Local drug delivery following percutaneous transluminal coronary angioplasty (PTCA) may prevent restenosis by achieving higher local tissue concentrations of drugs than systemic administration. However, it remains unknown whether vascular damage and the ensuing intimal thickening is associated with the degree of infusion pressure achieved by local delivery. Therefore, local delivery of normal saline was performed using a channeled balloon catheter (Transport) to the rabbit iliac artery with different infusion pressures of 0, 3, 5, 7, and 12 atm (n=4 for each). The extent of vascular damage and the development of intimal thickening were determined histopathologically 14 days after the procedure. In 10 additional rabbits, to assess the degree of vessel penetration, local delivery of indocyanine green dye solution was performed in a similar fashion. After 1 h, the green dye penetrated deeply at the higher infusion pressures of 7 and 12 atm. The incidence of internal clastic lamina laceration and occurrence of total occlusion as a result of thrombus formation demonstrated an increase proportional to the degree of local infusion pressure. When the vascular injury score in each arterial section was plotted against the infusion pressure, a significant relation was observed (r=0.717, p<0.0001). At 0, 3, 5, 7, and 12 atm, neointimal areas of 0.160+/-0.005, 0.163+/-0.008, 0.189+/-0.017, 0.260+/-0.027, and 0.329+/-0.033 mm2, respectively, were observed. Smooth muscle cell (SMC) proliferative activity also increased in proportion to the local infusion pressure. We have demonstrated for the first time that local delivery infusion pressure itself is related to the severity of vascular damage, resulting in the development of intimal thickening and an associated increase in SMC proliferative activity. Therefore, we suggest that infusion pressure is a key determinant of vascular injury during local drug delivery, with lower pressure causing the least neointimal response.