Abstract
We examined the effects of the nitrosoamine dephostatin on the nitric oxide (NO)/cyclic guanosine 3',5'-monophosphate (cGMP)-signalling in porcine iliac arteries. Dephostatin has been characterised as a tyrosine phosphatase inhibitor, but Western blot analyses showed that dephostatin did not augment tyrosine phosphorylation of arterial proteins. However, dephostatin relaxed pre-contracted arteries, and this effect was antagonised by the soluble guanylyl cyclase inhibitor 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Furthermore, dephostatin increased the cGMP content and the serine phosphorylation of vasodilator-stimulated phosphoprotein. Dephostatin also inhibited the relaxation induced by acetylcholine and the NO-donor S-nitroso-N-acetyl-penicillamine (SNAP). In contrast, dephostatin did not affect the NO-dependent actions of 1,2,3,4-Oxatriazolium, 3-(3-chloro-2-metylphenyl)-5-[[(4methylphenyl)sulfonyl]amino]-hydroxide inner salt (GEA 3175). Measurement of NO revealed that dephostatin accelerated the consumption of NO. In conclusion, dephostatin exerts dual effects on the NO/cGMP-signalling pathway in iliac arteries. The drug actions included scavenging of NO, but also stimulation of cGMP production. These effects were not related to inhibition of tyrosine phosphatases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / pharmacology
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Acetylcholine / pharmacology
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Animals
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Blotting, Western
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Cyclic GMP / metabolism
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Cyclic GMP / physiology*
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Enzyme Inhibitors / pharmacology
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Guanylate Cyclase / antagonists & inhibitors
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Hydroquinones / pharmacology*
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Iliac Artery / drug effects*
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Iliac Artery / metabolism
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Iliac Artery / physiology
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In Vitro Techniques
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Nitric Oxide / metabolism
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Nitric Oxide / physiology*
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Nitric Oxide Donors / pharmacology
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Oxadiazoles / pharmacology
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Penicillamine / analogs & derivatives
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Penicillamine / metabolism
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Penicillamine / pharmacology
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Phenylephrine / pharmacology
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Phosphoproteins / metabolism
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Phosphorylation / drug effects
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Protein Tyrosine Phosphatases / antagonists & inhibitors
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Protein Tyrosine Phosphatases / metabolism
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Quinoxalines / pharmacology
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Serine / metabolism
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Signal Transduction / drug effects*
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Swine
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Triazoles / pharmacology
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Tyrosine / metabolism
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Vasoconstrictor Agents / pharmacology
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Vasodilation / drug effects
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Vasodilator Agents / pharmacology
Substances
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1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one
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Enzyme Inhibitors
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GEA 3175
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Hydroquinones
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Nitric Oxide Donors
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Oxadiazoles
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Phosphoproteins
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Quinoxalines
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S-nitro-N-acetylpenicillamine
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Triazoles
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Vasoconstrictor Agents
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Vasodilator Agents
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dephostatin
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Phenylephrine
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Nitric Oxide
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Tyrosine
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Serine
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15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
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Protein Tyrosine Phosphatases
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Guanylate Cyclase
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Penicillamine
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Cyclic GMP
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Acetylcholine