ENDOTHELIN AND VEIN BYPASS GRAFTS IN EXPERIMENTAL ATHEROSCLEROSIS

Endothelin-1 (ET-1) is a potent vasoconstrictor whose serum concentration increases with the development of atherosclerosis. Coronary artery-vein bypass grafts are susceptible to vasospasm and to the development of accelerated atherosclerosis. Although ET-1 is thought to play a role in coronary vasospasm, the effect of ET-1 in atherosclerotic vein grafts is unknown. The responses of veins, arteries, and vein bypass grafts from normolipidemic and hyperlipidemic animals to ET-1 were therefore investigated. Vein bypass grafts were placed in the carotid position of 12 New Zealand White rabbits. Seven were fed a 1% cholesterol diet for 4 weeks before surgery and thereafter until harvest (hyperlipidemia), and five were fed a normal diet (normolipidemia). Vein grafts, contralateral common carotid arteries, and jugular veins were harvested 4 weeks after surgery. Whereas there were no histologic changes in veins or carotids, normolipidemic vein grafts developed intimal hyperplasia and hyperlipidemic vein grafts developed atherosclerosis. Isometric tension studies with ET-1 (10(-12) to 10(-6) M) showed that hyperlipidemia increased the maximal tension generated to ET-1 in the veins (660 +/- 80 to 1, 110 +/- 140 mg, mean +/- SEM; p<0.05), carotids (150 +/- 30 mg to 540 +/- 120 mg; p<0.05), and vein grafts (180 +/- 20 to 450 +/- 60 mg; p<0.001). Vein grafts from both normolipidemic and hyperlipidemic animals generated less maximal tension, with a decrease in sensitivity compared with contralateral veins (normolipidemia 8.78 +/- 0.28 versus 7.57 +/- 0.11; p<0.01; hyperlipidemia 8.04 +/- 0.08 versus 7.69 +/- 0.05, p<0.01; veins versus vein grafts -log[ED50], mean +/- SEM). However, the sensitivities of vein grafts were similar to that of the common carotid in normolipidemia (7.88 +/- 0.13) and hyperlipidemia (7.64 +/- 0.18). Vein grafts showed a biphasic response to ET, with initial relaxation to lower doses (10(-12) to 10(-10) M) followed by contraction at higher concentrations, but hyperlipidemic VG did not relax to low ET-1 concentrations. Carotid arteries in normolipidemia and hyperlipidemia showed a pattern of responses similar to those of the vein grafts. These findings suggest that in nonatherosclerotic vein grafts, ET-1 relaxes vein grafts at physiologic concentrations. However, in atherosclerotic vein grafts, ET-1 does not relax the vein graft and therefore may predispose the vein graft to vasospasm.