Dual actions of dephostatin on the nitric oxide/cGMP-signalling pathway in porcine iliac arteries.
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.
Persson
Anna Asplund
AA
Department of Medicine and Care, Division of Pharmacology, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden.
Gunnarsson
Peter
P
Lindström
Eva
E
Grenegård
Magnus
M
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
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