Role of SK Ca and IK Ca in endothelium-dependent hyperpolarizations of the guinea-pig isolated carotid artery

Pascale Gluais, Gillian Edwards, Arthur H. Weston, John R. Falck, Paul M. Vanhoutte, Michel Félétou

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Abstract

This study was designed to determine whether the endothelium-dependent hyperpolarizations evoked by acetylcholine in guinea-pig carotid artery involve a cytochrome P450 metabolite and whether they are linked to the activation of two distinct populations of endothelial K Ca channels, SK Ca and IK Ca. The membrane potential was recorded in the vascular smooth muscle cells of the guinea-pig isolated carotid artery. All the experiments were performed in the presence of N ω-L-nitro arginine (100 μM) and indomethacin (5 μM). Under control conditions (Ca 2+: 2.5 mM), acetylcholine (10 nM to 10 μM) induced a concentration- and endothelium-dependent hyperpolarization of the vascular smooth muscle cells. Two structurally different specific blockers of SK Ca, apamin (0.5 μM) or UCL 1684 (10 μM). produced a partial but significant inhibition of the hyperpolarization evoked by acetylcholine whereas charybdotoxin (0.1 μM) and TRAM-34 (10 μM), a nonpeptidic and specific blocker of IK Ca. were ineffective. In contrast, the combinations of apamin plus charybdotoxin, apamin plus TRAM-34 (10 μ) or UCL 1684 (10 μM) plus TRAM-34 (10 μM) virtually abolished the acetylcholine-induced hyperpolarization. In the presence of a combination of apamin and a subeffective dose of TRAM-34 (5 μM), the residual hyperpolarization produced by acetylcholine was not inhibited further by the addition of either an epoxyeicosatrienoic acid antagonist, 14,15-EEZE (10 μM) or the specific blocker of BK Ca, iberiotoxin (0.1 μM). In presence of 0.5 mM Ca 2+, the hyperpolarization in response to acetylcholine (1 μM) was significantly lower than in 2.5 mM Ca 2+. The EDHF-mediated responses became predominantly sensitive to charybdotoxin or TRAM-34 but resistant to apamin. This investigation shows that the production of a cytochrome P450 metabolite, and the subsequent activation of BK Ca, is unlikely to contribute to the EDHF-mediated responses in the guinea-pig carotid artery. Furthermore, the EDHF-mediated response involves the activation of both endothelial IK Ca and SK Ca channels, the activation of either one being able to produce a true hyperpolarization.

Original languageEnglish (US)
Pages (from-to)477-485
Number of pages9
JournalBritish Journal of Pharmacology
Volume144
Issue number4
DOIs
StatePublished - Feb 2005

Fingerprint

Apamin
Carotid Arteries
Acetylcholine
Endothelium
Guinea Pigs
Charybdotoxin
Vascular Smooth Muscle
Cytochrome P-450 Enzyme System
Smooth Muscle Myocytes
Indomethacin
Membrane Potentials
Arginine
TRAM 34
Acids
Population
endothelium-dependent hyperpolarization factor

Keywords

  • 14,15-EEZE
  • Ca -activated potassium channel
  • Cytochrome P450, smooth muscle
  • EDHF
  • Endothelium
  • TRAM-34
  • UCL 1684

ASJC Scopus subject areas

  • Pharmacology

Cite this

Role of SK Ca and IK Ca in endothelium-dependent hyperpolarizations of the guinea-pig isolated carotid artery. / Gluais, Pascale; Edwards, Gillian; Weston, Arthur H.; Falck, John R.; Vanhoutte, Paul M.; Félétou, Michel.

In: British Journal of Pharmacology, Vol. 144, No. 4, 02.2005, p. 477-485.

Research output: Contribution to journalArticle

Gluais, Pascale ; Edwards, Gillian ; Weston, Arthur H. ; Falck, John R. ; Vanhoutte, Paul M. ; Félétou, Michel. / Role of SK Ca and IK Ca in endothelium-dependent hyperpolarizations of the guinea-pig isolated carotid artery. In: British Journal of Pharmacology. 2005 ; Vol. 144, No. 4. pp. 477-485.
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