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Role of potassium channels in endothelium-dependent relaxation resistant to nitroarginine in the rat hepatic artery

Zygmunt, Peter M. LU and Högestätt, Edward D. LU (1996) In British Journal of Pharmacology 117(7). p.1600-1606
Abstract

1. In the presence of indomethacin (IM, 10 μM) and N(ω)-nitro-L-arginine (L-NOARG, 0.3 mM), acetylcholine (ACh) induces an endothelium-dependent smooth muscle hyperpolarization and relaxation in the rat isolated hepatic artery. The potassium (K) channel inhibitors, tetrabutylammonium (TBA, 1 mM) and to a lesser extent 4-aminopyridine (4-AP, 1 mM) inhibited the L-NOARG/IM-resistant relaxation induced by ACh, whereas apamin (0.1-0.3 μM), charybdotoxin (0.1-0.3 μM), iberiotoxin (0.1 μM) and dendrotoxin (0.1 μM) each had no effect. TBA also inhibited the relaxation induced by the receptor-independent endothelial cell activator, A23187. 2. When combined, apamin (0.1 μM)+charybdotoxin (0.1 μM), but not apamin (0.1 μM)+iberiotoxin (0.1 μM) or... (More)

1. In the presence of indomethacin (IM, 10 μM) and N(ω)-nitro-L-arginine (L-NOARG, 0.3 mM), acetylcholine (ACh) induces an endothelium-dependent smooth muscle hyperpolarization and relaxation in the rat isolated hepatic artery. The potassium (K) channel inhibitors, tetrabutylammonium (TBA, 1 mM) and to a lesser extent 4-aminopyridine (4-AP, 1 mM) inhibited the L-NOARG/IM-resistant relaxation induced by ACh, whereas apamin (0.1-0.3 μM), charybdotoxin (0.1-0.3 μM), iberiotoxin (0.1 μM) and dendrotoxin (0.1 μM) each had no effect. TBA also inhibited the relaxation induced by the receptor-independent endothelial cell activator, A23187. 2. When combined, apamin (0.1 μM)+charybdotoxin (0.1 μM), but not apamin (0.1 μM)+iberiotoxin (0.1 μM) or a triple combination of 4-AP (1 mM)+apamin (0.1 μM)+iberiotoxin (0.1 μM), inhibited the L-NOARG/IM-resistant relaxation induced by ACh. At a concentration of 0.3 μM, apamin+charybdotoxin completely inhibited the relaxation. This toxin combination also abolished the L-NOARG/IM-resistant relaxation induced by A23187. 3. In the absence of L-NOARG, TBA (1 mM) inhibited the ACh-induced relaxation, whereas charybdotoxin (0.3 μM)+apamin (0.3 μM) had no effect, indicating that the toxin combination did not interfere with the L-arginine/NO pathway. 4. The gap junction inhibitors halothane (2 mM) and 1-heptanol (2 mM), or replacement of NaCl with sodium propionate did not affect the L-NOARG/IM-resistant relaxation induced by ACh. 5. Inhibition of Na+/K+-ATPase by ouabain (1 mM) had no effect on the L-NOARG/IM-resistant relaxation induced by ACh. Exposure to a K+-free Krebs solution, however, reduced the maximal relaxation by 13% without affecting the sensitivity to ACh. 6. The results suggest that the L-NOARG/IM-resistant relaxation induced by ACh in the rat hepatic artery is mediated by activation of K-channels sensitive to TBA and a combination of apamin+charybdotoxin. Chloride channels, Na+/K+-ATPase and gap junctions are probably not involved in the response. It is proposed that endothelial cell activation induces secretion of an endothelium-derived hyperpolarizing factor(s) (EDHF), distinct from NO and cyclo-oxygenase products, which activates more than one type of K-channel on the smooth muscle cells. Alternatively, a single type of K-channel, to which both apamin and charybdotoxin must bind for inhibition to occur, may be the target for EDHF.

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author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Acetylcholine, Arteries, Hyperpolarization, Membrane potential, Nitric oxide, Potassium channels, Vascular endothelium
in
British Journal of Pharmacology
volume
117
issue
7
pages
7 pages
publisher
The British Pharmacological Society
external identifiers
  • scopus:0029912917
ISSN
0007-1188
DOI
10.1111/j.1476-5381.1996.tb15327.x
language
English
LU publication?
no
id
c7db75f1-2beb-4d81-b5d9-751e6af2b57a
date added to LUP
2019-05-31 21:39:52
date last changed
2019-09-26 04:37:09
@article{c7db75f1-2beb-4d81-b5d9-751e6af2b57a,
  abstract     = {<p>1. In the presence of indomethacin (IM, 10 μM) and N(ω)-nitro-L-arginine (L-NOARG, 0.3 mM), acetylcholine (ACh) induces an endothelium-dependent smooth muscle hyperpolarization and relaxation in the rat isolated hepatic artery. The potassium (K) channel inhibitors, tetrabutylammonium (TBA, 1 mM) and to a lesser extent 4-aminopyridine (4-AP, 1 mM) inhibited the L-NOARG/IM-resistant relaxation induced by ACh, whereas apamin (0.1-0.3 μM), charybdotoxin (0.1-0.3 μM), iberiotoxin (0.1 μM) and dendrotoxin (0.1 μM) each had no effect. TBA also inhibited the relaxation induced by the receptor-independent endothelial cell activator, A23187. 2. When combined, apamin (0.1 μM)+charybdotoxin (0.1 μM), but not apamin (0.1 μM)+iberiotoxin (0.1 μM) or a triple combination of 4-AP (1 mM)+apamin (0.1 μM)+iberiotoxin (0.1 μM), inhibited the L-NOARG/IM-resistant relaxation induced by ACh. At a concentration of 0.3 μM, apamin+charybdotoxin completely inhibited the relaxation. This toxin combination also abolished the L-NOARG/IM-resistant relaxation induced by A23187. 3. In the absence of L-NOARG, TBA (1 mM) inhibited the ACh-induced relaxation, whereas charybdotoxin (0.3 μM)+apamin (0.3 μM) had no effect, indicating that the toxin combination did not interfere with the L-arginine/NO pathway. 4. The gap junction inhibitors halothane (2 mM) and 1-heptanol (2 mM), or replacement of NaCl with sodium propionate did not affect the L-NOARG/IM-resistant relaxation induced by ACh. 5. Inhibition of Na<sup>+</sup>/K<sup>+</sup>-ATPase by ouabain (1 mM) had no effect on the L-NOARG/IM-resistant relaxation induced by ACh. Exposure to a K<sup>+</sup>-free Krebs solution, however, reduced the maximal relaxation by 13% without affecting the sensitivity to ACh. 6. The results suggest that the L-NOARG/IM-resistant relaxation induced by ACh in the rat hepatic artery is mediated by activation of K-channels sensitive to TBA and a combination of apamin+charybdotoxin. Chloride channels, Na<sup>+</sup>/K<sup>+</sup>-ATPase and gap junctions are probably not involved in the response. It is proposed that endothelial cell activation induces secretion of an endothelium-derived hyperpolarizing factor(s) (EDHF), distinct from NO and cyclo-oxygenase products, which activates more than one type of K-channel on the smooth muscle cells. Alternatively, a single type of K-channel, to which both apamin and charybdotoxin must bind for inhibition to occur, may be the target for EDHF.</p>},
  author       = {Zygmunt, Peter M. and Högestätt, Edward D.},
  issn         = {0007-1188},
  keyword      = {Acetylcholine,Arteries,Hyperpolarization,Membrane potential,Nitric oxide,Potassium channels,Vascular endothelium},
  language     = {eng},
  month        = {01},
  number       = {7},
  pages        = {1600--1606},
  publisher    = {The British Pharmacological Society},
  series       = {British Journal of Pharmacology},
  title        = {Role of potassium channels in endothelium-dependent relaxation resistant to nitroarginine in the rat hepatic artery},
  url          = {http://dx.doi.org/10.1111/j.1476-5381.1996.tb15327.x},
  volume       = {117},
  year         = {1996},
}