Effects of a 20-HETE antagonist and agonists on cerebral vascular tone

Ming Yu, Liana Cambj-Sapunar, Franz Kehl, Kristopher G. Maier, Kazuhiko Takeuchi, Noriyuki Miyata, Tsuyoshi Ishimoto, L. Manmohan Reddy, John R. Falck, Debebe Gebremedhin, David R. Harder, Richard J. Roman

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)297-306
Number of pages10
JournalEuropean Journal of Pharmacology
Volume486
Issue number3
DOIs
StatePublished - Feb 23 2004

Keywords

  • 20-HETE
  • Agonist
  • Antagonist
  • Middle cerebral artery
  • Subarachnoid hemorrhage

ASJC Scopus subject areas

  • Pharmacology

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