Gasser, Jurg Andreas; (1991) Studies on the platelet adenosine A2 receptor. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

AIMS: Platelets are thought to contribute to the early development of atherosclerosis and they play a central role in thrombotic events. Platelet aggregation is regulated by a number of agonists such as ADP, catecholamines, collagen and thrombin. The inhibitors of platelet function can be divided into four major classes which act through specific surface receptors. They are prostacyclin, adenosine, prostaglandin Dj and β2-adrenergic receptor agonists. Over the past few years a lot of information has been gathered about the role of prostacyclin in the regulation of platelet function and its involvement in thrombotic processes. There is less information about the role of adenosine in these processes. My aim therefore was to study transmembrane signalling through the adenosine receptor in patients heterozygous for familial hypercholesterolaemia, a condition associated with premature atherosclerosis. In addition insulin-dependent diabetic patients with retinopathy were studied as abnormal platelet function has been postulated to play a role in this disorder. Parallel to the investigations with adenosine and the stable analogue 5'-N-ethylcarboxamidoadenosine experiments with prostacyclin were performed to find out more about possible interactions between the two pathways. Interactions between the two platelet inhibitors might be expected since they appear to share the same postreceptor pathway. Adenosine may have an important function in cardiac ischaemia and myocardial infarction. It is postulated that adenosine produced by ectonucleotidases from ATP during ischaemia serves to improve tissue oxygenation by vasodilating coronary arteries, and limits the size of the thrombus through its inhibitory effect on platelet aggregation. Studies on platelet transmembrane signalling with adenosine in patients following myocardial infarction will be presented in this thesis. Because of the important role of catecholamines as modulators of platelet function and their suspected role in the precipitation of myocardial infarction, we also studied adrenaline-mediated responses in platelets from patients with familial hypercholesterolaemia and patients with myocardial infarction. It is known that rat platelets do not respond to the inhibitory effect of adenosine. This made it impossible to use rats as a model for diabetes or hypercholesterolaemia. I was therefore interested to investigate the site of the defect in signal transmission in this species.

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