Calcium channel antagonist verapamil inhibits neointimal formation and enhances apoptosis in a vascular graft model

Background: The potential of the calcium channel antagonist verapamil to ca use apoptosis (programmed cell death) is of considerable importance in arte rial injury where the loss of smooth muscle cells may contribute to a reduc tion in intimal hyperplasia development. The aim of this study was to deter mine whether verapamil induces vascular cell apoptosis after carotid artery synthetic grafting. Methods: Thirty-two adult-female Merino sheep received gelatin sealed fusif orm shape-Dacron grafts into the left common carotid artery at day 0, After operation animals were randomly allocated to either a control group or one of three treatment groups (groups 2, 3, and 4). Group I animals (n = 9) re ceived no treatment. For the treatment groups, intravenous verapamil was gi ven at a rate of 0.5 mg/kg per day in two divided doses. Group 2, 3. and 4 sheep were treated for 1, 2, and 4 weeks, respectively. Animals were sacrif iced at 4 weeks. Apoptosis was detected by terminal deoxynucleotidyl transf erase-mediated dUTP-fluorescent labelling. Proliferating cells and their ph enotype were determined by doublestaining with antiproliferation cellular n uclei antigen and anti-a-actin or anti-HAM-56. Results: There were significantly more apoptotic cells in the perigraft adv entitia in the 4-week treatment group than in the control group (P < 0.05). The average number of proliferating cells at 2 and 4 weeks in the intima w ere significantly less than in the control (P < 0.05). The average numbers of macrophages inside graft matrix in the 2 and 4 weeks treatment groups we re significantly less than for the control (P < 0.05). The number of prolif erating cells inside the graft was significantly lower at 4 weeks compared with control (P < 0.05). There was negative correlation between intimal PCN A expression and perigraft apoptotic expression level (P < 0.05). Conclusion: The antihypertensive agent verapamil inhibits intimal hyperplas ia through enhancing adventitial cell apoptosis and inhibiting intimal cell proliferation after vascular grafting. (C) 2001 Excerpta Medica, Inc. All rights reserved.