ENDOTHELIN-B RECEPTORS MEDIATE INTIMAL HYPERPLASIA IN AN ORGAN-CULTURE OF HUMAN SAPHENOUS-VEIN

Objective: Although a number of pharmacologic agents have been shown t o reduce intimal hyperplasia in animal models of restenosis, to date n o systemic agent has conclusively been shown to be effective in humans . Recently considerable attention has been directed towards endothelin (ET), a potent vasoconstrictor and a powerful mitogen for vascular sm ooth muscle cells, as a mediator of intimal hyperplasia. Endothelin-1 has been shown to be mitogenic for human saphenous vein smooth muscle cells, and expression also is elevated in human vein graft stenosis. T he aim of this study was the investigation of whether ET receptor anta gonists can attenuate neointima formation in a laboratory model of vei n graft intimal hyperplasia and the determination of whether the effec ts are mediated by a specific ET receptor subtype. Methods: We used an organ culture of human saphenous vein, a well-validated model of vein graft intimal hyperplasia. Paired segments of human long saphenous ve in were cultured with and without the following antagonists: bosentan, a nonselective ET receptor antagonist; BQ 123, a specific endothelin- A antagonist; or BQ 788, a specific endothelin-B (ETB) antagonist Afte r 14 days in the culture, the segments were fixed and processed and th e sections were immunostained to facilitate the measurements of neoint imal thickness with a computerized image analysis system. Results: The nonselective antagonist bosentan and the ETB selective antagonist BQ 788 significantly reduced neointima formation by 70% (P = .001) and 50 % (P = .03), respectively, but the ETA antagonist BQ 123 had no signif icant effect on the reduction of neointima formation (P = 1.0). Conclu sion: The results of this study imply an important role for ET as a me diator of human vein graft intimal hyperplasia and imply further that a specific ETB antagonist may have a therapeutic potential for the pre vention of vein graft stenosis.