Regulation of Adrenergic and Imidazole Preferring Receptors in the Rabbit

Yakubu, Momoh A (1989) Regulation of Adrenergic and Imidazole Preferring Receptors in the Rabbit. PhD thesis, University of Glasgow.

Abstract

The studies reported in this thesis were designed to investigate the effects of chronic adrenoceptor drug treatment on central and peripheral alpha2-adrenoceptor number in the rabbit. In addition, functional studies were carried out using the central depressor response to clonidine injection and vascular pressor response to bolus doses of alpha-methylnoradrenaline injection to examine central and peripheral responses, respectively. The effects of chronic adrenergic drug treatment on alpha- and beta-adrenoceptor number were examined in rabbit forebrain and hindbrain membranes and were compared with the effects in the periphery (kidney membranes) where appropriate. Also changes in receptor number were then compared with functional changes. In preliminary experiments, it was observed that [3H]yohimbine and [3H] idazoxan which have been described as alpha2-adrenoceptor ligands bind to the tissues used in these studies with different characteristics. This observation led to detailed examination and characterization of these binding sites (chapter three). The displacement of these ligands from their binding sites by a range of adrenergic drugs was examined. It was found that [3H]yohimbine bound to alpha2-receptors while [3H]idazoxan in addition to binding at alph2-receptors bound principally to a non-adrenergic site. In chapter four, the effects of chronic treatment with the alpha2-adrenoceptor antagonists yohimbine and idazoxan on alpha2-adrenergic receptors were examined and compared with effects on the non-adrenergic site labelled by [3H] idazoxan. Functional changes occurring as a result of these treatments were also examined. Chronic yohimbine and idazoxan treatments significantly attenuated both vascular pressor responses to alpha-methylnoradrenaline bolus doses and the central depressor response to intracisternal clonidine. Yohimbine treatment significantly elevated [3H]yohimbine binding to both forebrain and hindbrain but reduced [3H]idazoxan binding to kidney membranes with no change in the brain. Idazoxan treatment significantly increased [3H] yohimbine binding to the forebrain and decreased [3H]idazoxan binding to the kidney. In chapter five, the effects of chronic amitriptyline treatment either alone or in combination with idazoxan or yohimbine on alpha2-adrenergic and non-adrenergic binding sites along with effects on beta-adrenoceptor number were studied. Increasing catecholamine concentrations in the brain indirectly by chronic amitriptyline administration, significantly reduced [3H]yohimbine binding to the hindbrain but not the forebram. [3H] Idazoxan binding sites were not significantly affected by this treatment. Neither treatment with amitriptyline alone nor when combined with alpha2-adrenoceptor antagonists had any significant effects on the number of [3H]dihydroalprenolol ([3H]DHA) binding sites. Chapter six examined the effects of direct infusion of catecholamines into the rabbit brain via intracerebroventricular infusion. Neither adrenaline nor noradrenaline had any significant effect on [3H]DHA or [3H]yohimbine binding sites although chronic adrenaline but not noradrenaline infusion significantly attenuated the depressor response to clonidine injection. Adrenaline infusion significantly reduced [3H]idazoxan binding to the right cerebrum. Chapter seven studied effects of chronic guanabenz infusion on both number and function of alpha2-adrenoceptors. Chronic infusion with the alpha2-adrenoceptor agonist guanabenz significantly reduced [3H] yohimbine binding to both forebrain and hindbrain although no changes in kidney membranes were observed, while the number of [3H]idazoxan binding site in the kidney but not the forebrain or hindbrain was significantly reduced. Both the depressor and pressor responses to clonidine and alpha-methylnoradrenaline respectively were significantly attenuated by this treatment. Chapter eight was aimed at bringing all the results in this thesis together, making comparisons, drawing conclusions and making proposals for future studies. In this thesis it was observed that agonists can cause down regulation and antagonists up-regulation of the [3H] yohimbine binding site. Finally, no changes in beta-adrenoceptor number were observed in the rabbit brain during either catecholamine or amitriptyline treatments. This contrasts with observations in rat brain and reports of changes in beta-adrenoceptor number during catecholamine infusion into the periphery of rabbits. Small subtype changes may have occurred which were not detected, or alternatively, beta-adrenoceptors in rabbit brain are relatively resistant to down-regulation.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Pharmacology
• Date of Award: 1989
• Depositing User: Enlighten Team
• Unique ID: glathesis:1989-77838
• 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/77838