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Title: The effect of pH on the function of the adenosine receptor
Author: Crawford, S. P.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1999
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This thesis describes an investigation into the effect of pH on adenosine receptors and provides a characterisation of the adenosine receptors within the mesenteric arterial bed. Initial radioligand binding of [3H]-CGS 21680 to rat striatal membranes indicates that the adenosine A2A receptor agonists, 2-methoxyadenosine and 2-ethoxyadenosine, are pH-sensitive ligands which give biphasic displacement curves at low pH values with a high affinity, GTP-sensitive state only becoming apparent at the reduced pH of 5.5. Experiments describing the mechanisms involved in the increased responsiveness of the rat mesenteric arterial bed to adenosine at low pH show that the increased relaxation to adenosine at pH 6.2 was not due to a change in the sensitivity of the smooth muscle to cAMP, but perhaps a change in receptor-effector coupling or adenosine metabolism. Additionally, it appears that the predominant action of adenosine receptors in this tissue is mediated by the opening of KATP channels. However, the pH sensitivity was maintained in the presence of elevated KC1 suggesting that this pH effect was not mediated at the level of potassium channels. The adenosine receptors causing dilation of third generation mesenteric arteries were identified. The agonist order of potency and effect of antagonists suggests the presence of A2B receptors, and it seems unlikely that the A1 and A2A receptors play an important role in the vasodilator responses to adenosine in this tissue. In addition, there is another, as yet unidentified site, which may correspond to the A3 receptor. It is concluded from the work presented that there are high and low affinity states of the A2A receptor which are pH sensitive. However, no functional correlate in the pH sensitivity of the A2A receptor was detected in the perfused rat mesenteric arterial bed. Instead the pH sensitivity displayed in this tissue may therefore be due to action at another receptor and/or a change in adenosine metabolism.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available