Effects Of Prostaglandin E₁ And Valsartan On Restenosis After Balloon-induced Carotid Injury In Rabbit

Restenosis is a major complication which limits the long-term efficacy of CEA and PTCA. Migration and proliferation of activated medial smooth muscle cells (SMCs) is considered to be an important mechanism in this process. Objective1. To establish a restenosis model by balloon-induced carotid injury in rabbit and investigate the mechanism of restenosis.2. To investigate the effects of the specific angiotensin II (Ang II) AT₁-receptor blocker (Valsartan) and Prostaglandin E₁ (PGE₁) on restenosis after common carotid balloon injury in rabbits.MethodsBalloon-induced injuries in right common carotids were performed on forty rabbits. After operation, all rabbits were randomly divided into four groups: control group ( n = 10 ) , PGE₁ treated-group ( n = 10 ), Valsartan treated-group ( n = 10 ), and both PGE₁ and Valsartan treated group ( n = 10 ). In PGE₁-treated group, the rabbits were injected with PGE₁ l0d ( 0.2 11 g-kg-1 ?d-1 ) through ear vein. In Valsartan-treated group, the rabbits were administrated with Valsartan lOd (10 mg-kg-1 -d-1 ). Changes of the levels of plasma endothelin-1 ( ET-1 ), thromboxane B2(TXB2), 6-keto-PGF₁ and the ratio of TXB2/6-keto-PGF1 were measured by radioimmunoassay ( RIA ) before operation and 3 days, 1 week, 2 weeks, 4 weeks, 8 weeks after operation respectively. Four weeks and eight weeks after injury, five rabbits of each group were randomly sacrificed and segments of balloon-injured carotids were excised for pathomorphological examination. The injured carotid segments were processed to examine SMCs proliferation by hematoxylin-eosin staining, proliferation cell nuclear antigen (PCNA) immunohistochemistry staining and apoptotic body staining by terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL). Results1. Both PGE₁ and AT₁-receptor antagonist (Valsartan) had marked effects on plasma levels of endothelin ET-1, thromboxane TXB2 and 6-keto-PGF₁. The most dramatic effects on ET-1 levels were seen in rabbits treated with both PGE₁ and Valsartan, where the levels were reduced significantly compared with untreated rabbits in control group (p< 0.01). TXB2 levels greatly increased after carotid injury in control group but decreased markedly in rabbits treated with PGE₁ or valsartan (P< 0.01). In untreated animals, 6-keto-PGF₁ levels decreased significantly after injury. But for the PGEi, valsartan and therapeutic alliance groups, there were significant increases in levels of this prostaglandin derivative (P < 0.05).2. PGE₁, valsartan and therapeutic alliance treatment led to a significant reduction in the neointimal and medial thickness and the extent of lumen restenosis compared with untreated animals at 4 weeks or 8 weeks. All treatments were effective in reducing neointimal and medial areas and significantly (p < 0.01) reduced cell proliferation.3. PGE₁, valsartan and therapeutic alliance treatment had markedeffects on ratio of apoptosis and PCNA at 4 weeks or 8 weeks. The most dramatic effects on ratio of apoptosis and PCNA were observed in rabbits treated with both PGE₁ and Valsartan, where the ratio of apoptosis was increased significantly and the ratio of PCNA was greatly decreased compared with control animals (p < 0.05). Conclusion1. After balloon-induced injury, the changes of the levels of plasma ET-1, TXB2, 6-keto-PGFl and the ratio of TXB2/6-keto-PGF₁ may play an important role in restenosis.2. PGEi, valsartan and therapeutic alliance treatment may have preventive effects on restenosis by maintaining the balance of plasma ET-1, TXB2, 6-keto-PGF₁ and the ratio of TXB2/6-keto-PGF₁,. There is synergistic effect between PGEi and valsartan.3. The pathophysiological mechanism of restenosis being especially complicated, it seems that therapeutic alliance treatment is superior to single treatment.