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Cross-talk between adenosine and the oxatriazole derivative GEA 3175 in platelets
Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0003-3184-0427
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2005 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 517, no 3, 149-157 p.Article in journal (Refereed) Published
Abstract [en]

We examined the interplay between adenosine and the nitric oxide (NO)-containing oxatriazole derivative GEA 3175 in human platelets. The importance of cyclic guanosine 3′5′-monophosphate (cGMP)-inhibited phosphodiesterases (PDEs) was elucidated by treating the platelets with adenosine combined with either GEA 3175 or the PDE3-inhibitor milrinone. The drug combinations provoked similar cyclic adenosine 3′5′-monophosphate (cAMP) responses. On the contrary, cGMP levels were increased only in GEA 3175-treated platelets. Both drug combinations reduced P-selectin exposure, platelet adhesion and fibrinogen-binding. However, adenosine together with GEA 3175 was more effective in inhibiting platelet aggregation and ATP release. Thrombin-induced rises in cytosolic Ca2+ were suppressed by the two drug combinations. Adenosine administered with GEA 3175 was, however, more effective in reducing Ca2+ influx.

In conclusion, the interaction between adenosine and GEA 3175 involves cGMP-mediated inhibition of PDE3. The results also imply that inhibition of Ca2+ influx represent another cGMP-specific mechanism that enhances the effect of adenosine.

Place, publisher, year, edition, pages
2005. Vol. 517, no 3, 149-157 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-30677DOI: 10.1016/j.ejphar.2005.05.019Local ID: 16282OAI: oai:DiVA.org:liu-30677DiVA: diva2:251500
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Pharmacological evaluation of the NO/cGMP signalling system
Open this publication in new window or tab >>Pharmacological evaluation of the NO/cGMP signalling system
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Platelet activation and inhibition are tightly balanced processes, regulated by various endogenous molecules. In this regard, the endothelium plays a key role in mediating inhibition of platelets by releasing nitric oxide (NO) and cAMP-elevating prostaglandins.

The present study put emphasis on drugs that activate directly or modulate the NO/cGMP signalling pathway.

The specific aims were i) to compare two different NO-containing compounds; namely the S-nitrosothiol SNAP and the oxatriazole derivative GEA 3175; ii) to evaluate the mechanism of drug action of the nitrosoamine dephostatin; iii) to investigate cross-talk mechanisms between the NO/cGMP and the cAMP signalling pathways. These studies were perfom1ed using human blood platelets and iliac arteries obtained from pigs.

The present data revealed that SNAP but not GEA 3175 released detectable amounts of NO. Despite that, both compounds elevated cGMP, inhibited rises in [Ca2+]i and stimulated phosphorylation of vasodilator stimulated phosphoprotein (VASP). Moreover, the results showed that NO/cGMP-induced inhibition of Ca2+ responses, but not NO/cGMP-mediated V ASP phosphorylation, was rapidly desensitised. The results showed that an unstable NO-donor more effectively induced desensitisation.

Dephostatin, originally characterised as a protein tyrosine phosphatase (PTP) inhibitor, was found to modulate the NO/cGMP signalling in a complex way. More specifically, dephostatin is an effective NO-scavenger and surprisingly, it also serves as a source of NO and thereby induces cGMPmediated vasorelaxation. In platelets, dephostatin abolished NO/cGMP-mediated inhibition of cytosolic Ca2+, but augmented NO/cGMP-induced VASP phosphorylation.

cGMP-induced inhibition of type 3 phosphodiesterases (PDE3) enhanced adenosine-mediated inhibition of platelets. This effect was of main importance for the suppression of several platelet responses. However, inhibition of Ca2+ influx was another cGMP-specific mechanism contributing to a powerful inhibition of the platelets.

In conclusion: The present results show that release of NO from drug molecules is not a prerequisite for NO/cGMP-mediated cellular and intracellular responses. On the contrary, drug stability in terms of NO-release appears to be crucial in platelet desensitisation to NO. Therefore it is important to gain more knowledge about the NO/cGMP-signalling pathway regarding future drug design of NO-containing drugs. The findings presented in this thesis suggest that dephostatin can prove to be a very useful tool in this area of research.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2005. 82 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 919
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-31869 (URN)17696 (Local ID)91-85297-56-8 (ISBN)17696 (Archive number)17696 (OAI)
Public defence
2005-11-24, Elsa Brändströmssalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-10-01Bibliographically approved

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Asplund Persson, AnnaZalavary, StefanLindström, EvaWhiss, Per ABengtsson, TorbjörnGrenegård, Magnus

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