Perivascular delivery of losartan with surgical fibrin glue prevents neointimal hyperplasia after arterial injury.
OBJECTIVE
Long-term success of revascularization procedures is limited by recurrent stenosis, a reduction in vascular lumen area that results from neointimal hyperplasia. Inhibitors of the renin-angiotensin system, such as losartan, have potential to prevent recurrent stenosis; however, to date, efficacy has not been demonstrated in either animal models or human beings. While we have previously reported that treatment with a satisfactory dose may be an important element in obtaining efficacy, oral delivery cannot achieve the required concentration. We therefore tested the ability of losartan to restrict neointimal hyperplasia after local delivery of an elevated dose in a fibrin glue.


METHODS
The porcine saphenous artery was subjected to balloon angioplasty. Losartan (25 micromol/mL) was applied directly to the adventitial surface of the injured vessel after mixing with 1.0 mL of Tisseel. Neointimal formation was quantified after 14 days with morphometry, and immunologic staining was used to monitor expression of proteins associated with cell proliferation, migration, and phenotypic modulation.


RESULTS
A statistically significant decrease of 82% (n = 5) in neointimal area was obtained with losartan, and cell proliferation, as defined by proliferating cell nuclear antigen (PCNA) expression, was inhibited by 97%. Reduced cyclin A expression in losartan-treated vessels confirmed that cell cycle progression was blocked; however, the presence of cytokeratin 8 and tenascin in the media and neointima of injured vessels, regardless of treatment, suggested that losartan does not restrict phenotypic modulation. Inhibition of MT1-MMP (MMP-14) expression by losartan indicated that this inhibitor likely suppresses cell migration as well.


CONCLUSIONS
These data demonstrate that losartan can effectively prevent recurrent stenosis when delivered locally with a fibrin glue such as Tisseel. Our results also indicate that losartan may operate by interfering with the expression of proteins required for cell cycle progression and migration.


CONCLUSIONS
Release of angiotensin II in response to vascular injury may promote neointimal hyperplasia, because this hormone can stimulate smooth muscle cell proliferation and migration. This study demonstrates that local application of an angiotensin receptor antagonist, losartan, to the site of injury can effectively prevent neointimal hyperplasia after balloon angioplasty. Application of losartan to the perivascular surface of the injured vessel in a surgical fibrin glue enabled delivery of a dose that exceeds the maximum attainable, via a systemic delivery route. The glue also served as a depot from which the drug was slowly released over time. Treatment with losartan may be a viable approach for controlling neointimal hyperplasia at locations (eg, grafts) that are accessible during a surgical procedure.
Moon
Michael C
MC
Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, Winnipeg, MB, Canada.
Molnar
Katerina
K
Yau
Lorraine
L
Zahradka
Peter
P
D000287:Administration, Topical; D000800:Angioplasty, Balloon / Q000009:adverse effects; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001157:Arterial Occlusive Diseases / Q000209:etiology / Q000517:prevention & control; D001158:Arteries / Q000187:drug effects* / Q000293:injuries; D016503:Drug Delivery Systems / Q000379:methods*; D015718:Fibrin Tissue Adhesive / Q000008:administration & dosage; D006965:Hyperplasia; D019808:Losartan / Q000008:administration & dosage*; D008297:Male; D023421:Models, Animal; D016037:Single-Blind Method; D013552:Swine; D014014:Tissue Adhesives / Q000008:administration & dosage; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D015718:Fibrin Tissue Adhesive; D014014:Tissue Adhesives; D019808:Losartan