Effects of L-749,329, an ETA/ETB endothelin receptor antagonist, in a porcine coronary artery injury model of vascular restenosis

Background-Previous studies in animal models of angioplasty have suggested a role in neointimal hyperplasia for endothelins (ETs), potent vasoconstric ting peptides that also exert growth-promoting effects. The present studies were undertaken to test the hypothesis that endothelin receptor blockade c an reduce neointimal thickening in injured porcine coronary arteries. Methods and Results-An ETA/ETB antagonist, L-749,329, was evaluated as an i nhibitor of intimal thickening in a porcine balloon/stent model of coronary artery injury. L-749,329 competitively inhibited [I-125]ET-1 binding to po rcine ETA (IC50 approximate to0.3 nmol/L) or ETB (IC50 approximate to 20 nm ol/L) receptors and inhibited ET-l-stimulated signaling in cell culture. In anesthetized pigs, big ET-l-stimulated increases in systemic blood pressur e were totally inhibited after intravenous infusion of L-749,329 (greater t han or equal to0.2 mg . kg(-1) . h(-1)). In vascular injury studies, pigs w ere treated with vehicle or L-749,329 (1 mg . kg(-1) . h(-1)) beginning 2 d ays before and continuing 28 days after experimental angioplasty. Left ante rior descending, left circumflex, and/or right coronary arteries were injur ed by inflation of an angioplasty balloon wrapped with a coiled metallic st ent. After 28 days, mean neointimal thickness in the L-749,329-treated grou p was reduced by 9.0% compared with vehicle-treated controls, but this effe ct was not statistically significant (P=0.13). Conclusions-Blockade of endothelin receptors for 28 days with only a mixed ETA/ETB receptor antagonist is insufficient to substantially inhibit intima l hyperplasia after balloon/stent coronary artery injury in the pig, in con trast to results with a selective ETA antagonist. The effects of selective or mixed ETA/ETB antagonists in diseased vessels remain to be determined in this model.