The local control of vascular tone by perivascular nerves and the endothelium: Changes after X-irradiation and in atherosclerosis


In this thesis, the local regulation of vascular tone has been studied in normal, X-irradiated and atherosclerotic blood vessels, primarily using in vitro pharmacological techniques. In the first section, the early effects of a single dose of 4500 rad X-radiation on vasomotor control was studied in the NZW rabbit central ear artery 1, 4 and 6 weeks following exposure. Sympathetic neurotransmission was attenuated by 1 week postirradiation, with a greater reduction occuring after 4 and 6 weeks respectively. A reduction in both endothelium-dependent and independent relaxations, with no change in the contractile response to NA, indicated that the relaxant efficiency of the smooth muscle was reduced following irradiation. The neuromodulatory actions of CGRP and NPY were enhanced 6 weeks following irradiation. The second section studies the development of atherosclerosis- induced alterations in local vasomotor control during maturation in the WHHL rabbit (an animal model of familial hypercholesterolemia). Animals were examined at 4, 6 and 12 months of age, with NZW rabbits being used as controls. In the WHHL rabbit ear and mesenteric arteries, endothelium-dependent relaxant responses increased with age, unlike responses in NZW rabbit arteries. Endothelium-independent relaxations in the ear and mesenteric arteries were not altered during maturation in WHHL rabbit arteries and also when compared with NZW arteries. In contrast, the thoracic aorta from 12-month-old WHHL rabbits exhibited reduced endothelium-dependent relaxant responses to ACh, which appeared to be linked to the degree of occlusion of the vessel wall by atheromatous plaque. In the WHHL rabbit basilar artery, endothelium-dependent relaxations also increased with age. However, the basilar artery was shown to differ from the ear and mesenteric arteries in that endothelium-independent relaxant responses also increased with age. In the WHHL rabbit ear and mesenteric arteries, sympathetic neurotransmission was significantly reduced when compared with NZW rabbits. In both arteries, the reduction in sympathetic neurotransmission appeared to be due to pre- as opposed to post-junctional factors. In an addendum, relaxation by substance P in the NZW rabbit mesenteric artery was found to be mediated by neurokinin-l (NK-l) receptors located on the endothelium, with substance P and [Glp6, L- Pro9]SP6-11 being selective agonists

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