Production of 20-HETE and its role in autoregulation of cerebral blood flow.
In the brain, pressure-induced myogenic constriction of cerebral arteriolar muscle contributes to autoregulation of cerebral blood flow (CBF). This study examined the role of 20-HETE in autoregulation of CBF in anesthetized rats. The expression of P-450 4A protein and mRNA was localized in isolated cerebral arteriolar muscle of rat by immunocytochemistry and in situ hybridization. The results of reverse transcriptase-polymerase chain reaction studies revealed that rat cerebral microvessels express cytochrome P-450 4A1, 4A2, 4A3, and 4A8 isoforms, some of which catalyze the formation of 20-HETE from arachidonic acid. Cerebral arterial microsomes incubated with [(14)C]arachidonic acid produced 20-HETE. An elevation in transmural pressure from 20 to 140 mm Hg increased 20-HETE concentration by 6-fold in cerebral arteries as measured by gas chromatography/mass spectrometry. In vivo, inhibition of vascular 20-HETE formation with N-methylsulfonyl-12, 12-dibromododec-11-enamide (DDMS), or its vasoconstrictor actions using 15-HETE or 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE), attenuated autoregulation of CBF to elevations of arterial pressure. In vitro application of DDMS, 15-HETE, or 20-HEDE eliminated pressure-induced constriction of rat middle cerebral arteries, and 20-HEDE and 15-HETE blocked the vasoconstriction action of 20-HETE. Taken together, these data suggest an important role for 20-HETE in the autoregulation of CBF.
Gebremedhin
D
D
Cardiovascular Research Center, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA.
Lange
A R
AR
Lowry
T F
TF
Taheri
M R
MR
Birks
E K
EK
Hudetz
A G
AG
Narayanan
J
J
Falck
J R
JR
Okamoto
H
H
Roman
R J
RJ
Nithipatikom
K
K
Campbell
W B
WB
Harder
D R
DR
D000577:Amides / Q000494:pharmacology; D000818:Animals; D002536:Cerebral Arteries / Q000502:physiology; D002560:Cerebrovascular Circulation; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D006706:Homeostasis; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors / Q000502:physiology*; D066298:In Vitro Techniques; D008861:Microsomes / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D013450:Sulfones / Q000494:pharmacology; D014661:Vasoconstriction
D000577:Amides; D006893:Hydroxyeicosatetraenoic Acids; D012333:RNA, Messenger; D013450:Sulfones; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; C117975:DDMS; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A