To our knowledge, these data provide the first evidence for the presence of nitrotyrosine in both normal and diseased kidneys. The significance of the findings in normals is unclear, but could be due to activation of constitutive NOS. However, the study clearly demonstrates increased production of ONOO. in proximal tubules of patients with DM, and suggests that oxidant injury of the proximal tubules plays an important part in the pathogenesis of DM.

1. Mechanical forces associated with blood flow play important roles in the acute control of vascular tone, the regulation of arterial structure and remodelling and the localization of atherosclerotic plaque. Uraemia is a proatherogenic process and is expected to be associated with impaired vascular reactivity.2. To study this, 12 male Wistar rats were rendered uraemic by five-sixths nephrectomy and 12 control rats were sham operated simultaneously. After 8 weeks a tail-cuff systolic blood pressure was recorded, blood samples were taken and the animals killed. Isolated femoral arteries were dissected and mounted on a pressure myograph and myogenic tone was assessed over a range of intravascular pressures from 40 to 160 mmHg. Histologically the arteries were comparatively examined for gross morphology, calcification and deposition of collagen.3.Biochemically the serum urea and creatinine were greater in the uraemic compared with the control rats (urea: 23.5+/-6 mmol/l and 6.8+/-01 mmol/l respectively, P not significant; creatinine: 130.7+/-13 mmol/l and 70.3+/-5 mmol/l respectively, P<0.01) but systolic blood pressure was the same in both groups (control, 97+/-1 mmHg; uraemic, 98+/-2 mmHg), compatible with mild uraemia.4. Myogenic tone was significantly greater in uraemic vessels (7.3+/-1.8% versus 2.3+/-0. 4% in control, P=0.01). The actual vessel lumen diameter was also smaller in pressurized uraemic vessels compared with control vessels (471+/-30 microm versus 604+/-33 microm, P<0.01) after equilibration in physiological salt solution. However, when incubated in calcium-free physiological salt solution, the passive internal diameter was similar in uraemic vessels (538+/-25 microm compared with 595+/-31 microm in control). Histologically, there were no differences between the two groups.5. We conclude that some aspects of vascular reactivity are altered in mild experimental uraemia as shown by a reduced internal lumen diameter and increased myogenic tone. Furthermore, these changes are apparent in the absence of hypertension and precede structural changes.