Remodeling of resistance arteries in renal failure: Effect of endothelin receptor blockade

Remodeling of vessels is a known feature of renal failure, but it is unclea r whether this represents an appropriate or inappropriate response to the k nown changes in blood flow, shear stress. and wall tension. To investigate remodeling in response to variations in blood flow, first-order mesenteric arteries were exposed to high- and low-flow conditions via the ligation of second-order branches, according to the technique described by Pourageaud a nd De Mey. The resulting changes in vessel geometric features, relative pro portions of intima and media, submicroscopic structure, and immunostaining for proliferating cell nuclear antigen (PCNA), endothelin-1 (ET-1), and ETA receptors were assessed in first-order mesenteric arteries under low-flow and high-flow conditions. Subtotally nephrectomized (SNX) animals were comp ared with sham-operated rats. Animals either were left untreated or were tr eated with the ETA receptor antagonist (ET-RA) LU-135252, because of sugges tions in the literature that ET is involved in vascular remodeling in uremi a. A highly significant increase in intimal thickness was noted in low-flow arteries (4.21 +/-1.39 mum) of SNX animals, compared with normal-flow arte ries (2.06 +/-0.61 mum), but this increase was not observed in sham-operate d rats (1.38 +/-0.77 in low-flow arteries versus 2.40 +/-0.35 mum in normal -flow arteries). The increase in intimal thickness in low-flow arteries was abrogated by ET-RA_ ne medial thickness was increased in untreated SNX ani mals (19.5 +/-3.61 mum), compared with sham-operated rats, and this increas e was also prevented by ET-RA. The medial thickness was not affected by low flow in either sham-operated or SNX animals. In parallel, the number of PC NA-positive intimal cells was higher in low-flow, but not high-flow, arteri es of SNX rats, compared with sham-operated rats. No significant change was observed in sham-operated animals. In the media, the number of PCNA-positi ve cells was higher in untreated SNX animals than in sham-operated rats. Th e number was even more markedly increased in high-flow, but not low-flow, v essels. This increase was abrogated by ET-RA. It is concluded that, in urem ic animals, the response of the intima to low flow and the response of the media to high flow are exaggerated. Both responses are apparently mediated by ET.