The role of cytochrome p-450 in salt-sensitive stroke in stroke-prone spontaneously hypertensive rats.
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.
Ying
Chen-Jiang
CJ
Department of Pharmacy, School of Pharmacy, Shujitsu University, Okayama, Japan.
Noguchi
Takanori
T
Aso
Hiroaki
H
Ikeda
Katsumi
K
Yamori
Yukio
Y
Nara
Yasuo
Y
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D002994:Clofibrate / Q000494:pharmacology; D000090762:Cytochrome P-450 CYP2J2; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism*; D020521:Stroke / Q000378:metabolism* / Q000517:prevention & control
D000924:Anticholesteremic Agents; D047493:PPAR alpha; D017673:Sodium Chloride, Dietary; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000090762:Cytochrome P-450 CYP2J2; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D042926:Cytochrome P-450 CYP4A; D002994:Clofibrate