TY - JOUR
T1 - Role of SK Ca and IK Ca in endothelium-dependent hyperpolarizations of the guinea-pig isolated carotid artery
AU - Gluais, Pascale
AU - Edwards, Gillian
AU - Weston, Arthur H.
AU - Falck, John R.
AU - Vanhoutte, Paul M.
AU - Félétou, Michel
PY - 2005/2
Y1 - 2005/2
N2 - 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.
AB - 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.
KW - 14,15-EEZE
KW - Ca -activated potassium channel
KW - Cytochrome P450, smooth muscle
KW - EDHF
KW - Endothelium
KW - TRAM-34
KW - UCL 1684
UR - http://www.scopus.com/inward/record.url?scp=14844289539&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=14844289539&partnerID=8YFLogxK
U2 - 10.1038/sj.bjp.0706003
DO - 10.1038/sj.bjp.0706003
M3 - Article
C2 - 15655533
AN - SCOPUS:14844289539
SN - 0007-1188
VL - 144
SP - 477
EP - 485
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 4
ER -