20-HETE contributes to the acute fall in cerebral blood flow after subarachnoid hemorrhage in the rat.
This study examined the effects of blocking the formation of 20-hydroxyeicosatetraenoic acid (20-HETE) on the acute fall in cerebral blood flow after subarachnoid hemorrhage (SAH) in the rat. In vehicle-treated rats, regional cerebral blood flow (rCBF) measured with laser-Doppler flowmetry fell by 30% 10 min after the injection of 0.3 ml of 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-octadecynoic acid (17-ODYA; 1.5 nmol intrathecally) and 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 1 h after induction of SAH. The concentration of 20-HETE in the cerebrospinal fluid rose from 12 +/- 2 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 IC(50) of <15 nM and human recombinant CYP4A11, CYP4F2, and CYP4F3 enzymes with an IC(50) of 42, 125, and 100 nM, respectively. These results indicate that 20-HETE contributes to the acute fall in rCBF after SAH in rats.
Kehl
Franz
F
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Cambj-Sapunar
Liana
L
Maier
Kristopher G
KG
Miyata
Noriyuki
N
Kametani
Shunishi
S
Okamoto
Hirotsugu
H
Hudetz
Anthony G
AG
Schulte
Marie L
ML
Zagorac
Drazen
D
Harder
David R
DR
Roman
Richard J
RJ
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D002245:Carbon Dioxide / Q000097:blood; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000166:cytology / Q000502:physiology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D008297:Male; D018715:Microscopy, Video; D010313:Partial Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects*; D013345:Subarachnoid Hemorrhage / Q000097:blood / Q000503:physiopathology*; D013997:Time Factors
D000578:Amidines; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; C000708209:HET0016; D006893:Hydroxyeicosatetraenoic Acids; D002245:Carbon Dioxide; C047008:17-octadecynoic acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid