title: Application of magnetic resonance imaging for evaluation of the efficacy of SB 217242 in neointimal formation.
abstract: Although several factors have been implicated in the pathophysiology of vascular neointimal formation and restenosis after balloon angioplasty, current therapies have failed to alleviate these conditions. Because endothelin-1 (ET-1) has been implicated in the pathogenesis of the neointimal growth, this study examined the in vivo efficacy of SB 217242, a potent nonpeptide mixed ETA/ETB receptor antagonist with high oral bioavailability, in the rat carotid balloon angioplasty model. A novel magnetic resonance imaging (MRI) approach was used for evaluation. MRI is a high-resolution, noninvasive spatial imaging modality that can serially monitor arterial luminal caliber in vivo, along with histologic evaluation. In vivo luminal volumes for the left carotid artery (LCA) were measured by MRI at baseline (before surgery) and again at 14 days after angioplasty. SB 217242 (30 mg/kg/day p.o.) was administered daily for 14 days after angioplasty. On day 14, SB 217242 provided 20% protection (p < 0.05) on neointimal-mediated decrease in luminal volume as measured by MRI. The non-ballooned right carotid arteries of both groups had significantly increased luminal volume on day 14 with respect to baseline values, indicating compensation for the decreased luminal size of the LCA. Histologic analysis of the mean intimal-to-medial ratio demonstrated that SB 217242 provided 42% (p < 0.05) protection. These results demonstrate that ET receptor antagonism can inhibit neointimal formation after balloon angioplasty and that MRI technology can provide valuable insight for noninvasive assessment of vascular lesion development.
authors.affiliation: SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chandra
authors.forename: S
authors.initials: S
authors.lastname: Sarkar
authors.forename: J D
authors.initials: JD
authors.lastname: Elliot
authors.forename: E H
authors.initials: EH
authors.lastname: Ohlstein
mesh_terms: D000800:Angioplasty, Balloon; D000818:Animals; D002264:Carboxylic Acids / Q000494:pharmacology*; D002339:Carotid Arteries / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D065128:Endothelin Receptor Antagonists; D007189:Indans / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002264:Carboxylic Acids; D065128:Endothelin Receptor Antagonists; D007189:Indans; C098288:enrasentan