Interaction between angiotensin II receptors and alpha-adrenoceptors in the murine vascular system

Shafaroudi, Majid Malekzadeh (2004) Interaction between angiotensin II receptors and alpha-adrenoceptors in the murine vascular system. PhD thesis, University of Glasgow.

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The mouse major conductive (aorta and carotid and superior mesenteric arteries) and small resistance arteries (first branch mesenteric artery) have a multiple population of adrenoceptor (ARs) and angiotensin II (Ang II) receptors capable of initiating contraction or relaxation. This thesis uses pharmacological methods to describe responses mediated by these receptors and to explore interactions between them. On mouse aorta Ang II had a dual effect that could be best observed in the presence of elevated tone (by 5HT), initially causing contraction at lower concentrations, followed by a slow relaxant effect that became dominant over time or at higher concentrations. The contraction was attenuated by Losartan and the relaxation by PD123319 (AT1 and AT2 antagonists, respectively) indicating physiologically opposing actions of AT1 and AT2 receptors. The relaxation was abolished by L-NAME or endothelium removal, revealing a larger contraction to Ang II. This indicates an AT1 action to contract vascular smooth muscle directly and an AT2 action on endothelium to release nitric oxide. The potential influence of Ang II on the effects of noradrenaline was studied. First the interaction of the relaxant (endothelial) effects of the two agents was explored by testing the effect of a "relaxant" concentration of Ang II (30nM) against the effects of UK14304, an alpha2-AR agonist, serving as a surrogate for noradrenaline in order to avoid activation of other adrenoceptors. This revealed no synergism or other significant interaction, which contrasted with a strong interaction between Ang II and the contractile effects of alpha2-AR activation in other blood vessels. Ang II was then tested against the contractile effects of noradrenahne, applied as a cumulative concentration response curve. Preincubation with Ang II (30nM) significantly reduced the contractile response to NA (p<0.0001); this effect was enhanced by losartan and blocked by PD123319. Thus the major influence of Ang II upon noradrenaline's actions is an AT2-mediated attenuation that becomes greater if AT1 receptors are blocked. In both carotid and superior (main) mesenteric arteries the contractile effect of Ang II was dominant. In first branch mesenteric arteries the main effect of angiotensin II was relaxation; this was reversed to contraction by L-NAME suggesting that it was of endothelial origin. The balance of smooth muscle contractile (AT1) and endothelial relaxant (AT2) -mediated responses, thus varies amongst arteries. A fluorescent derivative of Ang II, Rhodamine-Angiotensin II-Human (Rho-Ang II-H), was used to visualise angiotensin receptors on dissociated arterial cells and intact vessels, employing confocal microscopy. Losartan and PD123319 were used as competitor ligands to identify the receptor subtypes that were labelled by the fluorescent compound. This provided evidence for the presence of both AT receptor subtypes on both smooth muscle and endothelial cells. This was accomplished on both aorta and main (superior) mesenteric arteries. In conclusion, mouse arterial endothelium has AT2 that promote the release of nitric oxide, detectable as smooth muscle relaxation and vascular smooth muscle has contractile AT1. This shows that the previously demonstrated dual, opposing actions of angiotensin II are due to receptors situated on different cell types. There was also, however, evidence for the presence of both receptor types on both smooth muscle and endothelial cells. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Pharmacology, physiology.
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: McGrath, Prof. J.C. and Daly, Dr. C.J.
Date of Award: 2004
Depositing User: Enlighten Team
Unique ID: glathesis:2004-71139
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 May 2019 10:49
Last Modified: 15 Jun 2021 10:21

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