Walsh, Thomas F.

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 ETA/ETBantagonist, 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 ETA(IC50≈0.3 nmol/L) or ETB(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 ETA/ETBreceptor antagonist is insufficient to substantially inhibit intimal hyperplasia after balloon/stent coronary artery injury in the pig, in contrast to results with a selective ETAantagonist. The effects of selective or mixed ETA/ETBantagonists in diseased vessels remain to be determined in this model.