CHARACTERIZATION OF ANGIOTENSIN-II RECEPTOR-MEDIATED RESPONSES AND INHIBITION OF INTIMAL HYPERPLASIA IN EXPERIMENTAL VEIN GRAFTS BY THE SPECIFIC ANGIOTENSIN-II RECEPTOR INHIBITOR, L158,809

Objectives: This study characterises pharmacologically the angiotensin II receptor in experimental vein grafts and examines the effect of th e angiotensin II receptor (type I) antagonist (L158,809) on the format ion of vein graft intimal hyperplasia in vivo, as well as the in vitro physiological response to angiotensin II of vein grafts after chronic oral L158,809 treatment. Materials: Thirty New Zealand White rabbits had a right carotid interposition bypass graft using the external jugu lar vein and were killed on the 28th postoperative day. Design: To cha racterise the angiotensin II receptors, concentration response curves to angiotensin II were obtained in vitro in the presence or absence of L158,809. To determine the effect of L158,809 on the development of i ntimal hyperplasia, 10 animals received chronic oral therapy with L158 ,809 (10mg/kg/dny; begun 5 days before surgery and continued until har vest) and 10 animals received vehicle only as controls. These grafts w ere harvested either for histology (n = 6 per group) or for in vitro i sometric tension studies to angiotensin II. Results: The monophasic co ntractile response to angiotensin II in the untreated vein grafts coul d be inhibited in a concentration dependent manner by L158,809 with fi rst order kinetics. Chronic oral treatment with L158,809 produced a 48 % decrease in intimal thickness from 82 +/- 1 mu m (mean +/- S.E.M.) i n the controls to 43 +/- 7 mu m in the treated vein grafts (p=0.002). There was also a significant decrease (45%) in the medial thickness be tween the control (76+/-6 mu m) and L158,809 treated (42 +/- 6 mu m) v ein grafts (p = 0.007). The responses to angiotensin II were abolished in the vein grafts by chronic L158,809 therapy Conclusions: This stud y suggests that vein graft angiotensin II responses are mediated throu gh a type 1 receptor and that chronic inhibition with L158,809, signif icantly reduces intimal hyperplasia and medial hypertrophy in experime ntal vein grafts and concomitantly abolishes the in vitro responses to angiotensin II. Therefore, angiotensin II acting through AT1 receptor s mediates a significant part of the intimal hyperplastic response in vein grafts.