Huang P, Hawthorne W J, Peng A, Angeli G L, Medbury H J, Fletcher J P
Department of Surgery, University of Sydney, Westmead Hospital, NSW, 2145, Westmead, Australia.
Am J Surg. 2001 Jun;181(6):492-8. doi: 10.1016/s0002-9610(01)00615-8.
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.
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 1 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-alpha-actin or anti-HAM-56.
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).
The antihypertensive agent verapamil inhibits intimal hyperplasia through enhancing adventitial cell apoptosis and inhibiting intimal cell proliferation after vascular grafting.
钙通道拮抗剂维拉帕米引发细胞凋亡（程序性细胞死亡）的可能性在动脉损伤中具有相当重要的意义，因为平滑肌细胞的丢失可能有助于减少内膜增生的发展。本研究的目的是确定维拉帕米在颈动脉人工血管移植后是否会诱导血管细胞凋亡。
32只成年雌性美利奴羊在第0天接受了明胶密封的梭形涤纶移植血管植入左颈总动脉。术后动物被随机分为对照组或三个治疗组之一（第2、3和4组）。第1组动物（n = 9）未接受治疗。对于治疗组，静脉注射维拉帕米，剂量为每天0.5 mg/kg，分两次给药。第2、3和4组绵羊分别治疗1、2和4周。动物在4周时处死。通过末端脱氧核苷酸转移酶介导的dUTP-荧光标记检测细胞凋亡。通过抗增殖细胞核抗原与抗α-肌动蛋白或抗HAM-56双重染色来确定增殖细胞及其表型。
4周治疗组移植血管外膜周围的凋亡细胞明显多于对照组（P <0.05）。内膜在2周和4周时增殖细胞的平均数量明显少于对照组（P <0.05）。2周和4周治疗组移植血管基质内巨噬细胞的平均数量明显少于对照组（P <0.05）。与对照组相比，4周时移植血管内增殖细胞的数量明显减少（P <0.05）。内膜增殖细胞核抗原（PCNA）表达与移植血管周围凋亡表达水平之间呈负相关（P <0.05）。
降压药维拉帕米通过增强血管移植后外膜细胞凋亡和抑制内膜细胞增殖来抑制内膜增生。
