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P2U-receptor mediated endothelium-dependent but nitric oxide-independent vascular relaxation

Malmsjö, Malin LU ; Edvinsson, Lars LU and Erlinge, David LU (1998) In British Journal of Pharmacology 123(4). p.719-729
Abstract
1. The dilator effect of extracellular adenosine triphosphate (ATP) has mainly been characterized as a direct effect on smooth muscle or as an endothelium-dependent effect mediated by nitric oxide (NO) or prostaglandins. We tested the hypothesis that endothelium-derived hyperpolarizing factor (EDHF) may also be involved. Dilator effects were studied in vitro by continuous recording of isomeric tension in cylindrical segments of rat blood vessels precontracted by noradrenaline (NA), in the presence of indomethacin (10 microM). 2. By screening different blood vessels in the rat we found that both acetylcholine (ACh) and ATP dilate mesenteric arteries with a resting tone of 1 mN by an endothelium-dependent non-NO mechanism. With an increased... (More)
1. The dilator effect of extracellular adenosine triphosphate (ATP) has mainly been characterized as a direct effect on smooth muscle or as an endothelium-dependent effect mediated by nitric oxide (NO) or prostaglandins. We tested the hypothesis that endothelium-derived hyperpolarizing factor (EDHF) may also be involved. Dilator effects were studied in vitro by continuous recording of isomeric tension in cylindrical segments of rat blood vessels precontracted by noradrenaline (NA), in the presence of indomethacin (10 microM). 2. By screening different blood vessels in the rat we found that both acetylcholine (ACh) and ATP dilate mesenteric arteries with a resting tone of 1 mN by an endothelium-dependent non-NO mechanism. With an increased resting tone (4 mN) the dilatation was mediated by NO. Thus by varying the resting tension the different dilator mechanisms could be examined. However, in the carotid artery the dilatation was solely mediated by an endothelium-dependent NO mechanism, even at different resting tones (1 and 4 mN). 3. The N-nitro-L-arginine methyl ester (L-NAME)-resistant dilatation to ACh and ATP was further inhibited by the NO-scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO), indicating L-NAME insensitive NO-synthesis. 4. In carotid arteries and mesenteric arteries at high resting tones (4 mN) the ATP-dilatation was totally inhibited by endothelium removal or L-NAME (10(-3) M). In mesenteric arteries at low resting tone (1 mN) the ATP, UTP (uridine-triphosphate) and 2-MeSATP (2methylthioATP)-dilatation was totally inhibited by endothelium removal. However, L-NAME in combination with indomethacin attenuated only 5% of the UTP dilatation, 70% of the ATP dilatation but all of the 2-MeSATP-dilatation. The inhibitors of Ca2+-activated K+ channels charybdotoxin (0.5 x 10(-7) M) together with apamin (10(-6) M), and the cytochrome P450 inhibitor, SKF 525A (10(-4) M), each in combination with indomethacin. L-NAME and PTIO (0.5 x 10(-3) M) totally abolished the remaining ATP and UTP-dilatation. This indicates a dilatation mediated by an endothelium-dependent non-NO factor, probably EDHF. 5. Agonist potency (UTP>ATP>>2-MeSATP), indicates that the EDHF-mediated dilatation was stimulated by a P2U-receptor, possibly by a selective pyrimidine-receptor. In contrast, a P2Y-receptor stimulated NO-mediated dilatation (2-MeSATP=ATP>UTP). 6. In conclusion, the dilator effects of ATP and especially UTP can be mediated by an endothelium-dependent non-NO-mediated mechanism, probably EDHF, mediated by a P2U-receptor, possibly a selective pyrimidine-receptor, while NO-mediated dilatation is stimulated mainly by a P2Y1-receptor. Furthermore, the EDHF-dilatation is dependent on the resting tone of the blood vessel. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Vascular reactivity, EDHF, nitric oxide, P2Y-, P2U-purinoceptor, pyrimidine-receptor, dilatation, endothelium
in
British Journal of Pharmacology
volume
123
issue
4
pages
719 - 729
publisher
The British Pharmacological Society
external identifiers
  • pmid:9517392
  • scopus:0031990815
ISSN
1476-5381
DOI
10.1038/sj.bjp.0701660
language
English
LU publication?
yes
id
4c7d51f4-8062-4690-a205-d0aba875e2aa (old id 1112616)
date added to LUP
2008-07-10 10:28:51
date last changed
2017-01-01 06:46:08
@article{4c7d51f4-8062-4690-a205-d0aba875e2aa,
  abstract     = {1. The dilator effect of extracellular adenosine triphosphate (ATP) has mainly been characterized as a direct effect on smooth muscle or as an endothelium-dependent effect mediated by nitric oxide (NO) or prostaglandins. We tested the hypothesis that endothelium-derived hyperpolarizing factor (EDHF) may also be involved. Dilator effects were studied in vitro by continuous recording of isomeric tension in cylindrical segments of rat blood vessels precontracted by noradrenaline (NA), in the presence of indomethacin (10 microM). 2. By screening different blood vessels in the rat we found that both acetylcholine (ACh) and ATP dilate mesenteric arteries with a resting tone of 1 mN by an endothelium-dependent non-NO mechanism. With an increased resting tone (4 mN) the dilatation was mediated by NO. Thus by varying the resting tension the different dilator mechanisms could be examined. However, in the carotid artery the dilatation was solely mediated by an endothelium-dependent NO mechanism, even at different resting tones (1 and 4 mN). 3. The N-nitro-L-arginine methyl ester (L-NAME)-resistant dilatation to ACh and ATP was further inhibited by the NO-scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO), indicating L-NAME insensitive NO-synthesis. 4. In carotid arteries and mesenteric arteries at high resting tones (4 mN) the ATP-dilatation was totally inhibited by endothelium removal or L-NAME (10(-3) M). In mesenteric arteries at low resting tone (1 mN) the ATP, UTP (uridine-triphosphate) and 2-MeSATP (2methylthioATP)-dilatation was totally inhibited by endothelium removal. However, L-NAME in combination with indomethacin attenuated only 5% of the UTP dilatation, 70% of the ATP dilatation but all of the 2-MeSATP-dilatation. The inhibitors of Ca2+-activated K+ channels charybdotoxin (0.5 x 10(-7) M) together with apamin (10(-6) M), and the cytochrome P450 inhibitor, SKF 525A (10(-4) M), each in combination with indomethacin. L-NAME and PTIO (0.5 x 10(-3) M) totally abolished the remaining ATP and UTP-dilatation. This indicates a dilatation mediated by an endothelium-dependent non-NO factor, probably EDHF. 5. Agonist potency (UTP>ATP>>2-MeSATP), indicates that the EDHF-mediated dilatation was stimulated by a P2U-receptor, possibly by a selective pyrimidine-receptor. In contrast, a P2Y-receptor stimulated NO-mediated dilatation (2-MeSATP=ATP>UTP). 6. In conclusion, the dilator effects of ATP and especially UTP can be mediated by an endothelium-dependent non-NO-mediated mechanism, probably EDHF, mediated by a P2U-receptor, possibly a selective pyrimidine-receptor, while NO-mediated dilatation is stimulated mainly by a P2Y1-receptor. Furthermore, the EDHF-dilatation is dependent on the resting tone of the blood vessel.},
  author       = {Malmsjö, Malin and Edvinsson, Lars and Erlinge, David},
  issn         = {1476-5381},
  keyword      = {Vascular reactivity,EDHF,nitric oxide,P2Y-,P2U-purinoceptor,pyrimidine-receptor,dilatation,endothelium},
  language     = {eng},
  number       = {4},
  pages        = {719--729},
  publisher    = {The British Pharmacological Society},
  series       = {British Journal of Pharmacology},
  title        = {P2U-receptor mediated endothelium-dependent but nitric oxide-independent vascular relaxation},
  url          = {http://dx.doi.org/10.1038/sj.bjp.0701660},
  volume       = {123},
  year         = {1998},
}