We investigated the hypothesis that a preglomerular diffusional shunt for O(2) stabilized renal PO(2) and that changes in intrarenal PO(2) determined nephron nitric oxide (NO) availability for blunting of the tubuloglomerular feedback (TGF) response. The inspired O(2) content of anesthetized rats was changed from normal (21%) to low (10%) or high (100%) for 30-45 min. Direct recordings of PO(2) in the lumens of proximal and distal tubules demonstrated significantly (P < 0.05) lower values at all sites in spontaneously hypertensive rats compared to normotensive Wistar Kyoto (WKY) rats. Low inspired O(2) did not change intratubular PO(2), but high inspired O(2) increased PO(2) modestly (25-50%; P < 0.01) in both strains and at both sites. Addition of 7-nitroindazole (7-NI; 10(-4) M) to artificial tubular fluid perfusing the loop of Henle of WKY nephrons to block neuronal (type 1) nitric oxide synthase in the macula densa increased TGF but this increase was less (P < 0.01) in nephrons of rats breathing high vs. normal inspired O(2) (1.8 ± 0.4 vs. 3.4 ± 0.3 mmHg; P < 0.01). In conclusion, the PO(2) in the renal tubules was effectively buffered from even extreme changes in arterial PO(2), consistent with a functionally important preglomerular O(2) diffusional shunt. However, high inspired PO(2) increased intratubular PO(2) sufficiently to blunt the effects of NO derived from the macula densa, likely reflecting bioinactivation of NO by reactive oxygen species generated at increased PO(2) levels. Thus, the preglomerular diffusional shunt appeared to stabilize intrarenal PO(2) during changes in arterial oxygen and to protect NO signaling within the kidney.