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

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 ≈0.3 nmol/L) or ET B (IC 50 ≈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.