Differences in the renal metabolism of arachidonic acid by cytochrome P450 have been reported in the spontaneously hypertensive rat (SHR) and Wistar-Koyto rats, but the contribution of this system to the development of hypertension is unclear. The present study compared renal P450 activity and blood pressure in SHR and Brown-Norway rats (BN) under control conditions and in response to an elevation in sodium intake; genetic linkage analysis was performed in an F₂ population (n=219) derived from these strains. Basal renal P4504A enzyme activity measured by conversion of [¹⁴C]arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) was significantly greater in the kidneys of adult SHR (n=7) than of BN (n=8) (82±7 versus 60±5 pmol/min per milligram protein). Renal 20-HETE production fell 45% in SHR and 22% in BN in which salt intake was elevated by drinking of saline instead of water for 2 weeks. Mean arterial pressure averaged 157±3 mm Hg in SHR (n=9) and 100±2 mm Hg in BN fed a normal salt diet, and it rose to 170±7 mm Hg (P<.05) in SHR and fell to 90±3 mm Hg (P<.05) in BN (n=8) after sodium intake was elevated. A polymorphic marker, D5Rjr1, that spanned a repeated element in the P4504A1 gene on chromosome 5, where all three P4504A isoforms are located, was used for genotyping of the F₂ population. The P4504A genotype did not cosegregate with baseline mean arterial pressure in the F₂ population; however, significant linkage was observed with the change in mean arterial pressure after sodium intake of the rats was elevated. The degree of linkage differed in male and female rats, and the highest LOD score (3.6) was observed in male F₂ rats with a BN grandfather. These findings suggest that the difference in renal P450 activity in SHR and BN does not contribute to the development of hypertension in this F₂ population, but it may play some role in determining the blood pressure response to an elevation in salt intake.