Effect of 20-HETE inhibition on infarct volume and cerebral blood flow after transient middle cerebral artery occlusion.
This study examined the effects of an inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis, N-(3-chloro-4-morpholin-4-yl)phenyl-N'-hydroxyimido formamide (TS-011), on infarct volume, volume at risk, cerebral blood flow (CBF), and levels of cytochrome P450 (CYP450) eicosanoids in the brain after transient occlusion of the middle cerebral artery (t-MCAO) in rats. TS-011 (0.1 mg/kg, iv) reduced cortical infarct volume by approximately 70% and total infarct volume by 55%. TS-011 had no effect on the volume at risk or CBF during or up to 30 mins after the ischemic period. TS-011 reduced the delayed fall in CBF seen 2 h after reperfusion. The levels of CYP450 eicosanoids were similar in the ischemic and contralateral hemispheres after t-MCAO. TS-011 reduced 20-HETE levels in cerebral tissue by 80% but had no effect on the levels of EETs. Administration of another 20-HETE inhibitor, HET0016 (0.01 to 1.0 mg/kg, iv) or a 20-HETE antagonist 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (10 mg/kg, iv) also reduced infarct size. These results indicate that inhibitors of the synthesis or vasoconstrictor effects of 20-HETE reduce infarct size in rats after cerebral ischemia. The effects of TS-011 are not associated with changes in the area at risk or CBF and may be because of a potential protective effect in neurons subjected to ischemic stress.
Renic
Marija
M
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Klaus
Judith A
JA
Omura
Tomohiro
T
Kawashima
Naoya
N
Onishi
Michihito
M
Miyata
Noriyuki
N
Koehler
Raymond C
RC
Harder
David R
DR
Roman
Richard J
RJ
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004195:Disease Models, Animal; D005559:Formamides / Q000494:pharmacology / Q000627:therapeutic use*; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors*; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017078:Laser-Doppler Flowmetry; D008297:Male; D013058:Mass Spectrometry; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
D005559:Formamides; D006893:Hydroxyeicosatetraenoic Acids; D009025:Morpholines; C503100:N-(3-chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide; D018696:Neuroprotective Agents; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System