Two distinct pathways account for EDHF-dependent dilatation in the gracilis artery of dyslipidaemic hApoB +/+ mice

Stéphane Krummen, J R Falck, Eric Thorin

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

A universal endothelium-derived hyperpolarising factor (EDHF - non-NO/non-PGI 2) has not been identified. EDHF, however, is essential for the physiological control of resistance artery tone. The impact of dyslipidaemia (DL), a risk factor for cardiovascular diseases, on the nature and the efficacy of EDHF has not been evaluated yet. Pressurised (80 mmHg) gracilis arterial segments isolated from mice expressing the human apoB-100 and C57B1/6 wild-type (WT) mice were used. EDHF-dependent dilatations to acetylcholine (ACh) were measured in the presence of L-NNA (100 μM, NOS inhibitor) and indomethacin (10 μM, COX inhibitor). Maximal EDHF-induced dilatations were increased in DL when compared to WT (95 ± 2 versus 86 ± 4% in WT; P < 0.05). Combination of apamin and charybdotoxin strongly reduced (P < 0.05) ACh-induced dilatation in WT (22 ± 4%) and DL (25 ± 5%). Combined addition of barium (Ba 2+) and ouabain abolished EDHF-induced dilatations in WT arteries (13 ± 3%; P < 0.05). In vessels isolated from DL mice, however, only the addition of 14,15-EEZE (a 14,15-EET antagonist) to Ba 2+ and ouabain prevented EDHF-induced dilatations (5 ± 3% compared to 54 ± 11% in the presence of combined Ba 2+ and ouabain; P < 0.05). Our data suggest that EDHF-mediated dilatation depends on the opening of endothelial SK Ca and IK Ca channels. This is associated with the opening of K ir channels and activation of the Na +/K +-ATPase pump on smooth muscle cells leading to dilatation. In arteries from DL mice, a cytochrome P450 metabolite likely to be 14,15-EET equally contributes to the dilatory action of ACh. The early increased efficacy of EDHF in arteries isolated from DL mice may originate from the duplication of the EDHF pathways.

Original languageEnglish (US)
Pages (from-to)264-270
Number of pages7
JournalBritish Journal of Pharmacology
Volume145
Issue number2
DOIs
StatePublished - May 2005

Keywords

  • EDHF
  • Endothelium
  • Gracilis artery
  • Hypercholesterolemia
  • Mouse
  • Triglycerides

ASJC Scopus subject areas

  • Pharmacology

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