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 cause apoptosis (programmed cell death) is of considerable importance in arterial injury where the loss of smooth muscle cells may contribute to a reduction in intimal hyperplasia development. The aim of this study was to determine whether verapamil induces vascular cell apoptosis after carotid artery synthetic grafting. Methods: Thirty-two adult-female Merino sheep received gelatin sealed fusiform 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) received no treatment. For the treatment groups, intravenous verapamil was given 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 sacrificed at 4 weeks. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP-fluorescent labelling. Proliferating cells and their phenotype were determined by doublestaining with antiproliferation cellular nuclei antigen and anti-a-actin or anti-HAM-56. Results: There were significantly more apoptotic cells in the perigraft adventitia 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 were 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 were significantly less than for the control (P < 0.05). The number of proliferating cells inside the graft was significantly lower at 4 weeks compared with control (P < 0.05). There was negative correlation between intimal PCNA expression and perigraft apoptotic expression level (P < 0.05). Conclusion: The antihypertensive agent verapamil inhibits intimal hyperplasia through enhancing adventitial cell apoptosis and inhibiting intimal cell proliferation after vascular grafting. (C) 2001 Excerpta Medica, Inc. All rights reserved.