Application of in vivo and ex vivo magnetic resonance imaging for evaluation of tranilast on neointima formation following balloon angioplasty of the rat carotid artery.
OBJECTIVE
Recent studies suggest that tranilast inhibits a variety of agents implicated in neointimal growth and restenosis in experimental animal models and humans. We report here a study evaluating the efficacy of tranilast in the rat carotid artery balloon angioplasty model, a model that mimics many aspects of the percutaneous transluminal angioplasty procedure in humans. Efficacy was determined based on in vivo and ex vivo magnetic resonance imaging (MRI) as well as by histomorphometry. The utility of this study, using a reverse paradigm, is to investigate if agents successful in the clinic can demonstrate efficacy in this animal model primary screen as measured by MRI and histomorphometry.


METHODS
Tranilast (300 mg/kg/day, p.o.) was administered to Sprague-Dawley rats 3 days prior to balloon injury and continued for 14 days after injury. Three methods of measuring the vascular injury that occurs in this model were employed: (1) in vivo MRI, used to measure in vivo lumen volumes for the carotid artery once at baseline (pre-surgery) and again at 14 days post angioplasty; (2) ex vivo MRI (and histomorphometry), used to evaluate the total arterial wall thickness and the intima-to-media ratio; and (3) analysis of collagen density, used to evaluate the efficacy of tranilast to abrogate collagen synthesis and deposition following vascular injury.


RESULTS
Tranilast provided 33% protection (P<0.05) from angioplasty-induced lumen narrowing as measured by MRI in vivo. The results of the ex vivo MR analysis of total wall thickness showed a 14% protection of angioplasty-induced narrowing (P<0.05), and the mean intima-to-media ratio showed a 39% (P<0.006) protection for the tranilast-treated rats. Histological analysis of the mean intima-to-media ratio demonstrated that tranilast provided 36% (P<0. 01) protection in the intima-to-media ratio. Further, treatment with tranilast showed a 52% reduction in collagen density of the intimal layer and a 70% reduction in collagen density of the medial layer of the injured arteries.


CONCLUSIONS
The data obtained by in vivo MRI, ex vivo MRI, histology and collagen analysis demonstrate that tranilast provided significant beneficial effects in inhibiting neointimal formation in the rat carotid artery model. Also this study, to the best of our knowledge, is the first to harness complimentary information from various technologies, including lumen patency by in vivo MRI, neointimal formation by ex vivo MRI and conventional histomorphometry, and histological analysis for collagen density, to provide a comprehensive understanding of the pathology in this disease model.
Ohlstein
E H
EH
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406-0939, USA. ohlstein@sbphrd.com
Romanic
A M
AM
Clark
L V
LV
Kapadia
R D
RD
Sarkar
S K
SK
Gagnon
R
R
Chandra
S
S
D000704:Analysis of Variance; D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D018926:Anti-Allergic Agents / Q000627:therapeutic use*; D002339:Carotid Arteries; D002404:Catheterization; D003094:Collagen / Q000032:analysis; D003327:Coronary Disease / Q000628:therapy*; D004195:Disease Models, Animal; D008279:Magnetic Resonance Imaging; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D017539:Tunica Intima / Q000033:anatomy & histology* / Q000187:drug effects / Q000378:metabolism; D062367:ortho-Aminobenzoates / Q000627:therapeutic use*
D018926:Anti-Allergic Agents; D062367:ortho-Aminobenzoates; D003094:Collagen; C012293:tranilast