Stroke-prone spontaneously hypertensive rats (SHRSP/Izm) are salt sensitive: they develop severe hypertension and die of stroke within a short time after salt loading. We studied the role of cytochrome P-450 (CYP) isoforms in the brain and the effect of clofibrate to investigate the mechanism of salt sensitive stroke-proneness in SHRSP/Izm. Male SHRSP/Izm at 9 weeks of age were fed a regular diet with or without 0.25% clofibrate and given a 1% NaCl solution for drinking water for 10 d. The expression levels of CYP4A1, 2C11, and 2C23 were measured by Western blotting. Cerebral blood flow was measured with a laser Doppler method and blood vessel diameters were measured under microscopic observation. SHRSP/Izm died within 60 d after salt loading; however, clofibrate prolonged the survival (mean life span, 33+/-7 vs. 215+/-23 d, p<0.0001) without significant attenuation of the severe hypertension. CYP4A1 and CYP2C11 expression levels were lower in SHRSP/Izm than those in age-matched male spontaneously hypertensive rats (SHR/Izm) in the cerebral cortex (p<0.05). Salt loading down-regulated CYP2C11 expression in the cerebral cortex of SHRSP/Izm (p<0.05). No obvious change in cerebral CYP4A1 was observed in either salt-loaded SHRSP/Izm or SHR/Izm. Clofibrate significantly up-regulated the expression of cerebral CYP2C11 and significantly attenuated its salt-induced suppression (p<0.05). Additionally, clofibrate significantly increased blood vessel diameters (p<0.01) and cerebral blood flow (p<0.0001). CYP2C11 plays an important role in regulating cerebral blood flow and, as a result, in preventing stroke in the salt-sensitive stroke-prone SHRSP/Izm.