Arachidonate dilates basilar artery by lipoxygenase-dependent mechanism and activation of K(+) channels.
Dilatation of cerebral arterioles in response to arachidonic acid is dependent on activity of cyclooxygenase. In this study, we examined mechanisms that mediate dilatation of the basilar artery in response to arachidonate. Diameter of the basilar artery (baseline diameter = 216 +/- 7 micrometer) (means +/- SE) was measured using a cranial window in anesthetized rats. Arachidonic acid (10 and 100 microM) produced concentration-dependent vasodilatation that was not inhibited by indomethacin (10 mg/kg iv) or N(G)-nitro-L-arginine (100 microM) but was inhibited markedly by baicalein (10 micrometerM) or nordihydroguaiaretic acid (NDGA; 10 microM), inhibitors of the lipoxygenase pathway. Dilatation of the basilar artery was also inhibited markedly by tetraethylammonium ion (TEA; 1 mM) or iberiotoxin (50 nM), inhibitors of calcium-dependent potassium channels. For example, 10 microM arachidonate dilated the basilar artery by 19 +/- 7 and 1 +/- 1% in the absence and presence of iberiotoxin, respectively. Measurements of membrane potential indicated that arachidonate produced hyperpolarization of the basilar artery that was blocked completely by TEA. Incubation with [(3)H]arachidonic acid followed by reverse-phase and chiral HPLC indicated that the basilar artery produces relatively small quantities of prostanoids but large quantities of 12(S)-hydroxyeicosatetraenoic acid (12-S-HETE), a lipoxygenase product. Moreover, the production of 12-HETE was inhibited by baicalein or NDGA. These findings suggest that dilatation of the basilar artery in response to arachidonate is mediated by a product(s) of the lipoxygenase pathway, with activation of calcium-dependent potassium channels and hyperpolarization of vascular muscle.
Faraci
F M
FM
Departments of Internal Medicine and Pharmacology, Cardiovascular Center, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA. frank-faraci@uiowa.edu
Sobey
C G
CG
Chrissobolis
S
S
Lund
D D
DD
Heistad
D D
DD
Weintraub
N L
NL
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D001488:Basilar Artery / Q000187:drug effects / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044950:Flavanones; D005419:Flavonoids / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008084:Lipoxygenase / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019789:Tetraethylammonium / Q000494:pharmacology; D014316:Tritium; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D044950:Flavanones; D005419:Flavonoids; D010455:Peptides; D015221:Potassium Channels; D014316:Tritium; D019335:Nitroarginine; D016718:Arachidonic Acid; C006680:baicalein; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D019789:Tetraethylammonium; C064719:iberiotoxin; D008084:Lipoxygenase; D019001:Nitric Oxide Synthase; D007213:Indomethacin