Reduction of Experimental Vein Graft Intimal Hyperplasia by Ketanserin

Abstract

Intimal hyperplasia is considered to be the result of smooth muscle cell proliferation. Experimental vein grafts (VG) in the rabbit develop intimal hyperplasia and a contractile response to serotonin (5-HT), mediated by a 5-HT2 receptor. 5-HT is known to stimulate smooth muscle cell proliferation in vitro and therefore may be linked to the development of intimal hyperplasia. This study examines the effect of a 5-HT2 antagonist, ketanserin (KT) on vein graft morphology and function at 14 and 28 days after grafting. Forty-three New Zealand White rabbits underwent common carotid interposition bypass grafting. Twenty-two were treated with KT (0.86 mg/kg/day po) 5 days prior to surgery and thereafter until harvest. The remaining 21 animals acted as controls. VG were harvested at 14 (VG14) and 28 (VG28) days for histology or vasoreactivity. Twenty-three VG were harvested by pressure fixation and the midportions of the grafts were examined by videomorphometry. Standard isometric tension studies in response to serotonin and norepinephrine (NE) were performed on the rings from the remaining 20 VG. Contralateral external jugular veins (CV) from both groups were studied to assess the functional toxicity of KT. There were no toxic effects to KT noted. KT therapy did not affect the functional activity of the CV at 14 or 28 days when compared to controls. When compared to controls, KT significantly reduced the intimal thickness (49 ± 11 vs 113 ± 24 μm; P = 0.04) and there was an increase in luminal area (16.89 ± 2.13 vs 8.41 ± 1.50 mm2; P < 0.02) in VG28 only. There were no changes in sensitivity to NE or 5-HT in the KT group compared to the controls at either 14 or 28 days. In KT-treated grafts compared to control grafts maximal tensions in response to NE and 5-HT were increased in VG14 (NE, 0.42 ± 0.2 vs 0.21 ± 0.05 g; 5-HT, 0.68 ± 0.37 vs 0.31 ± 0.11 g; P > 0.05) and were significantly greater in VG28 (NE, 1,42 ± 0.38 vs 0,47 ± 0.06 g; 5-HT, 1.44 ± 0.46 vs 0.3 ± 0.18 g; P < 0.05). In conclusion, this study shows that KT reduces the thickness of intimal hyperplasia with an increase in the responsiveness of smooth muscle cells in VG and a twofold increase in luminal area. Therefore, short-term therapy with KT may be beneficial in controlling intimal hyperplasia in the revascularized patient.