A ROLE FOR ENDOGENOUS ENDOTHELIN-1 IN NEOINTIMAL FORMATION AFTER RAT CAROTID-ARTERY BALLOON ANGIOPLASTY - PROTECTIVE EFFECTS OF THE NOVEL NONPEPTIDE ENDOTHELIN RECEPTOR ANTAGONIST SB-209670

The observation that levels of the mitogenic peptide endothelin-1 are elevated in the human coronary sinus after percutaneous transluminal coronary angioplasty (PTCA) has implicated endothelin-1 in the etiology of vascular restenosis. The present study examined this hypothesis in both an in vitro and an in vivo rat model of neointimal formation by using the novel nonpeptide endothelin receptor antagonist SB 209670. In vitro, endothelin-1 (1 nmol/L) induced a ninefold increase in rat aortic vascular smooth muscle [H-3]thymidine incorporation. This endothelin A receptor-mediated effect was completely inhibited by SB 209670 (IC50, 6.2+/-2.2 nmol/L). In vivo, acute intra-arterial administration of exogenous endothelin-1 (5 to 500 pmol/kg over a 30-minute period immediately after angioplasty) dose-dependently augmented the degree of neointimal formation (by up to 150% when assessed 14 days after surgery). This response was evident as early as 7 days after angioplasty. Hemodynamic studies indicated that this action was unrelated to a systemic presser action of the peptide. Administration of SB 209670 (2.5 mg/kg IP, twice a day for 3 days before and for 2 weeks after surgery) reduced neointimal formation by approximate to 50% relative to control animals. Thus, the data indicate for the first time that (1) endothelin-1 promotes neointimal formation in vivo and (2) endogenous endothelin-1 is involved in the pathogenesis of angioplasty-induced lesion formation in the rat. Endothelin receptor antagonists such as SB 209670 may therefore serve as useful adjuncts to PTCA, attenuating the degree of vascular restenosis observed after vascular wall injury.