1. Polymeric-based perivascular delivery of a nitric oxide donor inhibits intimal thickening after balloon denudation arterial injury: role of nuclear factor-kappaB.
- Author
-
Kaul S, Cercek B, Rengstrom J, Xu XP, Molloy MD, Dimayuga P, Parikh AK, Fishbein MC, Nilsson J, Rajavashisth TB, and Shah PK
- Subjects
- Animals, Arteries drug effects, Arteries injuries, Arteries pathology, Bleeding Time, Cell Division drug effects, Cyclic GMP metabolism, Hyperplasia metabolism, Hyperplasia pathology, Hyperplasia prevention & control, Lactic Acid, Male, Platelet Aggregation, Polyglycolic Acid, Polylactic Acid-Polyglycolic Acid Copolymer, Polymers, Proliferating Cell Nuclear Antigen metabolism, Rats, Rats, Sprague-Dawley, Tunica Intima injuries, Tunica Intima pathology, Angioplasty, Balloon adverse effects, Drug Delivery Systems, NF-kappa B metabolism, Nitric Oxide metabolism, Spermine administration & dosage, Tunica Intima drug effects
- Abstract
Objectives: To examine the effect of a polymeric-based periadventitial delivery of a nitric oxide (NO)-releasing diazeniumdiolate, spermine/NO (SPER/NO), on balloon injury-induced neointimal hyperplasia in rat ileofemoral arteries., Background: Reduced local bioavailability and adverse side effects limit systemic administration of NO to modulate vascular response to injury., Methods: A polylactic-polyglycolic acid polymeric matrix containing 2.5% SPER/NO (w/w) was applied around the injured arteries. Quantitative histomorphometry was performed at day 14, proliferating cell nuclear antigen (PCNA) immunohistochemistry at day 3 to assess effects on smooth muscle proliferation and electrophoretic mobility shift assay to evaluate effects on transcription factor, nuclear factor-kappaB (NF-kappaB)., Results: Treatment with SPER/NO reduced the intimal area (0.011 +/- 0.009 vs. 0.035 +/- 0.006 mm2 control, p < 0.01) and the intima to media ratio (0.089 +/- 0.062 vs. 0.330 +/- 0.057 control, p < 0.005). Spermine/nitric oxide produced a profound inhibition of PCNA-positive cells (>75%, p < 0.005) and significantly suppressed the injury-induced activation of NF-kappaB. Vascular cyclic guanosine monophosphate (cGMP) levels were elevated after treatment with the SPER/NO (0.28 +/- 0.03 vs. 0.17 +/- 0.02 pmol/mg tissue control, p < 0.01). The inhibitory effects on neointimal proliferation were localized to the site of application of SPER/NO and were not associated with any changes in platelet aggregation or bleeding time. Neither SPER nor polymer alone had any significant effects on any of the variables examined., Conclusions: Polymeric-based perivascular delivery of a NO donor produces a marked localized inhibition of neointimal proliferation in balloon-injured arteries. This phenomenon is associated with suppression of NF-kappaB activation and elevation of the vascular cGMP at the site of injury.
- Published
- 2000
- Full Text
- View/download PDF