Application of serial in vivo magnetic resonance imaging to evaluate the efficacy of endothelin receptor antagonist SB 217242 in the rat carotid artery model of neointima formation.
BACKGROUND
Alleviating vascular restenosis after percutaneous transluminal angioplasty remains a formidable challenge. Although multiple factors have been implicated in the pathophysiology of this vascular remodeling disorder, only limited therapeutic success has been achieved. Endothelin (ET)-1 has recently been implicated in the pathogenesis of neointimal growth. We report the in vivo efficacy of SB 217242, a nonpeptide dual ET(A)/ET(B) receptor antagonist with high oral bioavailability, in the rat carotid artery balloon angioplasty model.


RESULTS
The lumen volumes of carotid arteries were estimated serially with magnetic resonance imaging (MRI) at baseline and at day 7 and day 14 after balloon catheter-induced denudation of the carotid arterial wall in the rat. Histomorphometric analysis was performed at day 14 after surgery to quantitate intimal hyperplasia. Statistical analysis was performed with ANOVA followed by post hoc Newman-Keuls multiple comparison test. In comparison to vehicle-treated animals, a 20% protection (P<0.05) from reduction was shown in the estimated lumen volume with long-term administration of SB 217242 (15 mg/kg BID p.o.). Histologic analyses indicated a 42% decrease (P<0.05) in neointimal growth. The MRI lumen volumes had a significant correlation with the corresponding histologic indices.


CONCLUSIONS
Serial MRI provides the opportunity to assess the progression of vascular lumen volume in vivo after balloon angioplasty. MRI measurements can, in conjunction with in vitro histologic measurements, contribute to the understanding of the actions of pharmacologic agents in experimental models of neointima formation. With the use of serial MRI and histologic measurements, it is demonstrated that protection from both lumen volume reduction and neointima formation is obtained in this model by use of a potent, nonpeptide dual ET(A)/ET(B) receptor antagonist, SB 217242. Furthermore, this study provides additional support to the implication of ET-1 in the pathophysiology of neointima formation.
Chandra
S
S
Department of Physical and Structural Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA. sudeep_chandra-1@sbphrd.com
Clark
L V
LV
Coatney
R W
RW
Phan
L
L
Sarkar
S K
SK
Ohlstein
E H
EH
D000800:Angioplasty, Balloon; D000818:Animals; D002264:Carboxylic Acids / Q000627:therapeutic use*; D002339:Carotid Arteries / Q000187:drug effects* / Q000254:growth & development* / Q000473:pathology; D016893:Carotid Stenosis / Q000517:prevention & control / Q000628:therapy; D065128:Endothelin Receptor Antagonists; D007189:Indans / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D017539:Tunica Intima / Q000187:drug effects* / Q000254:growth & development* / Q000473:pathology
D002264:Carboxylic Acids; D065128:Endothelin Receptor Antagonists; D007189:Indans; C098288:enrasentan