S18886, a selective TP receptor antagonist, inhibits development of atherosclerosis in rabbits

Worth, Nathalie F., Berry, Celia L., Thomas, Anita C. and Campbell, Julie H. (2005) S18886, a selective TP receptor antagonist, inhibits development of atherosclerosis in rabbits. Atherosclerosis, 183 1: 65-73. doi:10.1016/j.atherosclerosis.2005.02.034


Author Worth, Nathalie F.
Berry, Celia L.
Thomas, Anita C.
Campbell, Julie H.
Title S18886, a selective TP receptor antagonist, inhibits development of atherosclerosis in rabbits
Journal name Atherosclerosis   Check publisher's open access policy
ISSN 0021-9150
Publication date 2005-11
Sub-type Article (original research)
DOI 10.1016/j.atherosclerosis.2005.02.034
Volume 183
Issue 1
Start page 65
End page 73
Total pages 9
Place of publication Clare, Ireland
Publisher Elsevier Ireland
Collection year 2005
Language eng
Subject C1
270100 Biochemistry and Cell Biology
730106 Cardiovascular system and diseases
Formatted abstract
Objective:
To investigate the effect of S 18886, a novel TP (thromboxane A2 and prostaglandin endoperoxide) receptor antagonist, on the development of aortic fatty streaks and advanced lesions in a rabbit model of atherosclerosis and restenosis.

Methods and results:
The right iliac artery of 96 rabbits (8 groups, n = 12/group) was balloon injured, then the animals were fed a cholesterol-enriched diet for 6 weeks. In Groups 1-4, concomitant oral administration of S18886 at 5 mg/kg/day over the 6-week-period reduced the intima to media ratio of lesions in the uninjured aorta and injured iliac artery, the accumulation of macrophages and the expression of ICAM-1 compared with I mg/kg/day S 18886, 30 mg/kg/day aspirin and placebo, with no effect on body weight or plasma cholesterol levels. In Groups 5-8, 2 weeks of treatment with 5 mg/kg/day S 18886 reduced the intima to media ratio of restenosing lesions when pre-formed iliac artery lesions underwent a second balloon injury at week 6. The smaller lesions resulting from S 18886 treatment correlated with a significant decrease in the neointimal area occupied by macrophages, as well as in ICANI-1 expression, with no effect on the smooth muscle component. Aspirin treatment had no significant effect on the neointimal smooth muscle component, but partially inhibited macrophage infiltration, without inhibiting ICAM-1 expression.

Conclusion:

Inhibition of the TP receptor using S 18886 causes a significant decrease in the recruitment of monocyte/macrophages within fatty streaks in the uninjured aorta and within primary and restenosing atherosclerotic lesions in the iliac artery of rabbits. Since TP receptor agonists, such as thromboxane A2, prostanoid endoperoxides and isoprostanes participate in vessel wall inflammation and are localized and increased in atherosclerotic plaques, treatment with S18886 may enhance atherosclerotic lesion stability by attenuating inflammatory processes that ultimately lead to plaque rupture.
Keyword Tp Receptor Antagonist
Icam-1 Expression
Atherosclerosis
Restenosis
Macrophages
Peripheral Vascular Disease
Thromboxane A(2)
Antiplatelet Agents
Aspirin Resistance
Expression
Disease
Prostacyclin
Prevention
Contribute
Patterns
Lesions
Q-Index Code C1

 
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Created: Wed, 15 Aug 2007, 05:50:09 EST