Localized versus systemic angiotensin II receptor inhibition of intimal hyperplasia in experimental vein grafts by the specific angiotensin II receptor inhibitor L158,809

Background, This study examines the effect of the angiotensin II receptor (type I) antagonist (L158,809) on the formation of vein graft intimal hyperplasia in vivo, by both localized and systemic administration. Methods, Forty New Zealand White rabbits underwent right carotid interposition bypass grafting with the external jugular vein and were killed on postoperative day 28. To determine the effect of L158, 809 on the development of intimal hyperplasia, 10 animals received long-term oral therapy with L158,809 (10 mg/kg/day, begun 5 days before operation and continued until harvest), 10 animals underwent coating of the grafts with a pluronic gel containing L158, 809 (10(-5) mol/L), and 20 animals were controls (10 with and 10 without pluronic gel). These grafts were harvested for either histologic analysis (n = 6 per group) or in vitro isometric tension studies to angiotensin II (n = 4 per group). Results. Long-term oral treatment with L158 809 produced a 43% decrease ill intimal thickness from 76 +/- 6 mu m (mean +/- SEM in the control animals to 43 +/- 7 mu m in the treated vein grafts (p = 0.002). There was also a significant decrease (44%) in the medial thicknesses between the control (75 +/- 4 mu m) and L158,809-treated (42 +/- 6 mu m) vein grafts (p = 0.007). The contractile responses to angiotensin II wne abolished in the vein grafts by long-term L158,809 therapy. Local application by gel of L158,809 produced a significant decrease (33%) in the intimal thickness (48 +/- 3 mu m) but no change in medial thicknesses (76 +/- 6 mu m) compared with control grafts. The contractile responses to angiotensin II were unchanged in the vein grafts by local L158, 809 therapy. Conclusions, This study shows that a local single application of L158,809 will reduce the intimal response but not the medial response in vein grafts, whereas long-term treatment will reduce intimal hyperplasia and the medial response in experimental vein grafts. Therefore angiotensin II acting through AT(1) receptors mediates a significant part of the intimal hyperplastic response in vein grafts that appears to involve two phases: an acute intimal response requiring short-term therapy and a long-term medial response that requires prolonged therapy.