Contribution of 20-HETE to vasodilator actions of nitric oxide in the cerebral microcirculation.
OBJECTIVE
The present study examined the contributions of a rise in cGMP versus a fall in 20-HETE levels to the vasodilator response to nitric oxide (NO) in the cerebral circulation of the rat.


METHODS
Intact rat middle cerebral and basilar arteries were bathed in physiological saline solution containing indomethacin (5 micromol/L) and baicalein (0.5 micromol/L) and pressurized at 90 mm Hg. Relaxations to sodium nitroprusside (SNP) were studied before and after addition of [1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one] (ODQ, a guanylyl cyclase blocker), 8R,9S, 11S-(-)-9-methoxy-carbamyl-8-methyl-2,3,9,10-tetrahydro-8, 11-epoxy-1H,8H,11H-2,7b,11a-trizadibenzo-(a,g)-cycloocta-(c, d, e)-trinden-1-one (KT5823, a protein kinase G blocker), and 20-hydroxyeicosatetraenoic acid (20-HETE). Cerebral blood flow was measured by using a laser Doppler flow probe over a thin cranial window in anesthetized rats, and the effects of intracerebroventricular infusion of 1-hexamine, 6-(2-hydroxy-1-methyl-2-nitrosohydrazino)N-methyl (MAHMA nonoate) and dibromododecenyl methylsulfimide (DDMS) were determined.


RESULTS
SNP-induced dilation of serotonin-preconstricted (0.2 micromol/L) middle cerebral arteries (10(-7) to 10(-3) mol/L) was attenuated in arteries treated with ODQ (10 micromol/L) or KT5823 (1 micromol/L) by 52% and 27%, respectively. Preventing the NO-induced fall in intracellular 20-HETE, by adding 20-HETE (100 nmol/L) to the bath, reduced the dilation to SNP by 62%. Simultaneous administration of ODQ and 20-HETE markedly attenuated the SNP-induced dilation by 90%. In basilar arteries, ODQ (10 micromol/L) alone completely blocked the response to SNP. Infusion of MAHMA nonoate (10 nmol/min ICV) in anesthetized rats increased cerebral blood flow by 52% before and 8% after blockade of the endogenous production of 20-HETE with DDMS (50 pmol/min).


CONCLUSIONS
These results suggest that NO dilates cerebral arteries through both cGMP-dependent and cGMP-independent pathways and that inhibition of 20-HETE formation contributes to the cerebral vasodilator response to NO both in vitro and in vivo.
Alonso-Galicia
M
M
Departments of Physiology, Medical College of Wisconsin, Milwaukee 53226-0509, USA.
Hudetz
A G
AG
Shen
H
H
Harder
D R
DR
Roman
R J
RJ
D000241:Adenosine / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000502:physiology; D002227:Carbazoles; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D006152:Cyclic GMP / Q000502:physiology*; D042926:Cytochrome P-450 CYP4A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006834:Hydrazines / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism / Q000494:pharmacology*; D007211:Indoles; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D020768:Middle Cerebral Artery / Q000187:drug effects* / Q000502:physiology; D006899:Mixed Function Oxygenases / Q000032:analysis / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
C105785:1-hexanamine-6-(2-hydroxy-1-methyl-2-nitrosohydrazine)-N-methyl; C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000470:Alkaloids; D000577:Amides; D002227:Carbazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006834:Hydrazines; D006893:Hydroxyeicosatetraenoic Acids; D007211:Indoles; D010069:Oxadiazoles; D011810:Quinoxalines; D013450:Sulfones; D014665:Vasodilator Agents; C073601:KT 5823; D009599:Nitroprusside; D009569:Nitric Oxide; 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; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D000241:Adenosine