Hadoke P W, Wadsworth R M, Wainwright C L, Butler K D, Giddings M J
Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, Scotland, UK.
Coron Artery Dis. 1996 Aug;7(8):599-608. doi: 10.1097/00019501-199608000-00007.
Thrombin, a potent stimulator of smooth muscle cell proliferation and inhibitor of endothelial cell growth, has been implicated as an important mediator of restenosis after angioplasty. Acute administration of the thrombin inhibitor r-hirudin reduced restenosis in animal models of angioplasty, possibly by inhibiting smooth muscle cell proliferation. Because thrombin-induced proliferation requires prolonged exposure to the agonist, it was hypothesized that a greater reduction in lesion size could be achieved by chronic administration of r-hirudin.
To determine whether prolonged treatment with r-hirudin would reduce lesion size and improve vascular function in a rabbit model of neointimal proliferation.
Male New Zealand white rabbits were fed a high-cholesterol diet for 4 weeks, after which they were subjected to balloon injury of the left subclavian artery. The rabbits were assigned to one of three groups: control (no drug); acute r-hirudin treatment (0.33 mg/kg intravenously plus 0.48 mg/kg per h subcutaneously for 24 h); or chronic r-hirudin treatment (0.33 mg/kg intravenously plus 0.6 mg/kg per h subcutaneously for 28 days). After surgery the rabbits were fed a normal diet and killed 30 days later. Left (angioplastied) and right (control) subclavian arteries were removed for morphological and functional analysis.
Angioplasty in control, untreated rabbits produced large neointimal lesions [15.0 +/- 1.8% of the area within the external elastic lamina (EEL)], comprised mainly of smooth muscle cells (34 +/- 16 cells/section) and lipid-rich macrophage or foam cells (118 +/- 51 cells/section). Acute r-hirudin treatment neither inhibited smooth muscle cell proliferation (35 +/- 12 cells/section) nor reduced neointimal lesion size (23.5 +/- 4.6% of the area within the EEL). Chronic r-hirudin treatment significantly increased the number of proliferating cells (55 +/- 15 cells/section, P < 0.05) and the size of the lesions (28.5 +/- 5.6% of the area within the EEL, P < 0.05). Further more, treatment with r-hirudin appeared to exacerbate, rather than improve, angioplasty-induced functional alterations.
Prolonged treatment with r-hirudin neither inhibits vascular smooth muscle cell proliferation in rabbits after angioplasty of the left subclavian artery nor reduces the size of neointimal lesions. Furthermore, treatment with r-hirudin might impair endothelial cell function after angioplasty. This suggests that prolonged thrombin inhibition using this r-hirudin regimen is not suitable as an antirestenotic intervention.
凝血酶是平滑肌细胞增殖的强效刺激剂和内皮细胞生长的抑制剂，被认为是血管成形术后再狭窄的重要介质。急性给予凝血酶抑制剂重组水蛭素可减少血管成形术动物模型中的再狭窄，可能是通过抑制平滑肌细胞增殖实现的。由于凝血酶诱导的增殖需要长时间暴露于激动剂，因此推测长期给予重组水蛭素可更大程度地减小病变大小。
确定在兔内膜增生模型中，长期使用重组水蛭素治疗是否会减小病变大小并改善血管功能。
雄性新西兰白兔喂食高胆固醇饮食4周，之后对其左锁骨下动脉进行球囊损伤。将兔子分为三组之一：对照组（未用药）；重组水蛭素急性治疗组（静脉注射0.33 mg/kg，皮下注射0.48 mg/kg每小时，共24小时）；或重组水蛭素慢性治疗组（静脉注射0.33 mg/kg，皮下注射0.6 mg/kg每小时，共28天）。手术后兔子喂食正常饮食，并在30天后处死。取出左（血管成形术侧）和右（对照）锁骨下动脉进行形态学和功能分析。
对照组未经治疗的兔子血管成形术后产生了大的内膜病变[外弹力膜（EEL）内面积的15.0±1.8%]，主要由平滑肌细胞（34±16个细胞/切片）和富含脂质的巨噬细胞或泡沫细胞（118±51个细胞/切片）组成。重组水蛭素急性治疗既未抑制平滑肌细胞增殖（35±12个细胞/切片），也未减小内膜病变大小（EEL内面积的23.5±4.6%）。重组水蛭素慢性治疗显著增加了增殖细胞数量（55±15个细胞/切片，P<0.05）和病变大小（EEL内面积的28.5±5.6%，P<0.05）。此外，重组水蛭素治疗似乎加剧而非改善了血管成形术引起的功能改变。
长期使用重组水蛭素治疗既不能抑制兔左锁骨下动脉血管成形术后血管平滑肌细胞增殖，也不能减小内膜病变大小。此外，重组水蛭素治疗可能会损害血管成形术后的内皮细胞功能。这表明使用这种重组水蛭素方案长期抑制凝血酶不适合作为抗再狭窄干预措施。
