Effects of L-749,329, an ET(A)/ET(B) endothelin receptor antagonist, in a porcine coronary artery injury model of vascular restenosis

• Published in: Circulation (New York, N.Y.) N.Y.), 2001-04, Vol.103 (14), p.1899-1905
• Main Authors: Huckle, W R, Drag, M D, Acker, W R, Powers, M, McFall, R C, Holder, D J, Walsh, T F, Schwartz, R S, Greenlee, W J, Johnson, Jr, R G
• Format: Article
• Language: English
• Subjects: Acetamides - pharmacology; Animals; Binding, Competitive - drug effects; Blood Pressure - drug effects; Cell Line; Cells, Cultured; Coronary Disease - pathology; Coronary Disease - physiopathology; Coronary Disease - prevention & control; Coronary Vessels - drug effects; Coronary Vessels - pathology; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; 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
• ISSN: 0009-7322; 1524-4539

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. 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). 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.