5-Hydroxytryptamine, Phenylephrine and Endothelium-Dependent Relaxant Factor in the Rat Aorta: Effects and Interactions

Dainty, Ian Albert (1989) 5-Hydroxytryptamine, Phenylephrine and Endothelium-Dependent Relaxant Factor in the Rat Aorta: Effects and Interactions. PhD thesis, University of Glasgow.

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The purpose of the work presented in this thesis was to examine the influence of the vascular endothelium on the effect of stimulation of a-adrenoceptors, 5-HT receptors and muscarinic receptors in the isolated rat thoracic aorta. The work has been divided into five main areas, i) the dependence on extracellular Ca2+ of the contractions to the relatively selective a1-adrenoceptor agonist phenylephrine and to 5-hydroxytryptamine and also the effect of the presence of the endothelium on their contractile responses, ii) the role of the initial tension placed on the tissues in the subsequent responses of the tissues to agonists and influence of the endothelium on this 'length-tension' relationship, iii) the effect of the endothelium on activation mediated by 5-HT receptors, iv) classification of the muscarinic receptor mediating endothelium-dependent relaxations in this preparation and v) the effect of a lipid metabolite of ischaemia (palmitoyl carnitine) which may have a modulatory role on the effect of the endothelium in ischaemic conditions. The major findings of the study are briefly summarised below. 1. When rat aortic rings are incubated in PSS with no added Ca2+, addition of CaCl2 in the presence of PhE but not 5-HT caused a contraction of the preparation. The contractions to CaCl2 in the presence of 5-HT were much smaller than those observed when 5-HT was added in the presence of 2.5mM [Ca2+]. In contrast, the responses to PhE were consistent at each concentration of Ca2+ irrespective of whether the agonist was added before or after Ca2+. 2. Pre-exposure of the preparations to 5-HT but not PhE appeared to attenuate the subsequent contractile response to CaCl2 in the presence of the same agonist. 3. Pre-incubation with BAY K 8644 caused a significant increase in the contraction to CaCl2 in the presence of both 5-HT and PhE. The magnitude of this increase was greatest for '5-HT/Ca2+-re-addition. 4. Addition of BAY K 8644 at the end of a cumulative concentration-response curve (CCRC) to CaCl2 produced a marked contraction in the presence of PhE and also 5-HT. 5. Mild depolarisation with KCl and hyperpolarisation with BRL 34915 caused similar degrees of potentiation and attenuation of the concentration-response curves to 5-HT and PhE. 6. Chronic pretreatment of the rats with LiCl caused attenuation of the response of the aorta to both PhE and 5-HT. This effect was greatest for PhE and in the presence of the endothelium. 7. The optimum conditions for resting tension (hence length) of the tissue for demonstration of contraction per se and the basal release of EDRF (depression of contractility) or stimulated release of EDRF (relaxation) did not necessarily coincide and were dependent upon how the data was expressed. 8. The degree of induced tone influenced the apparent sensitivity of the tissue to endothelium-dependent relaxations such that the higher the degree of induced tone then the lower the subsequent sensitivity to endothelium-dependent relaxations. 9. Removal of the endothelium increased the sensitivity and maximum contractile response of the preparations to both 5-HT and PhE. 10. The depression of the maximum contractile response by the presence of the endothelium was inversely related to the intrinsic activity of a series of 5-HT2-receptor agonists. 11. There was no evidence for an endothelium dependent relaxation to 5-HT receptor stimulation though an endothelium-independent relaxation at high concentravion: of 5-HT and 5-CT was revealed. 12. Using selective antagonists, the muscarinic receptor mediating endothelium-dependent relaxations was found to be of the M2 muscarinic receptor subtype. 13. The receptor subtype was different from the M2 subtype found in the atria but similar to that found in non vascular smooth muscle. 14. In contrast to the muscarinic receptor found in non-vascular smooth muscle preparations, the endothelium-dependent relaxations to muscarinic agonists of different efficacies were unaffected by chronic pre-treatment of the animals with LiCl. 15. In addition to reversing the relaxation induced by ACh, palmitoyl carnitine caused concentration-dependent inhibition of the endothelium-dependent relaxations to ACh, ATP and A23187 but had no significant effect on the endothelium-independent relaxations to sodium nitroprusside and did not augment the agonist-induced tone of the preparation. 16. BAY K 8644 reversed and inhibited the ACh-induced relaxations. This effect was accompanied by an increase in the agonist-induced tone of the preparation. 17. Using a simple overflow techniquethe inhibitory action of palmitoyl carnitine was found be at a site at the endothelium to inhibit release/synthesis of EDRF.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Physiology
Date of Award: 1989
Depositing User: Enlighten Team
Unique ID: glathesis:1989-77922
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 30 Jan 2020 15:48
Last Modified: 30 Jan 2020 15:48
URI: http://theses.gla.ac.uk/id/eprint/77922

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