© 1995 American Heart Association, Inc.
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Mechanism of Inhibition of Neointimal Formation by the Angiotensin-Converting Enzyme Inhibitor Cilazapril
A Study in Balloon Catheter–Injured Rat Carotid Arteries
From the Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Correspondence to Jürgen Fingerle, Pharma Division, Preclinical Research, PRPV, F. Hoffmann-La Roche Ltd, CH-4002 Basel, Switzerland.
Abstract 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 effects of cilazapril on all phases of the response to injury, ie, on proliferation of smooth muscle cells (SMCs) in the media, their migration, their proliferation in the neointima, and their deposition of extracellular matrix in the neointima. Although treatment was discontinued after 2 weeks, the inhibitory effect of cilazapril on neointimal formation was evident even 52 weeks after injury. The amount of extracellular matrix deposited in the intima during cilazapril treatment was decreased by 20% 2 weeks after injury, but no effect was seen if tissues were analyzed at 4 or 52 weeks. [3H]Thymidine-labeled cells (pulse labeling 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 neointimal cells in the cilazapril-treated rats as judged from continuous labeling experiments was inhibited by 86%. Taken together, these data suggest an antiproliferative effect on medial SMCs and an inhibition of SMC migration into the intima by cilazapril. Since intimal extracellular matrix deposition was only delayed, the decrease in medial SMC proliferation and subsequent migration seems to be the main reason for the reduction of neointima formation.
Key Words: rat • smooth muscle cell • proliferation • migration • cilazapril
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