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). Furthermore, 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.
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