This thesis examines the influence of perivascular nerves and the vascular endothelium on the local control of vascular tone with particular emphasis on how these mechanisms are affected by age and in atherosclerosis. Using the method of in vitro pharmacology, it was shown that ATP is a cotransmitter with noradrenaline (NA) in the hepatic artery of the rabbit and that the response of the vessel to the purine is mediated by ATP acting through post-junctional P2x-purinoceptors. Acetylcholine (ACh) induced a vasodilatation that was entirely dependent on the presence of an intact endothelium whereas adenosine, ATP and 2-methylthio ATP (a selective P2y-purinoceptor agonist) were shown to elicit a relaxation that was independent of the endothelium. The presence of nerve fibres containing substance P (SP), calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) were demonstrated in the hepatic artery of the rabbit. Furthermore, it was shown that CGRP and VIP mediated a vasodilatation in the absence of endothelium whereas SP produced a relaxation that was endothelium-dependent. Changes in the reactivity of hepatic and saphenous arteries from male and female rabbits (2-36 months) in response to directly acting vasoconstrictor agents (NA, a, methylene ATP (a, meATP), KCl); endothelium-dependent vasodilator agents (ACh, SP); endothelium-independent vasodilator agents (CGRP, VIP, ATP) and transmural nerve stimulation are described. Male and female Watanabe Heritable Hyperlipidaemic (WHHL) rabbits (4-12 months) were used as a model for human homozygous hypercholesterolemia. After an initial reduction in endothelium-dependent vasodilatation, there was an increase in relaxation at 12 months, when plaques were present. Contractions to sympathetic nerve stimulation was also reduced at 12 months. The effects of acrylamide, which is regarded as a model for autonomic neuropathy, on the response of the hepatic, saphenous and basilar arteries are also described
