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Title: Pharmacological characterisation of B-adrenoceptor-mediated vasodilatation and the role of endothelium in rat isolated arteries
Author: Rea, Adrian
Awarding Body: Glasgow Caledonian University
Current Institution: Glasgow Caledonian University
Date of Award: 2011
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Abstract:
There is still some controversy regarding the signalling mechanisms and role of endothelium in β~-adrenoceptor-mediated vasodilatation. This study aimed to investigate further the role of the endothelium in β-adrenoceptor mediated vasodilatation in rat aorta and femoral resistance arteries. Relatively little is known about the β-adrenoceptor sub types present in resistance arteries. This study was carried out to further characterise the β-adrenoceptor subtypes, and second messenger systems, mediating relaxation in rat femoral resistance arteries. Functional studies were perfomed by in vitro recording of isometric tension using rat aortic rings mounted in organ baths and rat femoral resistance arteries mounted on a wire myograph. Cyclic nucleotides were measured using enzyme-immunoassay. Although resting tension appeared to have little influence on phenylephrine responses, stretch did appear to play a small role in the activity of NOS with increases in resting tension appearing to increase the maximum response to phenylephrine in the presence of L-NAME. L-NAME-treatment and endothelial denudation increased the potency and maximum response of phenylephrine. Endothelium denudation resulted in a greater maximum response than L-NAME treatment, suggesting either that L-NAME inhibition of NOS is not complete or that there is another factor, other than NO, being released from the endothelium which attenuates the phenylephrine response. With no adjustment of pre-constrictor concentration, it may appear that endothelium denudation or inhibition of NOS causes an attenuation of isoprenaline relaxations, however when the pre-constrictor concentration is adjusted so as to create a similar level of tension in control, L-NAME treated, and endothelial-denuded preparations, isoprenaline produced a similar concentration-dependent relaxation in all preparations. This study also demonstrated that isoprenaline mediates vasorelaxation through elevating cAMP levels with no effect on cGMP levels. Thus, this study found that isoprenaline relaxation in rat aorta is endothelium-independent and via the generally recognised transduction pathway of adenylyl cyclase/cAMP. Inhibitors of the adenylyl cyclase/cAMPIPKA had no effect on isoprenaline relaxations, however it was also demonstrated that inhibitors of adenylyl cyclase did not attenuate the isoprenaline-mediated increase in cAMP levels. Therefore suggesting that these inhibitors are failing to cause a si,gnificant inhibition of adenylyl cyclase and protein kinase A. In rat femoral resistance arteries, the results with L-NAME demonstrate that ~- adrenoceptor-mediated relaxation is also independent of nitric oxide synthase. The non-conventional partial agonist, CGP 12177, induced relaxation in rat femoral resistance arteries pre-constricted with the α1-adrenoceptor agonist, phenylephrine. However, CGP 12177 failed to cause a relaxation in arteries pre-constricted with the thromboxane agonist, U46619. CL 316243, a potent and selective β~3-adrenoceptor agonist, produced no relaxation in phenylephrine-constricted arteries. This study also demonstrated a shift in the phenylephrine CRC by CGP 12177 in rat femoral resistance arteries, demonstrating further that CGP 12177 is acting as an u )-adrenoceptor antagonist. The present study therefore found no evidence that selective β3-adrenoceptor and low affinity state β1-adrenoceptor agonists mediate vasodilatation via the same pathway as isoprenaline suggesting that the relaxation mediated by these compounds does not occur through β- adrenoceptors.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.554311  DOI: Not available
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