Characterization of endothelium-dependent relaxation in guinea pig basilar artery - Effect of hypoxia and role of cytochrome P450 mono- oxygenase
Petersson, Jesper LU ; Zygmunt, Peter M. LU
; Jönsson, Peter
LU
and Högestätt, Edward D.
LU
(1998)
In Journal of Vascular Research
35(4).
p.285-294
- Abstract
In the guinea pig basilar artery, acetylcholine and the calcium ionophore A23187 induced endothelium-dependent relaxations, which were not significantly affected by the nitric oxide (NO) synthase inhibitor N(ω)- nitro-L-arginine (L-NOARG; 0.3 mM) or the guanylate cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one; 1-10 μM), or by these inhibitors combined. However, acetylcholine (10μM) and A23187 (3 μM) each significantly increased the tissue level of cGMP in the absence but not in the presence of L-NOARG, suggesting that NO is released from the vascular endothelium in this blood vessel. Treatment with the potassium (K) channel inhibitors charybdotoxin (0.1 μM) plus apamin (0.1 μM), a toxin mixture previously shown to... (More)
In the guinea pig basilar artery, acetylcholine and the calcium ionophore A23187 induced endothelium-dependent relaxations, which were not significantly affected by the nitric oxide (NO) synthase inhibitor N(ω)- nitro-L-arginine (L-NOARG; 0.3 mM) or the guanylate cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one; 1-10 μM), or by these inhibitors combined. However, acetylcholine (10μM) and A23187 (3 μM) each significantly increased the tissue level of cGMP in the absence but not in the presence of L-NOARG, suggesting that NO is released from the vascular endothelium in this blood vessel. Treatment with the potassium (K) channel inhibitors charybdotoxin (0.1 μM) plus apamin (0.1 μM), a toxin mixture previously shown to inhibit relaxations mediated by endothelium-derived hyperpolarizing factor (EDHF) in this artery, had no effect on the A23187- induced relaxation but slightly inhibited the response to acetylcholine (E(max) was reduced by 24%). When the action of EDHF was prevented by these K channel inhibitors, the remaining relaxation was abolished by either ODQ (1 μM) or L-NOARG (0.3 mM), indicating that NO, apart from EDHF, contributes to the endothelium-dependent relaxations. Furthermore, ODQ (10 μM) abolished the relaxation induced by the NO donor S-nitroso-N-acetylpenicillamine. Thus, activation of soluble guanylate cyclase seems to be the only mechanism through which NO causes relaxation in this artery. When vessels were exposed to grave hypoxia (pO2 = 6 mm Hg), the NO-mediated relaxation (induced by acetylcholine in the presence of charybdotoxin plus apamin) disappeared. In contrast, EDHF-mediated responses (elicited by acetylcholine in the presence of L-NOARG) were only marginally affected by hypoxia (E(max) was reduced by 16%). 17-Octadecynoic acid (50 μM) and 5,8,11,14-eicosatetraynoic acid (10 μM), inhibitors ofcytochrome P450-dependent oxidation ofarachidonic acid, failed to inhibit the acetylcholine-induced relaxation in the presence of L- NOARG. The cytochrome P450-dependent arachidonic acid metabolite 11,12- epoxyecosatrienoic acid (0.3-3.0 μM) had no relaxant effect per se. In conclusion, EDHF and NO are both mediators of endothelium-dependent relaxations in the guinea pig basilar artery. However, during grave hypoxia, EDHF alone mediates acetylcholine-induced relaxation. The results further suggest that EDHF is not a metabolite of arachidonic acid formed by cytochrome P450 mono-oxygenase or generated by another oxygen-dependent enzyme in this artery.
(Less)
- author
- Petersson, Jesper
LU
; Zygmunt, Peter M.
LU
; Jönsson, Peter
LU
and Högestätt, Edward D.
LU
- publishing date
- 1998-07-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Arachidonic acid, Cerebral arteries, Cyclic nucleotides, Cytochrome P, Hyperpolarization, Hypoxia, Membrane potential, Vascular endothelium
- in
- Journal of Vascular Research
- volume
- 35
- issue
- 4
- pages
- 10 pages
- publisher
- Karger
- external identifiers
-
- pmid:9701713
- scopus:0031821613
- ISSN
- 1018-1172
- DOI
- 10.1159/000025595
- language
- English
- LU publication?
- no
- id
- 2d556d5e-af57-41ec-bbe3-bee6b0ba4bb0
- date added to LUP
- 2019-05-31 21:37:46
- date last changed
- 2024-01-01 08:59:28
@article{2d556d5e-af57-41ec-bbe3-bee6b0ba4bb0,
abstract = {{<p>In the guinea pig basilar artery, acetylcholine and the calcium ionophore A23187 induced endothelium-dependent relaxations, which were not significantly affected by the nitric oxide (NO) synthase inhibitor N(ω)- nitro-L-arginine (L-NOARG; 0.3 mM) or the guanylate cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one; 1-10 μM), or by these inhibitors combined. However, acetylcholine (10μM) and A23187 (3 μM) each significantly increased the tissue level of cGMP in the absence but not in the presence of L-NOARG, suggesting that NO is released from the vascular endothelium in this blood vessel. Treatment with the potassium (K) channel inhibitors charybdotoxin (0.1 μM) plus apamin (0.1 μM), a toxin mixture previously shown to inhibit relaxations mediated by endothelium-derived hyperpolarizing factor (EDHF) in this artery, had no effect on the A23187- induced relaxation but slightly inhibited the response to acetylcholine (E(max) was reduced by 24%). When the action of EDHF was prevented by these K channel inhibitors, the remaining relaxation was abolished by either ODQ (1 μM) or L-NOARG (0.3 mM), indicating that NO, apart from EDHF, contributes to the endothelium-dependent relaxations. Furthermore, ODQ (10 μM) abolished the relaxation induced by the NO donor S-nitroso-N-acetylpenicillamine. Thus, activation of soluble guanylate cyclase seems to be the only mechanism through which NO causes relaxation in this artery. When vessels were exposed to grave hypoxia (pO<sub>2</sub> = 6 mm Hg), the NO-mediated relaxation (induced by acetylcholine in the presence of charybdotoxin plus apamin) disappeared. In contrast, EDHF-mediated responses (elicited by acetylcholine in the presence of L-NOARG) were only marginally affected by hypoxia (E(max) was reduced by 16%). 17-Octadecynoic acid (50 μM) and 5,8,11,14-eicosatetraynoic acid (10 μM), inhibitors ofcytochrome P<sub>450</sub>-dependent oxidation ofarachidonic acid, failed to inhibit the acetylcholine-induced relaxation in the presence of L- NOARG. The cytochrome P<sub>450</sub>-dependent arachidonic acid metabolite 11,12- epoxyecosatrienoic acid (0.3-3.0 μM) had no relaxant effect per se. In conclusion, EDHF and NO are both mediators of endothelium-dependent relaxations in the guinea pig basilar artery. However, during grave hypoxia, EDHF alone mediates acetylcholine-induced relaxation. The results further suggest that EDHF is not a metabolite of arachidonic acid formed by cytochrome P<sub>450</sub> mono-oxygenase or generated by another oxygen-dependent enzyme in this artery.</p>}},
author = {{Petersson, Jesper and Zygmunt, Peter M. and Jönsson, Peter and Högestätt, Edward D.}},
issn = {{1018-1172}},
keywords = {{Arachidonic acid; Cerebral arteries; Cyclic nucleotides; Cytochrome P; Hyperpolarization; Hypoxia; Membrane potential; Vascular endothelium}},
language = {{eng}},
month = {{07}},
number = {{4}},
pages = {{285--294}},
publisher = {{Karger}},
series = {{Journal of Vascular Research}},
title = {{Characterization of endothelium-dependent relaxation in guinea pig basilar artery - Effect of hypoxia and role of cytochrome P<sub>450</sub> mono- oxygenase}},
url = {{http://dx.doi.org/10.1159/000025595}},
doi = {{10.1159/000025595}},
volume = {{35}},
year = {{1998}},
}