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Beneficial effect of a short-acting NO donor for the prevention of neointimal hyperplasia.

Abstract
Nitric oxide (NO)-based therapies effectively inhibit neointimal hyperplasia in animal models of arterial injury and bypass grafting, but are not available clinically. We created a simple, effective, locally applied NO-eluting therapy to prevent restenosis after vascular procedures. We investigated the efficacy of perivascular delivery of two distinctly different diazeniumdiolate NO donors, 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (PROLI/NO) (short half-life) and diazeniumdiolated poly(acrylonitrile) (PAN/NO) (long half-life), in powder or gel form (30% poloxamer 407), at inhibiting neointimal hyperplasia using the rat carotid artery injury model. Two weeks postinjury, all of the NO-eluting therapies successfully reduced neointimal hyperplasia. However, most dramatically, PROLI/NO powder reduced intimal area by 91.2% (p<0.05) versus injury alone. PROLI/NO powder was noted to reduce the medial area (40.2% vs injury alone, p<0.05), whereas other groups showed no such effect. Three days postinjury, each NO treatment group significantly reduced cellular proliferation. However, inflammatory markers revealed a distinct pattern: PAN/NO groups displayed increased leukocyte infiltration (p<0.05), whereas PROLI/NO groups displayed less macrophage infiltration (p<0.05). In conclusion, perivascular delivery of diazeniumdiolate NO donors in powder or gel form effectively inhibits neointimal hyperplasia. Application of short-acting PROLI/NO powder most effectively inhibited neointimal hyperplasia and inflammation and may represent a simple, clinically applicable NO-eluting therapy to prevent neointimal hyperplasia and restenosis after open vascular interventions.
AuthorsCharles G Pearce, Samer F Najjar, Muneera R Kapadia, Jozef Murar, Jason Eng, Brian Lyle, Oliver O Aalami, Qun Jiang, Joseph A Hrabie, Joseph E Saavedra, Larry K Keefer, Melina R Kibbe
JournalFree radical biology & medicine (Free Radic Biol Med) Vol. 44 Issue 1 Pg. 73-81 (Jan 01 2008) ISSN: 0891-5849 [Print] United States
PMID18045549 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Acrylic Resins
  • Diazonium Compounds
  • Dosage Forms
  • Ki-67 Antigen
  • Nitric Oxide Donors
  • diazeniumdiolated poly(acrylonitrile)
  • proline-nitric oxide
  • Proline
  • Leukocyte Common Antigens
Topics
  • Acrylic Resins (administration & dosage)
  • Animals
  • Carotid Artery, Common (drug effects, pathology)
  • Carotid Stenosis (prevention & control)
  • Diazonium Compounds (administration & dosage)
  • Dosage Forms
  • Drug Administration Schedule
  • Drug Delivery Systems
  • Half-Life
  • Hyperplasia (pathology, prevention & control)
  • Immunophenotyping
  • Inflammation (drug therapy)
  • Ki-67 Antigen
  • Leukocyte Common Antigens
  • Male
  • Nitric Oxide Donors (administration & dosage)
  • Proline (administration & dosage, analogs & derivatives)
  • Rats
  • Rats, Sprague-Dawley
  • Tunica Intima (drug effects, pathology)

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