SELECTIVE ANTAGONISM OF THE ETA-RECEPTOR REDUCES NEOINTIMAL HYPERPLASIA AFTER BALLOON-INDUCED VASCULAR INJURY IN PIGS

Balloon angioplasty has become an important intervention in clinical c ardiology; however, the technique is associated with a high incidence of restenosis, requiring repeated procedures. Endothelin-1 (ET-1), spe cifically through its action on ETA receptors, has been implicated in the cell proliferation and subsequent neointimal formation that leads to restenosis. Therefore we examined a potent antagonist of the ETA re ceptor, A127722.5, in a pig model of balloon angioplasty in iliac and carotid arteries. Ten pigs received A-127722.5 (7.5 mg/kg b.i.d.) oral ly, starting 3 days before angioplasty and continuing for 4 weeks; 10 additional pigs were treated with the same dosing regimen of the angio tensin-converting enzyme (ACE) inhibitor captopril (3.0 mg/kg b.i.d.), while a third group of 10 animals received placebo. At 2 and 4 weeks after the start of treatment, these doses of the ETA receptor antagoni st and ACE inhibitor blocked the presser responses induced by big ET-1 and angiotensin I, respectively. In the iliac arteries, neointimal fo rmation, neointimal/medial ratio, and maximal neointimal thickness wer e all significantly reduced, and the residual lumen area was significa ntly increased in pigs treated with the ETA receptor antagonist compar ed with placebo and captopril-treated groups. Medial collagen content, collagen deposition, and medial growth also were significantly reduce d relative to the placebo group. Beneficial effects also were observed in the carotid arteries, although the results were less striking. Cap topril was ineffective in protecting against the effects of balloon an gioplasty in both vessels. Our results indicate that an orally active and potent antagonist of the ETA receptor inhibits cell proliferation and synthesis of extracellular matrix in pigs and may provide an impor tant therapeutic approach to the prevention of restenosis.