Research shows that angiotensin II promotes inflammation and vascular smooth muscle proliferation. This is especially the case after vascular injury has occurred. These findings suggest angiotensin II may have a role in restenosis. Furthermore, high-dose administration of angiotensin converting enzyme (ACE) inhibitors reduces neointima formation in animal studies.

However, recent trials have not shown that ACE inhibitors have an effect on restenosis in humans. This may be because investigators were concerned about side effects, and so used systemic doses of ACE inhibitors too low to act against restenosis. One alternative to systemic dosing of ACE inhibitors is local delivery using drug-coated stents. With this strategy, investigators may be able to deliver high doses locally with minimal systemic side effects.

Accordingly, Dr. Wang and colleagues have studied stent delivery of the ACE inhibitor perindopril in a rabbit balloon injury model. They hypothesized that perindopril would inhibit neointima formation and inflammation at the site of injury.

They deployed channeled stents with embedded microspheres containing perindopril in the aortas of 8 New Zealand white rabbits. These stents release ACE inhibitor at the rate of 2 mg per day for 28 days. Another 8 rabbits received stents without ACE inhibitor. Subsequently, investigators subjected all stented aortas to a balloon injury. They also fed the animals a high cholesterol diet for the length of the study.

Investigators performed in vitro function analysis, morphological analysis of the intima/media ratio, evaluation of local inflammatory cell infiltrate, and evaluation of smooth muscle cell proliferation in these rabbits.

In vitro function: Results of the analysis revealed that the stents with perindopril delivered significant ACE inhibitory activity. This activity slowly decreased over time but was consistent through the final analysis at 25 days.

Degree of plaque formation: The mean intima/media ratio was significantly smaller in the perindopril group versus controls. This was true at both the day 7 and day 28 analyses.

Local inflammatory cell infiltrate: At day 7, the number of neutrophils in the intima was significantly lower in the perindopril treatment group compared with controls (p < 0.01).

Smooth muscle cell proliferation: PCNA immunohistochemistry was used as a measure of smooth muscle cell proliferation. The number of PCNA-positive cells in the perindopril stent group was not significantly different from controls (p = 0.65).

This study has shown that local and controlled delivery of high-dose perindopril can reduce neointima formation and inflammation without changes in smooth muscle cell proliferation. These results support previous research suggesting that ACE inhibition reduces neointima formation through inhibition of smooth muscle cell migration, rather than inhibition smooth muscle cell formation.

Dr. Wang said future human trials may evaluate the stent-based delivery of ACE inhibitors for suppression of ACE and angiotensin II activity.