The present study investigated the underlying mechanisms associated with the loss of responsiveness of veins grafted into the arterial circulation. In particular, the possibility that the altered response is related to modifications of the biologic properties of the vascular smooth muscle, of the endothelial cells or both was tested. Segments of jugular veins were grafted in the reverse position into the carotid arteries in rabbits. After 4 weeks the patent vein grafts and unoperated veins were removed, and endothelium-dependent (acetylcholine) and endothelium-independent (nitric oxide, SIN-1 [the active metabolite of molsidomine32]) relaxations were studied in vitro. In unoperated veins, acetylcholine, nitric oxide, and SIN-1 induced a concentration-dependent relaxation in the presence and absence of the endothelium, respectively. These relaxations were associated with a time-dependent accumulation of guanosine 3':5'-cyclic monophosphate (cyclic GMP). Both relaxation and production of cyclic GMP were inhibited by methylene blue and hemoglobin. Unstimulated veins with endothelium had a significantly higher content of cyclic GMP than did preparations without endothelial cells. This difference was abolished by hemoglobin and methylene blue. In vein grafts acetylcholine induced only minor endothelium-dependent relaxations, whereas nitric oxide and SIN-1 evoked concentration-dependent relaxations in preparations without endothelium, which were shifted significantly to the right compared to unoperated veins. In vein grafts the endothelium-mediated production of cyclic GMP (basal and stimulated by acetylcholine) was significantly reduced when compared to that in unoperated veins, and that evoked by SIN-1 was not different.(ABSTRACT TRUNCATED AT 250 WORDS)