Beneficial effects of NO-releasing derivative of flurbiprofen (HCT-1026) in rat model of vascular injury and restenosis.
One of the major problems related to the percutaneous transluminal coronary angioplasty technique is the renarrowing of the vessel, a phenomenon known as restenosis. NO and nonsteroidal anti-inflammatory drugs have been shown to play a role in this pathology. The main problem with the use of conventional NO donors is that they affect blood pressure and flow, and for these reasons, they cannot be used safely in clinical practice. The aim of this study was to evaluate, with the use of a rat model of balloon angioplasty, whether a structural derivative of flurbiprofen, containing an added NO-releasing moiety (HCT-1026), is able to reduce or prevent neointimal formation. Rats were treated for 14 days with equimolar doses of flurbiprofen (2, 7, and 21 mg/kg) or HCT-1026 (3, 10, and 30 mg/kg). After this 14-day treatment, HCT-1026 but not flurbiprofen significantly modified the neointima/media ratio. The reduction in the neointimal proliferation obtained with HCT-1026 was well correlated with an increase in nitrite/nitrate plasma levels and a reduced cell proliferation. Neither HCT-1026 nor flurbiprofen affected inducible NO synthase induction in injured vessels. In conclusion, HCT-1026 caused a significant reduction in restenosis that appears to be directly related to NO release. HCT-1026 may prove to be beneficial in preventing or delaying restenosis in humans.
Maffia
Pasquale
P
Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy.
Ianaro
Angela
A
Sorrentino
Raffella
R
Lippolis
Laura
L
Maiello
Francesco M
FM
del Soldato
Piero
P
Ialenti
Armando
A
Cirino
Giuseppe
G
D000284:Administration, Oral; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002339:Carotid Arteries / Q000201:enzymology / Q000473:pathology; D023903:Coronary Restenosis / Q000209:etiology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006965:Hyperplasia / Q000517:prevention & control; D007150:Immunohistochemistry; D008297:Male; D009569:Nitric Oxide / Q000097:blood*; D019001:Nitric Oxide Synthase / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013272:Stomach Diseases / Q000139:chemically induced / Q000473:pathology; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018809:Proliferating Cell Nuclear Antigen; C095631:nitroflurbiprofen; D009569:Nitric Oxide; D005480:Flurbiprofen; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat