Kinins and the events influenced by an angiotensin-converting enzyme inhibitor during neointima formation in the rat carotid artery

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ObjectiveIn balloon-injured rat carotid arteries, angiotensin-converting enzyme inhibitors (ACEI) decrease neointima formation, and a kinin receptor antagonist partially reverses this inhibitory effect. We studied which of the events leading to neointima formation are involved in the effects of ACEI and kinins.MethodsWe administered 5 mg/kg per day ramipril, either alone or combined with the kinin receptor antagonist icatibant (Hoe 140), on the days each wave occurred and studied the effects on neointima formation 14 days after balloon injury. Ramipril alone or combined with icatibant had no effect on neointima formation when administered from 2 days before to 3 or 5 days after balloon injury. In contrast, ramipril inhibited neointima formation when administered from day 7 to day 14. Treatment with icatibant had a small effect, which was sufficient to abolish the effects of ramipril (control 0.11 ± 0.01 mm2, ramipril 0.08 ± 0.01 mm2; P <0.05; ramipril plus icatibant 0.09 ± 0.01 mm2; NS, ramipril plus icatibant versus control). Thus ramipril was not effective when treatment was stopped after 3 or 5 days, but was mildly effective when treatment was administered during the second week. The effect on migration was studied by counting the number of neointimal cells in rats treated from 2 days before to 4 days after injury. Ramipril decreased the number of cells by 93% compared with controls (control 65.0 ± 13.5 cells/slice, ramipril 4.7 ± 2.0 cells/slice; P <0.001), and this effect was blunted significantly by icatibant (19.5 ± 5.7 cells/slice; P <0.009, versus ramipril; P <0.007, versus controls). The influence of treatment on the rate of proliferation (the 5′-bromo-2′-deoxyuridine index) was studied in the media 3 days, and in the neointima 7 and 10 days after balloon injury. Although proliferation peaked in the neointima after 7 days, there were no differences among the groups at any time. Thus neither ramipril nor icatibant affected the rate of proliferation at the times sampled. Ramipril increased cell density (cells/mm2) in the neointima, and this effect was abolished by cotreatment with icatibant (P < 0.05).ConclusionThe ACEI needs to be present throughout the experimental period to be most effective. ACEI act on neointima formation in part by inhibiting migration; thus, because ramipril was mildly effective when administered from 7 to 10 days after injury, it is likely that vascular smooth muscle cell migration also occurs continuously. Kinins help mediate roughly 30% of the effect of ACEI on migration. In addition, ACEI, through kinins, affect a process that increases the density of the cells in the neointima, perhaps by decreasing extracellular matrix deposition.

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