MECHANISM OF INHIBITION OF NEOINTIMAL FORMATION BY THE ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR CILAZAPRIL - A STUDY IN BALLOON CATHETER-INJURED RAT CAROTID ARTERIES

We investigated the mechanism of inhibition of neointima formation by the angiotensin-converting enzyme inhibitor cilazapril in a rat model of balloon-catheter injury in the carotid artery. We looked for the ef fects of cilazapril on all phases of the response to injury, ie, on pr oliferation of smooth muscle cells (SMCs) in the media, their migratio n, their proliferation in the neointima, and their deposition of extra cellular matrix in the neointima. Although treatment was discontinued after 2 weeks, the inhibitory effect of cilazapril on neointimal forma tion was evident even 52 weeks after injury. The amount of extracellul ar matrix deposited in the intima during cilazapril treatment was decr eased by 20% 2 weeks after injury, but no effect was seen if tissues w ere analyzed at 4 or 52 weeks. [H-3]Thymidine-labeled cells (pulse lab eling as well as 14-day continuous labeling) showed a decrease in SMC labeling in the tunica media by 50%, but no inhibition in the labeling indices was seen in the neointima. The fraction of unlabeled neointim al cells in the cilazapril-treated rats as judged from continuous labe ling experiments was inhibited by 86%. Taken together, these data sugg est an antiproliferative effect on medial SMCs and an inhibition of SM C migration into the intima by cilazapril. Since intimal extracellular matrix deposition was only delayed, the decrease in medial SMC prolif eration and subsequent migration seems to be the main reason for the r eduction of neointima formation.