TY - JOUR
T1 - Effects of a 20-HETE antagonist and agonists on cerebral vascular tone
AU - Yu, Ming
AU - Cambj-Sapunar, Liana
AU - Kehl, Franz
AU - Maier, Kristopher G.
AU - Takeuchi, Kazuhiko
AU - Miyata, Noriyuki
AU - Ishimoto, Tsuyoshi
AU - Reddy, L. Manmohan
AU - Falck, John R.
AU - Gebremedhin, Debebe
AU - Harder, David R.
AU - Roman, Richard J.
N1 - Funding Information:
This study was supported in part by Grants HL-59996, HL-29587 HL-36279 and GM-31278 from the National Institutes of Health and from the Robert A. Welch Foundation.
PY - 2004/2/23
Y1 - 2004/2/23
N2 - This study examined the effects of a 20-hydroxyeicosatetraenoic acid (20-HETE) antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (WIT002) and two agonists, 4-amino-N-(20-hydroxy-eicosa-5(Z),14(Z)-dienoyl) benzenesulfonamide (ABSA) and 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (WIT003), on the diameter of rat middle cerebral arteries in vitro and on cerebral blood flow in vivo. WIT003, ABSA and 20-HETE all had a similar effect to reduce the diameter of the middle cerebral artery by 26%. WIT003 and 20-HETE both increased intracellular Ca2+ concentration ([Ca2+]i) in vascular smooth muscle cells isolated from the middle cerebral artery. In contrast, WIT002 had no effect on the basal diameter of the middle cerebral artery but it attenuated the vasoconstrictor responses and the rise in [Ca2+] i in vascular smooth muscle cells following administration of 20-HETE and 5-hydroxytryptamine (5-HT). WIT003 partially restored the vasoconstrictor response to 5-HT in the middle cerebral artery after administration of an inhibitor of the endogenous synthesis of 20-HETE. Infusion of the 20-HETE agonists, WIT003 and ABSA, into cisterna magna of rats reduced baseline cerebral blood flow by 20%, whereas administration of the 20-HETE antagonist, WIT002, had no effect. Intracisternal injection of WIT002 attenuated the fall in cerebral blood flow following injection of blood into the cisterna magna, whereas administration of the 20-HETE agonist, ABSA, potentiated this response. These findings indicate that the 20-HETE agonists, WIT003 and ABSA, increase cerebral vascular tone both in vivo and in vitro and suggest blocking the vasoconstrictor actions of 20-HETE may be useful to prevent the acute fall in cerebral blood flow following subarachnoid hemorrhage.
AB - This study examined the effects of a 20-hydroxyeicosatetraenoic acid (20-HETE) antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (WIT002) and two agonists, 4-amino-N-(20-hydroxy-eicosa-5(Z),14(Z)-dienoyl) benzenesulfonamide (ABSA) and 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (WIT003), on the diameter of rat middle cerebral arteries in vitro and on cerebral blood flow in vivo. WIT003, ABSA and 20-HETE all had a similar effect to reduce the diameter of the middle cerebral artery by 26%. WIT003 and 20-HETE both increased intracellular Ca2+ concentration ([Ca2+]i) in vascular smooth muscle cells isolated from the middle cerebral artery. In contrast, WIT002 had no effect on the basal diameter of the middle cerebral artery but it attenuated the vasoconstrictor responses and the rise in [Ca2+] i in vascular smooth muscle cells following administration of 20-HETE and 5-hydroxytryptamine (5-HT). WIT003 partially restored the vasoconstrictor response to 5-HT in the middle cerebral artery after administration of an inhibitor of the endogenous synthesis of 20-HETE. Infusion of the 20-HETE agonists, WIT003 and ABSA, into cisterna magna of rats reduced baseline cerebral blood flow by 20%, whereas administration of the 20-HETE antagonist, WIT002, had no effect. Intracisternal injection of WIT002 attenuated the fall in cerebral blood flow following injection of blood into the cisterna magna, whereas administration of the 20-HETE agonist, ABSA, potentiated this response. These findings indicate that the 20-HETE agonists, WIT003 and ABSA, increase cerebral vascular tone both in vivo and in vitro and suggest blocking the vasoconstrictor actions of 20-HETE may be useful to prevent the acute fall in cerebral blood flow following subarachnoid hemorrhage.
KW - 20-HETE
KW - Agonist
KW - Antagonist
KW - Middle cerebral artery
KW - Subarachnoid hemorrhage
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UR - http://www.scopus.com/inward/citedby.url?scp=10744221010&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2004.01.009
DO - 10.1016/j.ejphar.2004.01.009
M3 - Article
C2 - 14985052
AN - SCOPUS:10744221010
SN - 0014-2999
VL - 486
SP - 297
EP - 306
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 3
ER -