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Am J Physiol Heart Circ Physiol (December 6, 2001). doi:10.1152/ajpheart.00924.2001
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Articles in PresS, published online ahead of print December 6, 2001
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00924.2001
Submitted on October 24, 2001
Accepted on December 4, 2001

20-HETE Contributes to the Acute Fall in Cerebral Blood Flow Following Subarachnoid Hemorrhage in the Rat

Franz Kehl1, Liana Cambj-Sapunar1, Kris G Maier1, Noriyuki Mijata2, Shunishi Kametani2, Hirotsugu Okamoto1, Anthony G Hudetz3, Marie L Schulte3, Drazen Zagorac4, David R Harder4, and Richard J Roman1*

1 Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
2 Taisho Pharmaceutical Co. Ltd, Saitama, Japan
3 Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA
4 Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, WI, USA

* To whom correspondence should be addressed. E-mail: rroman{at}post.its.mcw.edu.

This study examined the effects of blocking the formation of 20-hydroxyeicosatetraenoic acid (20-HETE) on the acute fall in cerebral blood flow following subarachnoid hemorrhage (SAH) in the rat. In vehicle treated rats, regional cerebral blood flow (rCBF) measured using laser Doppler flowmetry fell by 30% 10 min after the injection of 0.3 ml arterial blood into the Cisterna Magna and it remained at this level for 2 h. Pretreatment with inhibitors of the formation of 20-HETE, 17-ODYA (1.5 nmol, intrathecally) or N-hydroxy-N'- (4-butyl-2-methylphenyl)-formamidine (HET0016) (10 mg/kg iv), reduced the initial fall in rCBF by 40% and rCBF fully recovered after induction of SAH. The concentration of 20-HETE in the cerebrospinal fluid (CSF) rose from 12 ± 2 ng/ml to 199 ± 17 ng/ml after SAH in vehicle-treated rats. 20-HETE levels averaged only 15 ± 11 and 39 ± 13 ng/ml, in rats pretreated with 17-ODYA or HET0016, respectively. HET0016 selectively inhibited the formation of 20-HETE in rat renal microsomes with an IC50 of < 15 nM and human recombinant CYP4A11, CYP4F2 and CYP4F3 enzymes with an IC50 of 42, 125 and 100 nM, respectively. These results indicate that 20-HETE contributes to the acute fall in rCBF following SAH in rats.




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