Beneficial effect of a short-acting NO donor for the prevention of neointimal hyperplasia.
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.
Division of Vascular Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Charles G
CG
Pearce
Samer F
SF
Najjar
Muneera R
MR
Kapadia
Jozef
J
Murar
Jason
J
Eng
Brian
B
Lyle
Oliver O
OO
Aalami
Qun
Q
Jiang
Joseph A
JA
Hrabie
Joseph E
JE
Saavedra
Larry K
LK
Keefer
Melina R
MR
Kibbe
D000180:Acrylic Resins / Q000008:administration & dosage*; D000818:Animals; D017536:Carotid Artery, Common / Q000187:drug effects / Q000473:pathology*; D016893:Carotid Stenosis / Q000517:prevention & control; D003979:Diazonium Compounds / Q000008:administration & dosage*; D004304:Dosage Forms; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems; D006207:Half-Life; D006965:Hyperplasia / Q000473:pathology / Q000517:prevention & control; D016130:Immunophenotyping; D007249:Inflammation / Q000188:drug therapy; D019394:Ki-67 Antigen; D017493:Leukocyte Common Antigens; D008297:Male; D020030:Nitric Oxide Donors / Q000008:administration & dosage*; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology
D000180:Acrylic Resins; D003979:Diazonium Compounds; D004304:Dosage Forms; D019394:Ki-67 Antigen; D020030:Nitric Oxide Donors; C527445:diazeniumdiolated poly(acrylonitrile); C102043:proline-nitric oxide; D011392:Proline; D017493:Leukocyte Common Antigens