KININS AND THE EVENTS INFLUENCED BY AN ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR DURING NEOINTIMA FORMATION IN THE RAT CAROTID-ARTERY

Objective In balloon-injured rat carotid arteries, angiotensin-convert ing enzyme inhibitors (ACEI) decrease neointima formation, and a kinin receptor antagonist partially reverses this inhibitory effect. We stu died which of the events leading to neointima formation are involved i n the effects of ACEI and kinins. Methods We administered 5 mg/kg per day ramipril, either alone or combined with the kinin receptor antagon ist icatibant (Hoe 140), on the days each wave occurred and studied th e effects on neointima formation 14 days after balloon injury, Ramipri l alone or combined with icatibant had no effect on neointima formatio n when administered from 2 days before to 3 or 5 days after balloon in jury, in contrast, ramipril inhibited neointima formation when adminis tered from day 7 to day 14. Treatment with icatibant had a small effec t, which was sufficient to abolish the effects of ramipril (control 0. 11 +/- 0.01 mm(2), ramipril 0.08 +/- 0.01 mm(2); P < 0.05; ramipril pl us icatibant 0.09 +/- 0.01 mm(2); NS, ramipril plus icatibant versus c ontrol). Thus ramipril was not effective when treatment was stopped af ter 3 or 5 days, but was mildly effective when treatment was administe red during the second week The effect on migration was studied by coun ting 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 signif icantly by icatibant (19.5 +/- 5.7 cells/slice; P < 0.009, versus rami pril; P < 0.007, versus controls). The influence of treatment on the r ate 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, th ere were no differences among the groups at any time, Thus neither ram ipril nor icatibant affected the rate of proliferation at the times sa mpled. Ramipril increased cell density (cells/mm(2)) in the neointima, and this effect was abolished by cotreatment with icatibant (P < 0.05 ), Conclusion The 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 wh en administered from 7 to 10 days after injury, it is likely that vasc ular 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 t he cells in the neointima, perhaps by decreasing extracellular matrix deposition.