title: Dual actions of dephostatin on the nitric oxide/cGMP-signalling pathway in porcine iliac arteries.
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.
authors.affiliation: Department of Medicine and Care, Division of Pharmacology, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden.
authors.forename: Anna Asplund
authors.initials: AA
authors.lastname: Persson
authors.forename: Peter
authors.initials: P
authors.lastname: Gunnarsson
authors.forename: Eva
authors.initials: E
authors.lastname: Lindström
authors.forename: Magnus
authors.initials: M
authors.lastname: Grenegård
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006873:Hydroquinones / Q000494:pharmacology*; D007083:Iliac Artery / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013552:Swine; D014230:Triazoles / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; C093084:GEA 3175; D006873:Hydroquinones; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D010750:Phosphoproteins; D011810:Quinoxalines; C110881:S-nitro-N-acetylpenicillamine; D014230:Triazoles; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C084037:dephostatin; D010656:Phenylephrine; D009569:Nitric Oxide; D014443:Tyrosine; D012694:Serine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D017027:Protein Tyrosine Phosphatases; D006162:Guanylate Cyclase; D010396:Penicillamine; D006152:Cyclic GMP; D000109:Acetylcholine