Subcutaneous infusion of r-hirudin does not inhibit neointimal proliferation after angioplasty of the subclavian artery in cholesterol-fed rabbits.
BACKGROUND
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.


OBJECTIVE
To determine whether prolonged treatment with r-hirudin would reduce lesion size and improve vascular function in a rabbit model of neointimal proliferation.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Hadoke
P W
PW
Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, Scotland, UK.
Wadsworth
R M
RM
Wainwright
C L
CL
Butler
K D
KD
Giddings
M J
MJ
D017130:Angioplasty; D000818:Animals; D000991:Antithrombins / Q000008:administration & dosage* / Q000494:pharmacology; D002791:Cholesterol, Dietary / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D006629:Hirudins / Q000008:administration & dosage* / Q000494:pharmacology; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D011817:Rabbits; D012016:Reference Values; D013348:Subclavian Artery / Q000187:drug effects / Q000473:pathology*
D000991:Antithrombins; D002791:Cholesterol, Dietary; D006629:Hirudins