title: U74389F, a 21-aminosteroid antioxidant, improves neoendothelial morphology, but not neointimal thickening after balloon catheter injury.
abstract: U74389F is a compound in a family of 21-aminosteroids devoid of classical glucocorticoid action that inhibit lipid peroxidation. These compounds improve neurologic function and tissue survival after head or spinal cord injury. Dexamethasone inhibits development of intimal hyperplasia (IH) and improves attenuated nitric oxide (NO) production of the rabbit aorta subsequent to balloon catheter injury. We tested the hypothesis that U74389F is protective in a catheter-induced endothelial-denuded and arterial injury model. A 4-Fr Fogarty balloon (BALL) embolectomy catheter was passed through the thoracic aorta of New Zealand White rabbits treated with 15 mg/kg U74389F (LAZ) 2 days before and 1 week after injury. Animals were killed at 4 weeks after surgical intervention, and formation of IH was determined by calculating the intimal/medial ratio (I/M). The treatment groups of animals were injured untreated (BALL), injured treated (BALL/LAZ), uninjured treated (CONTROL/LAZ), and sham-operated treated (SHAM/LAZ). Scanning electron microscopy revealed that after injury lazaroid treatment produced an improvement of the neoendothelium (alignment in the direction of blood and fewer intercellular gaps) as compared with injured but untreated aortas. Relaxation to acetylcholine (NO formation) was impaired in aortic rings from catheterized animals; lazaroid treatment improved the relaxation to 10-6 mol/L acetylcholine but not to lower concentrations. I/M for SHAM/LAZ, BALL, and BALL/LAZ was 0.02 +/- 0.02, 21.6 +/- 1.6, and 17.2 +/- 2.5, respectively; BALL vs. BALL/LAZ, p < 0.06. An increased contractile response to 120 mmol/L KCl was observed after lazaroid treatment. This is the first report of lazaroid-mediated improvement in the neoendothelial morphology, improved neoendothelial NO generation, and augmented hypopolarizing contractile response, but no attenuation in the development of IH.
authors.affiliation: Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Subramanyam N
authors.initials: SN
authors.lastname: Murthy
authors.forename: Donald L
authors.initials: DL
authors.lastname: Akers
authors.forename: I-Li
authors.initials: IL
authors.lastname: Chen
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Osgood
authors.forename: Raphael
authors.initials: R
authors.lastname: Santiago
authors.forename: Vivian A
authors.initials: VA
authors.lastname: Fonseca
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kadowitz
authors.forename: Dennis B
authors.initials: DB
authors.lastname: McNamara
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001011:Aorta / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D002404:Catheterization / Q000009:adverse effects*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000293:injuries* / Q000473:pathology; D006965:Hyperplasia / Q000188:drug therapy; D008297:Male; D008855:Microscopy, Electron, Scanning; D005996:Nitroglycerin / Q000494:pharmacology; D011281:Pregnatrienes / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D017539:Tunica Intima / Q000187:drug effects / Q000293:injuries* / Q000473:pathology
chemical_list: D000975:Antioxidants; D011281:Pregnatrienes; C074965:U 74389F; D005996:Nitroglycerin