We examined the natural course of endothelium-dependent and -independent responses in reversed autogenous vein grafts during regeneration and tissue repair processes after vein grafting in dogs. Vein grafts implanted in the canine femoral artery were removed, cut into rings, and suspended in organ chambers for isometric tension recording at 3 days and 1, 2, 4, and 6 weeks after implantation. Endothelial cells were denuded from some rings. Control veins were taken from nonsurgically treated femoral veins. Acetylcholine caused endothelium-dependent relaxations in the control veins, whereas in the vein grafts there was no evidence of endothelium-dependent relaxations to acetylcholine 3 days after the operation. Acetylcholine caused endothelium-independent contractions throughout the study. The endothelium-dependent responses to ADP and calcium ionophore A23187 were constantly maintained. Three days after the operation, the amplitude of norepinephrine-induced contractions of the vein grafts was impaired, and at 1 week the amplitude was recovered, although it was significantly smaller than the amplitude of contractions of the control veins at any postoperative period. Endothelium-independent relaxations to sodium nitroprusside were maintained throughout the study. Thus, there was a selective loss of acetylcholine-mediated relaxation in vein grafts in the early postoperative stage, a time when the intima is not thickened. These altered responses in vein grafts in the early postoperative period may have a role in graft failure.