Effect of Paclitaxel Local Delivery on Neointimal Formation after Endothelial Denudation of the Rat Carotid Artery

Background and Objectives:Mechanisms of restenosis following successful coronary angioplasty (PTCA) are known as vascular smooth muscle cells (VSMCs) proliferation and migration, elastic recoil or vascular wall remodeling. Paclitaxel whose effect on the stabilization of microtubles leads to cell death is highly lipophilic, permitting easy pass through cell membrane, and has a long-term antiproliferative effect. This study was performed to evaluate effect of paclitaxel on VSMCs proliferation and whether locally delivered paclitaxel can prevent stenosis and neointimal formation in rat carotid artery injury model. Materials and Methods:Cultured VSMCs were exposed to sequential concentrations of paclitaxel in vitro, and proliferation inhibition was analyzed with H-thymidine incorporation. Paclitaxel of a suitable concentration was applied to the endothelium-denuded carotid artery of Fisher 344 inbred rats for 20 minutes. Angiogram and morphometric analysis of carotid artery was performed after 2 weeks. Results:H-thymidine incorporation in cultured VSMCs was decreased dose-dependently from the concentration of 0.1 μmol/L (2,454±149 cpm/ μg protein) to 100 μmol/L (1,323±69 cpm/μg protein) of paclitaxel by single and 20-minute exposure in the presence of platelet-derived growth factor (p<0.005). In the absence of platelet-derived growth factor, the decrement of H-thymidine incorporation was evident above the concentration of 5 μmol/L of paclitaxel. To evaluate in vivo effect, paclitaxel (0.1 or 1 μmol/L) was administered into the endothelium-denuded carotid artery by balloon injury and incubated for 20 minutes. Percent stenoses (32.2±9.8%) of paclitaxel-treated group was less than those (46.3±7.5%) of control group on histologic analysis (p<0.01). Paclitaxel-treated group also had wider lumen on carotid angiogram and less neointimal thickening than control on histologic examination (p<0.005). Conclusion:Proliferation of VSMCs was effectively inhibited and neointimal formation and luminal stenosis was prevented in rat carotid artery injury model by single, brief and local 논문접수일:1999년 3월 18일 심사완료일:1999년 11월 8일 교신저자:김승택, 361-711 충북 청주시 흥덕구 개신동 62 충북대학교 의과대학 내과학교실 전화:(0431) 269-6354·전송:(0431) 273-3252 E-mail:stkim@med.chungbuk.ac.kr