Back to Search
Start Over
Effects of L-749,329, an ET(A)/ET(B) endothelin receptor antagonist, in a porcine coronary artery injury model of vascular restenosis.
- Source :
-
Circulation [Circulation] 2001 Apr 10; Vol. 103 (14), pp. 1899-905. - Publication Year :
- 2001
-
Abstract
- Background: Previous studies in animal models of angioplasty have suggested a role in neointimal hyperplasia for endothelins (ETs), potent vasoconstricting peptides that also exert growth-promoting effects. The present studies were undertaken to test the hypothesis that endothelin receptor blockade can reduce neointimal thickening in injured porcine coronary arteries.<br />Methods and Results: An ET(A)/ET(B) antagonist, L-749,329, was evaluated as an inhibitor of intimal thickening in a porcine balloon/stent model of coronary artery injury. L-749,329 competitively inhibited [(125)I]ET-1 binding to porcine ET(A) (IC(50) approximately 0.3 nmol/L) or ET(B) (IC(50) approximately 20 nmol/L) receptors and inhibited ET-1-stimulated signaling in cell culture. In anesthetized pigs, big ET-1-stimulated increases in systemic blood pressure were totally inhibited after intravenous infusion of L-749,329 (>/=0.2 mg. kg(-1). h(-1)). In vascular injury studies, pigs were treated with vehicle or L-749,329 (1 mg. kg(-1). h(-1)) beginning 2 days before and continuing 28 days after experimental angioplasty. Left anterior descending, left circumflex, and/or right coronary arteries were injured by inflation of an angioplasty balloon wrapped with a coiled metallic stent. After 28 days, mean neointimal thickness in the L-749,329-treated group was reduced by 9.0% compared with vehicle-treated controls, but this effect was not statistically significant (P=0.13).<br />Conclusions: Blockade of endothelin receptors for 28 days with only a mixed ET(A)/ET(B) receptor antagonist is insufficient to substantially inhibit intimal hyperplasia after balloon/stent coronary artery injury in the pig, in contrast to results with a selective ET(A) antagonist. The effects of selective or mixed ET(A)/ET(B) antagonists in diseased vessels remain to be determined in this model.
- Subjects :
- Animals
Binding, Competitive drug effects
Blood Pressure drug effects
Cell Line
Cells, Cultured
Coronary Disease pathology
Coronary Disease physiopathology
Coronary Vessels pathology
Dose-Response Relationship, Drug
Endothelin-1 metabolism
Female
Iodine Radioisotopes
Male
Muscle, Smooth, Vascular cytology
Muscle, Smooth, Vascular drug effects
Muscle, Smooth, Vascular metabolism
Peptides, Cyclic pharmacology
Receptor, Endothelin A
Receptor, Endothelin B
Receptors, Endothelin metabolism
Signal Transduction drug effects
Swine
Tunica Intima drug effects
Tunica Intima pathology
Acetamides pharmacology
Coronary Disease prevention & control
Coronary Vessels drug effects
Endothelin Receptor Antagonists
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 103
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 11294810
- Full Text :
- https://doi.org/10.1161/01.cir.103.14.1899