Mechanisms involved in the early increase of serotonin contraction evoked by endotoxin in rat middle cerebral arteries

Raquel Hernanz, María J. Alonso, Ana M. Briones, Elisabet Vila, Ulf Simonsen, Mercedes Salaices

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31 Citations (Scopus)

Abstract

1. The present study investigated the mechanisms involved in the increased 5-hydroxytryptamine (5-HT) vasoconstriction observed in rat middle cerebral arteries exposed in vitro to lipopolysaccharide (LPS, 10 μg ml -1) for 1-5h. Functional, immunohistochemical and Western blot analysis and superoxide anion measurements by ethidium fluorescence were performed. 2. LPS exposure increased 5-HT (10 μM) vasoconstriction only during the first 4 h. In contrast to control tissue, indomethacin (10 μM), the COX-2 inhibitor NS 398 (10 μM), the TXA 2/PGH 2 receptor antagonist SQ 29,548 (1 μM) and the TXA 2 synthase inhibitor furegrelate (1 μM) reduced 5-HT contraction of LPS-treated arteries from hour one. The iNOS inhibitor aminoguanidine (0.1 mM) increased 5-HT contraction from hour three of LPS incubation. 3. The superoxide anion scavenger superoxide dismutase (SOD, 100 U ml -1) and the H 2O 2 scavenger catalase (1000 U ml -1), as well as the respective inhibitors of NAD(P)H oxidase and xanthine oxidase, apocynin (0.3 mM) and allopurinol (0.3 mM), reduced 5-HT contraction after LPS incubation. LPS induced an increase in superoxide anion levels that was abolished by PEG-SOD. 4. Subthreshold concentrations of the TXA 2 analogue U 46619, xanthine/xanthine oxidase and H 2O 2 potentiated, whereas those of sodium nitroprusside inhibited, the 5-HT contraction. 5. COX-2 expression was increased at 1 and 5 h of LPS incubation, while that of iNOS, Cu/Zn-SOD and Mn-SOD was only increased after 5 h. All the three vascular layers expressed COX-2 and Cu/Zn-SOD. iNOS expression was detected in the endothelium and adventitia after LPS. 6. In conclusion, increased production of TXA 2 from COX-2, superoxide anion and H 2O 2 enhanced vasoconstriction to 5-HT during the first few hours of LPS exposure; iNOS and SOD expression counteracted that increase at 5 h. These changes can contribute to the disturbance of cerebral blood flow in endotoxic shock.
Original languageEnglish
Pages (from-to)671-680
JournalBritish Journal of Pharmacology
Volume140
DOIs
Publication statusPublished - 1 Oct 2003

Keywords

  • Lipopolysaccharide
  • Middle cerebral artery
  • Nitric oxide
  • Oxygen radical
  • Thromboxane

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