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Title: A study of the mechanisms of action of nitric oxide in platelets : therapeutic potential of novel antithrombotic agents
Author: Crane, Michael Stuart
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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Ex vivo aggregometry and intracellular Ca2+ measurements combined with experiments utilising a NO-sensitive electrode were adopted to investigate NO-mediated cGMP-independent inhibition of platelet activation. Data obtained following pharmacological inhibition of sGC indicated that NO radical is the species required to elicit cGMP-independent antiplatelet effects. Furthermore, results revealed that plasma factors that cause extracellular generation of NO from NO-donors induce cGMP-independent antiplatelet effects to these donors. Further experiments were performed to identify possible intracellular targets for NO-mediated cGMP-independent antiplatelet effects. Platelet cyclooxygenase and extracellular Ca2+ entry events were both identified as potential intracellular targets for NO-mediated cGMP-independent signalling on platelets. To explore mechanisms involved in the formation of an antiplatelet NO reservoir, platelets were treated with a bolus dose of NO donor. Aggregometry data in conjunction with chemiluminescent S-nitrosothiol measurements indicated that low molecular weight thiols present in plasma may play an important role in the formation and activation of an S-nitrosothiol NO reservoir. Final experiments aimed to assess the therapeutic potential of novel NO donors as antiplatelet surfaces showed that the pre-treatment of prosthetic graft with a novel S-nitrosothiol, S-nitroso-N-valerylpenicillamine (SNVP), can reduce platelet adhesion, while NO-loaded zeolites may also form a high capacity NO-store with potent antiplatelet activity. Taken together, these data indicate novel NO signalling pathways that may occur both in the plasma environment and within platelets, further defining the inhibitory role of NO on platelet function. The pre-treatment of prosthetic grafts with SNVP and/or construction of grafts or stents with zeolites may prove to be potentially useful in the clinical setting as potent antiplatelet surfaces.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available