area in cilostazol treated rats was only 55.63% of that of vehicle-treated rats and the ratio of neointimal to medial area (I/M ratio) was also significantly decreased in cilostazol-treated rats. Compared to those of vehicle treated rats, platelet aggregation of cilostazol treated rats was significantly inhibited 7 and 15 days after first drug administration. A relatively weak but significant negative correlation was found between aggregation slope change and neointimal area in cilostazol treated rats. Compared to vehicle treated rats, there were significant elevations of cAMP levels in carotid arteries (15 days after first drug administration) and platelets (7 and 15 days after first drug administration) in cilostazol treated rats. Compared to vehicle treated rats, p27Kip were significantly increased, collagen production and CTGF was significantly decreased in the neointima of cilostazol treated rat carotid arteries. ^ Our data showed that cilostazol increased cAMP levels in platelets and SMCs in vivo. By elevating intracellular cAMP level, cilostazol effectively interfered with multiple components of the restenosis including inhibition of platelet aggregation, SMC proliferation and collagen production. Furthermore, our study indicated that maintaining high level of p27Kip and decreasing CTGF expression in the neointima might be two of the most important mechanisms for cilostazol to inhibit neointima formation. ^