Characterisation of GEA 3175 on human platelets; comparison with S-nitroso-N-acetyl-D,L-penicillamine.
By comparing the effect of two nitric oxide (NO)-containing compounds, we found that S-nitroso-N-acetyl-D,L-penicillamine (SNAP), but not GEA 3175 (1,2,3,4-Oxatriazolium,3-(3-chloro-2-metylphenyl)-5-[[(4-methylphenyl)sulfonyl]amino]-, hydroxide inner salt), released NO. Despite this, both drugs elevated cyclic guanosine 3',5'-monophosphate (cGMP) levels in human platelets. However, SNAP was more effective after short exposure times (5 and 20 s). The compounds also inhibited thrombin-induced rises in cytosolic Ca2+. Time studies revealed that the action of SNAP rapidly declined by increasing the length of incubation (from 5 s to 30 min). This desensibilisation phenomenon mainly involved the release of Ca2+ from intracellular stores. In comparison, GEA 3175-induced inhibition of cytosolic Ca2+ signalling was much more long-lasting. The soluble guanylyl cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reversed the effect of GEA 3175 on cytosolic Ca2+. Consequently, this inhibition depends solely on the increase in cGMP. In summary, differences between GEA 3175 and SNAP were observed in NO releasing, cGMP elevating and Ca2+ suppressive properties.
Department of Medicine and Care, Division of Pharmacology, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden. annas@imv.liu.se
Anna K
AK
Asplund Persson
Louise
L
Palmér
Peter
P
Gunnarsson
Magnus
M
Grenegård
D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*
C093084:GEA 3175; D014230:Triazoles; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D006152:Cyclic GMP