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Cellular target of voltage and calcium‐dependent K + channel blockers involved in EDHF‐mediated responses in rat superior mesenteric artery
Author(s) -
Ghisdal Philippe,
Morel Nicole
Publication year - 2001
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704348
Subject(s) - charybdotoxin , apamin , thapsigargin , chemistry , iberiotoxin , hyperpolarization (physics) , egta , potassium channel , biophysics , mesenteric arteries , tetraethylammonium , endocrinology , membrane potential , potassium channel blocker , medicine , calcium , biochemistry , artery , stereochemistry , potassium , biology , organic chemistry , nuclear magnetic resonance spectroscopy
We have investigated the cellular target of K + channel blockers responsible for the inhibition of the EDHF‐mediated relaxation in the rat mesenteric artery by studying their effects on tension, smooth muscle cell (SMC) membrane potential and endothelial cell Ca 2+ signal ([Ca 2+ ] endo ). In arteries contracted with prostaglandin F 2α (2.5 – 10 μ M ), relaxation evoked by ACh (0.01 – 3 μ M ) was abolished by a combination of charybdotoxin (ChTX, 0.1 μ M ) plus apamin (Apa, 0.1 μ M ) and was inhibited by 68±6% ( n =6) by 4‐aminopyridine (4‐AP, 5 m M ). ACh (0.001 – 3 μ M ) increased [Ca 2+ ] endo and hyperpolarized SMCs with the same potency, the pD 2 values were equal to 7.2±0.08 ( n =4) and 7.2±0.07 ( n =9), respectively. SMCs hyperpolarization to ACh (1 μ M ) was abolished by high K + solution or by ChTX/Apa. It was decreased by 66±5% ( n =6) by 4‐AP. The increase in [Ca 2+ ] endo evoked by ACh (1 μ M ) was insensitive to ChTX/Apa but was depressed by 58±16% ( n =6) and 27±4% ( n =7) by raising external K + concentration and by 4‐AP, respectively. The effect of 4‐AP on [Ca 2+ ] endo was not affected by increasing external K + concentration. In Ca‐free/EGTA solution, the transient increase in [Ca 2+ ] endo evoked by ACh (1 μ M ) was abolished by thapsigargin (1 μ M ) and was decreased by 75±7% ( n =5) by 4‐AP. These results show that inhibition of EDHF‐evoked responses by 4‐AP may be attributed to a decrease in the Ca 2+ release activated by ACh in endothelial cells. The abolition of SMCs hyperpolarization to ACh by ChTX/Apa is not related to an interaction with the [Ca 2+ ] endo .British Journal of Pharmacology (2001) 134 , 1021–1028; doi: 10.1038/sj.bjp.0704348