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Vascular and platelet eicosanoids in the aetiology and treatment of cardiovascular disease

Jeremy, Jamie Yancey; (1993) Vascular and platelet eicosanoids in the aetiology and treatment of cardiovascular disease. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Methods for the study of receptor-linked prostacyclin (PGI2) synthesis in blood vessels (from the rat, rabbit and man) and thromboxane A2 (TXA2) synthesis in human platelets were developed. The role of calcium, G proteins and protein kinase C in mediating eicosanoid synthesis in these tissues was also studied. These methods were applied in the investigation of: 1) PGI2 synthesis following hypothermic storage of blood vessels in preservation solutions used in organ transplantation, 2) the site of action of drugs known to modulate eicosanoid synthesis; for example, phosphodiesterase inhibitors (PDEIs), non-steroidal anti­ inflammatory drugs (NSAIDs) and copper chelators, 3) the mechanisms underlying altered synthesis of vascular PGI2 in diabetes mellitus (DM) and hepatic portal hypertension (HPH) in the rat. There were marked variations in the characterisitics of receptor-linked PGI2 release between species (human, rat and rabbit) whereas receptor- linked PGI2 release in different arteries and veins of the same species was remarkably similar. Hypothermic storage of blood vessels (rat, rabbit and human) in preservation solutions exerted minimal effects on PGI2 synthesis, a finding of relevance to transplant surgery. Apart from their accepted sites of action, NSAIDs (cyclooxygenase inhibitors) and PDEIs (cAMP elevators) were also found to inhibit eicosanoid synthesis at the signal transduction level. Copper chelators inhibited eicosanoid synthesis at the level of cyclooxygenase and lipoxygenase. In rats with DM, there were marked differential alterations of receptor-linked PGI2 synthesis in different vessels and in other non-vascular tissues (gastro-intestinal tract, urinary bladder, trachea). In rats with HPH, there were marked changes in receptor-linked PGI2 release by the aorta and mesenteric vasculature, indicating an adaptive series of events involving PGI2. The systems developed in this thesis are a convenient means of investigating not only eicosanoid synthesis but also drug action and the aetiology of vascular disease.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Vascular and platelet eicosanoids in the aetiology and treatment of cardiovascular disease
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10102236
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