Lazaroid Therapy (Methylaminochroman: U83836E) Reduces Vein Graft Intimal Hyperplasia

Abstract

The development of intimal hyperplasia is now recognized as a major impediment to graft patency and recent studies suggest that the infiltration of polymorphonucleocytes and oxygen free radical mediated injury are involved in the early development of intimal hyperplasia. This study examines the effect of a methylaminochroman, U83836E (Upjohn Company), a second generation lazaroid, in controlling the development of intimal hyperplasia and its associated smooth muscle cell physiological responses in an experimental model of vein bypass grafting. Twenty New Zealand White rabbits had a right carotid interposition bypass graft using the ipsilateral external jugular vein. Ten animals received chronic oral therapy with U83836E (10 mg/kg/day; begun 5 days before surgery and continued until harvest) and 10 control animals received vehicle only. All animals were sacrificed on the 28th postoperative day. Vein grafts were harvested either for morphology/videomorphometry (n= 6 per group) or forin vitroisometric tension studies (n= 4; four 5-mm rings per graft). The incorporation of [3H]thymidine into the cellular DNA of serum-stimulated rabbit aortic smooth muscle cells (passage 6th to 9th) was also assessed in the presence of increasing concentrations of U83836E (10−9to 10−4M). Treatment with U83836E produced a 41% decrease in overall mean intimal thickness in the U83836E-treated vein grafts compared to untreated vein grafts (P= 0.003). There were no differences in the medial thicknesses or luminal dimensions of the control and treated vein grafts. U83836E induced norepinephrine hypersensitivity in both jugular veins and vein grafts compared to controls. Other physiological contractile responses of the jugular veins and vein grafts were unaltered by U83836E. U83836E did not inhibit thein vitro[3H]thymidine incorporation in a dose-dependent manner until very high concentration when there was a significant and precipitous response with anIC50of 67 μM(114 μg/ml) and a maximal inhibition of 97 ± 2% (mean ± SEM) at 80 μM(137 μg/ml). Therapy with the methylaminochroman, U83836E, is beneficial in controlling the early development of intimal hyperplasia without significant changes in the physiological responses of the smooth muscle cells.