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(Circulation. 2001;103:1899.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Effects of L-749,329, an ET_A/ET_B Endothelin Receptor Antagonist, in a Porcine Coronary Artery Injury Model of Vascular Restenosis

William R. Huckle, PhD; Marlene D. Drag, DVM; Wayne R. Acker, BS; Michele Powers, BS; Rosemary C. McFall, BS; Daniel J. Holder, PhD; Thomas F. Walsh, PhD; Robert S. Schwartz, MD; William J. Greenlee, PhD; Robert G. Johnson, Jr, MD, PhD

From the Departments of Pharmacology (W.R.H., R.C.M., R.G.J.), Laboratory Animal Resources (M.D.D., W.R.A., M.P.), Biometrics (D.J.H.), and Exploratory Chemistry (T.F.W., W.J.G.), Merck Research Labs, West Point, Pa, and Division of Cardiovascular Diseases (R.S.S.), Department of Medicine, Mayo Clinic and Foundation, Rochester, Minn.

Correspondence to Dr William R. Huckle, Department of Biomedical Sciences & Pathobiology (0442), Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061. E-mail wrhuckle{at}vt.edu

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 [¹²⁵I]ET-1 binding to porcine ET_A (IC₅₀ 0.3 nmol/L) or ET_B (IC₅₀ 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.

Key Words: restenosis • endothelin • coronary disease • angioplasty

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