Effects of a 20-HETE antagonist and agonists on cerebral vascular tone.
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.
Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Ming
M
Yu
Liana
L
Cambj-Sapunar
Franz
F
Kehl
Kristopher G
KG
Maier
Kazuhiko
K
Takeuchi
Noriyuki
N
Miyata
Tsuyoshi
T
Ishimoto
L Manmohan
LM
Reddy
John R
JR
Falck
Debebe
D
Gebremedhin
David R
DR
Harder
Richard J
RJ
Roman
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004347:Drug Interactions; D006893:Hydroxyeicosatetraenoic Acids / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013345:Subarachnoid Hemorrhage / Q000503:physiopathology; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D000096926:Benzenesulfonamides
D002118:Calcium; D006893:Hydroxyeicosatetraenoic Acids; C494665:20-hydroxyeicosa-5(Z),14(Z)-dienoic acid; C494667:20-hydroxyeicosa-6(Z),15(Z)-dienoic acid; C494666:4-amino-N-(20-hydroxy-eicosa-5(Z),14(Z)-dienoyl) benzenesulfonamide; D000096926:Benzenesulfonamides; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid