Augmentation of endothelial function by endothelin antagonism in human saphenous vein conduits

Object. Cerebral revascularization with saphenous vein (SV) conduits is use d in the management of hard-to-treat lesions that require deliberate arteri al occlusion and in selected patients with occlusive vascular disease. Endo thelial dysfunction is thought to contribute to acute perioperative vasospa sm and chronic graft atherosclerosis. In the present study the authors exam ined the contribution of the potent vasoconstrictor endothelin-1 (ET-1) to endothelial dysfunction in human SVs. Methods. The effects of an ETA,B receptor antagonist (bosentan). an ETA rec eptor antagonist (BQ-123), and an ETB receptor antagonist (BQ-788) on in vi tro endothelium-dependent and -independent responses were studied in human SVs. Vascular segments were obtained in 34 patients who had undergone revas cularization procedures, and isometric dose-response curves (DRCs) were con structed using the isolated tissue bath procedure as follows: 1) cumulative DRCs to norepinephrine; and 2) DRCs to acetylcholine (ACh) and sodium nitr oprusside in the absence and presence of bosentan, BQ-123, or BQ-788. Maxim al vasodilatory responses and sensitivity were compared between groups. In the presence of bosentan (Experiment 1) and BQ-123 or BQ-788 (Experiment 2) , ACh responses were significantly augmented (percent maximum relaxation va lues: 7 +/- 2 [control] compared with 17 +/- 3 [bosen- tan], p < 0.002 [Exp eriment 1]; and 12 +/- 2 [control] compared with 29 +/- 2 [BQ-123] and 25 /- 2 [BQ-788]. p < 0.003 and p < 0.002, respectively [Experiment 2]). The s ensitivity of SVs to ACh was unaffected by treatment. These beneficial effe cts were specific for the endothelium. Conclusions. Blockade of ET receptors significantly improves endothelial fu nction in SVs. Furthermore, these effects appear to be independently and ma ximally mediated by antagonism of either ETA or ETB receptors. Intervention s aimed at improving endothelial function may serve to counter perioperativ e vasospasm and impede atherosclerosis in SVs used for revascularization pr ocedures.