1. Effects of L-749,329, an ET(A)/ET(B) endothelin receptor antagonist, in a porcine coronary artery injury model of vascular restenosis.
- Author
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Huckle WR, Drag MD, Acker WR, Powers M, McFall RC, Holder DJ, Walsh TF, Schwartz RS, Greenlee WJ, and Johnson RG Jr
- 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
- 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., 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)., 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.
- Published
- 2001
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