The Effect of Local Delivery of IBMX on the Neointimal Proliferation in Rat Carotid Balloon Injury Model

Abstract

Background：Hyperplastic neointima is one of the major mechanisms of restenosis following balloon angioplasty in selected patients with symptomatic angina pectoris. Elevation of cellular cyclic nucleotide levels such as cAMP and cGMP are known to inhibit the proliferation of vascular smooth muscle cells. 3-isobutyl-1-methylxanthine (IBMX increases intracellular cAMP and cGMP by nonselective inhibition of phosphodiesterases (PDEs. We conducted this study under the hypothesis that local delivery of IBMX could inhibit neointimal hyperplasia after balloon injury of the rat carotid artery. Methods：Left common carotid artery of 10 week old male Sprague-Dawley rats were subjected to arterial injury by 2F Fogarty balloon catheter. After injury, animals were allocated to the control groups (control 1；injury control and control 2；pluronic gel plus DMSO control and IBMX group, which received pluronic polymer gel, DMSO and IBMX mixture periadventitially. After 3 weeks, the rats were killed by overdose of ketamine, and the injured left arteries were pressure-fixed with 10% formalin and subjected to histomorphological analysis. Results：Mean body weight of rats was not statistically different among study groups. The mean area of neointima (control group 1：0.28±0.05 mm 2 , control group 2：0.27±0. 08 mm 2 , IBMX group：0.18±0.08 mm 2 ；p<0.05 and the mean ratio of neointima to medial area[versus (control group 1：1.89±0.37, control group 2：1.95±0.41, IBMX group：1.41±0.47；p<0.05] were significantly less in IBMX group. The mean area of external elastic lamina was significantly larger in control group 1 than IBMX group (0.57±0.07 mm 2 versus 0.47±0.10 mm 2 and mean luminal area showed no significant difference among groups (control group1：0.14±0.07 mm 2 , control group 2：0.10±0.05 mm 2 , control group 3：0.16±0.06 mm 2 . Conclusion ：Peri-adventitial single administration of IBMX showed its effectiveness in reducing the neointimal proliferation in rat carotid balloon injury model. Furthermore we observed the positive