Altered pressure-natriuresis in obese Zucker rats

It has not been examined whether the pressure-natriuresis response is altered in the insulin-resistant condition. Furthermore, despite an important role of nitric oxide (NO) in modulating pressure-natriuresis, no investigations have been conducted assessing the renal interstitial NO production in insulin resistance. The present study examined whether pressure-natriuresis was altered in insulin-resistant obese Zucker rats (OZ) and assessed the cortical and medullary nitrate/nitrite (NOx) levels with the use of the renal microdialysis technique. In OZ, serum insulin/glucose ratio (23.0±4.0 x 10^-8, n=9) and blood pressure (119±3 mmHg) were greater than those in lean Zucker rats (LZ, 7.0±1.9 x 10^-8 and 103±4 mm Hg, n=9). The pressure-natriuresis curve in OZ was shifted to higher renal perfusion pressure (RPP), and the slope was blunted compared with that in LZ (0.073±0.015 vs 0.217±0.047 μEq/min kidney weight/mm Hg, P<0.05). The basal renal NOx level was reduced in OZ (cortex, 4.032±0.331 μmol/L; medulla, 4.329±0.515 μmol/L) compared with that in LZ (cortex, 7.315±1.102 μmol/L; medulla: 7.698±0.964 μmol/L). Furthermore, elevating RPP increased the medullary NOx in LZ, but this pressure-induced response was lost in OZ. Four-week treatment with troglitazone, an insulin-sensitizing agent, improved hyperinsulinemia, systemic hypertension, and basal renal NOx levels (cortex, 5.639±0.286 μmol/L; medulla, 5.978±0.284 μmol/L), and partially ameliorated the pressure-natriuresis curves; the slope of pressure- natriuresis curves and elevated RPP-induced NOx, however, were not corrected. In conclusion, our study suggests that insulin resistance is closely associated with abnormal pressure-natriuresis and hypertension. These deranged renal responses to insulin resistance are most likely attributed to impaired medullary NO production within the medulla.