ROLE OF THE RENIN-ANGIOTENSIN SYSTEM IN NEOINTIMA FORMATION AFTER INJURY IN RABBITS

We investigated the role of the renin-angiotensin system in neointima formation in a species in which converting enzyme inhibitors have been so far ineffective in suppressing abnormal vascular repair. The effects of converting enzyme inhibition by perindopril and selective blockade of angiotensin subtype 1 receptor by DuP 753 were assessed on neointima formation after balloon injury of rabbit carotid artery. Myointimal growth was measured by histomorphometric analysis. In rabbits treated 6 days before and for 14 days after injury, perindopril (2 mg/kg per day PO, n=7) significantly reduced neointima formation (-51%, P<.01). DuP 753 (1 mg/d, n=8) infused perivascularly for 14 days in the vicinity of injured carotid artery also markedly suppressed myointimal thickening (-60%, P<.01). To determine whether angiotensin subtype 2 receptor was implicated in this vascular response, we infused CGP 42112A, a specific subtype 2 receptor ligand, continuously for 14 days according to the same protocol of DuP 753 administration. CGP 42112A (1 mg/d) did not change the neointima-media ratio, indicating that angiotensin subtype 2 receptors were not involved in myointimal hyperplasia in rabbits. Thus in rabbits, the renin-angiotensin system plays a major role in neointima formation, and the protective effect of perindopril appears to be mediated mainly by inhibition of angiotensin II production, because blockade of the subtype 1 receptor reduced myointimal growth in a manner similar to that of converting enzyme inhibition and because intracarotid infusion of angiotensin II (500 ng/min) at the site of injury enhanced the vascular response (+39%, P<.05). Bradykinin (500 ng/min) administered in the same conditions as angiotensin II did not modify neointima formation.