Agonist Regulation of Adrenergic Receptors in the Rabbit

Deighton, Nicola M (1988) Agonist Regulation of Adrenergic Receptors in the Rabbit. PhD thesis, University of Glasgow.

Abstract

Acute elevations of the circulating catecholamines, adrenaline and noradrenaline are observed in physiological situations such as exercise, posture change and stress. Pathological settings such as phaeochromocytoma, heart failure and cirrhosis may be associated with chronic increases in plasma catecholamines. These high catecholamine levels have been associated with decreases in adrenergic receptor responsiveness or desensitisation. A reduction in adrenergic receptor density or down regulation has also been detected under these conditions. However, although the in vitro effects of raised concentrations of plasma catecholamines have been widely studied, similar investigations in vivo are not so well characterised. In addition, some in vivo experimental models (e.g. rat phaeochromocytoma) have produced plasma catecholamine levels vastly exceeding those found in many pathological settings. Therefore, the current investigations principally aimed to evaluate the effects of moderate increases in circulating catecholamines in vivo on adrenergic receptor function and number in a rabbit model. The first series of experiments were designed to validate the methods used and characterise the receptor populations under investigation. To begin with, experiments were carried out to determine if the pro-aggregatory response to adrenaline in rabbit platelets was mediated (like human platelets) by alpha2 adrenoceptors. The ability of the alpha adrenoceptor antagonists, idazoxan, yohimbine and prazosin to inhibit the platelet pro-aggregatory responses to adrenaline was recorded and IC50 values concentration of antagonist required to produce fifty percent inhibition of response) were calculated. The alpha2 adrenoceptor antagonists, idazoxan and yohimbine were found to be more potent than the alpha1 adrenoceptor antagonist, prazosin at inhibiting the platelet pro-aggregatory response to adrenaline. Therefore, these results demonstrated that alpha2 adrenoceptors primarily mediate the platelet pro-aggregatory response to adrenaline in the rabbit. The specificity of [3H] yohimbine binding to alpha2 adrenoceptors in rabbit platelets and kidney was also determined. Displacement assays were performed and the ability of various unlabelled alpha adrenoceptor antagonists to compete for [3H] yohimbine binding sites was examined and expressed as KI (a measure of affinity) values. Yohimbine was found to have a considerably higher potency than prazosin for displacing [3H] yohimbine binding sites on rabbit platelets. Similarly, in rabbit kidney; prazosin and phentolamine were both less potent than yohimbine at displacing [3H] yohimbine binding. These results were consistent with [3H] yohimbine binding to alpha2 receptors in rabbit platelets and kidney. Subpopulations of beta adrenoceptors were characterised in the platelets, lymphocytes, heart and lung of the rabbit. The ability of the beta1 (atenolol or metoprolol) and beta2 (ICI 118551 ) adrenoceptor selective antagonists to displace the beta adrenoceptor selective [125I](-) Iodocyanopindolol (ICYP) from its binding sites in platelets and was assessed. ICI 118551 was found to be more potent than atenolol in displacing [125I](-) ICYP specific binding in both tissues. These findings were in agreement with previous studies showing that the beta adrenoceptors in rabbit platelets and lymphocytes (like humans) were largely beta2 in type. In a separate study, the beta1 adrenoceptor selective antagonist, metoprolol had a higher affinity than the beta2 selective ICI 118551 at inhibiting [125I](-) ICYP specific binding in rabbit heart and lung. These results confirmed that both the heart and the lung of the rabbit harbour a higher proportion of beta1 adrenergic receptors in the rabbit. Interestingly, the proportion of beta1 and beta2 adrenoceptors in rabbit lung were shown to be quite the inverse of most other mammalian species. (Abstract shortened by ProQuest.).

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Medicine, Physiology
• Date of Award: 1988
• Depositing User: Enlighten Team
• Unique ID: glathesis:1988-77684
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 14 Jan 2020 11:53
• Last Modified: 14 Jan 2020 11:53
• URI: https://theses.gla.ac.uk/id/eprint/77684