Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.804852
Title: Investigation of the adenosine receptors present on the thoracic aorta and coronary arteries of the rat
Author: Lewis, Cheryl
Awarding Body: University of Surrey
Current Institution: University of Surrey
Date of Award: 1995
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Abstract:
1. The classification of adenosine receptors has been summarised and the involvement of these receptors in the cardiovascular system has been described. 2. Adenosine and its analogues induced relaxations of the rat isolated thoracic aorta and the rat coronary arteries. The agonist potency orders indicate the presence of A2 receptors although the high potency of the A2a selective agonist CGS 21680 suggests that these relaxations were mediated via A2a receptors. However, as the maximal responses to CGS 21680 in the rat thoracic aorta was only 66% of the NECA maximal response, it is possible that CGS 21680 was acting as a partial agonist on the A2a receptors present on this tissue. 3. On the rat thoracic aorta, the endogenous nucleoside MTA was a very weak agonist but its effects were not inhibited by the non selective antagonist 8-SPT. This suggests that the relaxations induced by this agonist were not mediated by the A2a receptors on the aorta but by another site which is resistant to blockade by 8-SPT. However, MTA also appears to act as an antagonist on the A2a receptors on the rat aorta inhibiting the relaxations induced by the adenosine agonists with a potency similar to that of 8-SPT. 4. In the rat thoracic aorta, MTA, the non selective antagonist 8-SPT and the A2a selective antagonist PD 115,199 inhibited the relaxations induced by the adenosine agonists. However, NECA was inhibited to a greater extent than the other agonists by these antagonists. This suggests that all of these agonists, with the exception of MTA, were acting on the A2a receptors present on the aorta. It also suggests that CGS 21680, CPA, adenosine and APNEA may not be acting solely on this receptor. It is possible that these agonists were also acting on another site on the aorta which displays some resistance to blockade by these antagonists, hence the lesser degree of antagonism. This site may be the same xanthine-resistant site on the aorta at which MTA acts as a weak agonist. 5. A1 receptors are unlikely to be present on the rat thoracic aorta as an A1 selective concentration of DPCPX (1nM) did not inhibit the relaxations induced by APNEA, adenosine and CPA. The differing degrees of antagonism of the agonist responses by 8-SPT and MTA and the xanthine-resistant relaxant effects of MTA do not appear to involve A3 receptors as the agonist potency order produced in the presence of these antagonists was different to the potency order which would be expected if A3 receptors were present. 6. Initially, when studying the adenosine receptors in the rat coronary arteries using the Langendorff isolated heart technique, the concentration response curves for the adenosine agonists in the presence and absence of antagonists and L-NAME were carried out in separate hearts. However, interpretation of the increases in flow induced by the agonists became difficult due to other effects, such as decreases in basal flow, which were produced by the inhibitors. Therefore the effect of the inhibitors on the basal flow and the increases in flow induced by SNP and NECA were then investigated in a paired fashion in each heart. It was found that these inhibitors caused a decrease in the basal flow through the heart indicating vasoconstriction of the coronary vessels. This vasoconstriction lead to physiological/functional antagonism of the agonist induced responses causing a reduction in the vasodilation obtained. The results obtained with the agonist concentration response curves were subsequently reinterpreted in the light of this complication. 7. In the rat isolated heart, 8-SPT inhibited the increase in flow induced by the adenosine agonists confirming the involvement of the P1 receptors in this response and also suggesting that A3 receptors are not involved in mediating coronary vasodilation. 8. In the rat coronary arteries, the A2a selective antagonist PD 115,199 inhibited the increase in flow induced by NECA and CGS 21680. Whilst the concentration response curve produced by NECA was shifted to the right by PD 115,199 (30nM), a lower concentration of PD 115,199 (10nM) virtually abolished the concentration response curve produced by CGS 21680. Initially this suggested that both of these agonists act via the A2a receptors on this tissue although the different degrees of antagonism by PD 115,199 could not be explained. However, it was later found that PD 115,199 caused vasoconstriction of the coronary vessels which led to physiological/functional antagonism of the agonist responses and therefore a reduction in the vasodilations induced by the agonists. When taking this physiological antagonism into consideration, the concentration response curves for NECA in the presence and absence of PD 115,199 were very similar, suggesting that, in fact, PD 115,199 had no effect on the NECA induced responses. Therefore NECA was probably not acting via the A2a receptors but possibly via A2b receptors to produce vasodilatation of the coronary arteries. 9. Mechanical removal of the endothelium from the rat isolated aorta, or incubation of the intact aorta with the nitric oxide synthase inhibitor L-NAME (30μM), virtually abolished the relaxations induced by the adenosine agonists. This indicates that these responses are endothelium-dependent and are mediated via the nitric oxide pathway. Initially in the rat isolated heart, the presence of L-NAME inhibited the concentration response curves for NECA and CGS 21680 shifting the curves to the right, whilst abolishing the responses to CPA and adenosine, although this was due to their low potency in the absence of the inhibitor. This would imply that in the coronary arteries the agonist induced vasodilations are partially endothelium-dependent and are mediated via the endothelium and the vascular smooth muscle. However, it was found that L-NAME caused vasoconstriction of the coronary vessels, which led to physiological antagonism of the agonist responses and therefore a reduction in the vasodilations induced by the agonists. When this physiological antagonism was taken into consideration the concentration response curves of the agonists in the presence and absence of L-NAME were very similar indicating that L-NAME had no effect on the increases in flow induced by the agonists. This suggests that, unlike the rat thoracic aorta, the vasodilation induced by the adenosine agonists in the coronary arteries is endothelium-independent and does not involve the nitric oxide pathway.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.804852  DOI: Not available
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