Studies were designed to determine the effects of increases of renal perfusion pressure on the production of hydrogen peroxide (H(2)O(2)) and NO(2)(-)+NO(3)(-) within the renal outer medulla. Sprague-Dawley rats were studied with either the renal capsule intact or removed to ascertain the contribution of changes of medullary blood flow and renal interstitial hydrostatic pressure on H(2)O(2) and NO(2)(-)+NO(3)(-) production. Responses to three 30-minute step changes of renal perfusion pressure (from approximately 85 to approximately 115 to approximately 145 mm Hg) were studied using adjustable aortic occluders proximal and distal to the left renal artery. Medullary interstitial H(2)O(2) determined by microdialysis increased at each level of renal perfusion pressure from 640 to 874 to 1593 nmol/L, as did H(2)O(2) urinary excretion rates, and these responses were significantly attenuated by decapsulation. Medullary interstitial NO(2)(-)+NO(3)(-) increased from 9.2 to 13.8 to 16.1 mumol/L, with parallel changes in urine NO(2)(-)+NO(3)(-), but decapsulation did not significantly blunt these responses. Over the range of renal perfusion pressure, medullary blood flow (laser-Doppler flowmetry) rose approximately 30% and renal interstitial hydrostatic pressure rose from 7.8 to 19.7 cm H(2)O. Renal interstitial hydrostatic pressure and the natriuretic and diuretic responses were significantly attenuated with decapsulation, but medullary blood flow was not affected. The data indicate that pressure-induced increases of H(2)O(2) emanated largely from increased tubular flow rates to the medullary thick-ascending limbs of Henle and NO largely from increased medullary blood flow to the vasa recta. The parallel pressure-induced increases of H(2)O(2) and NO indicate a participation in shaping the "normal" pressure-natriuresis relationship and explain why an imbalance in either would affect the blood pressure salt sensitivity.