The aim of the experiments presented in this Thesis was to determine if nitric oxide (NO) could modulate in vitro myogenesis since activity and immunolocalisation of the neuronal isoform of the enzyme, nitric oxide synthase was demonstrated in neonatal rat skeletal muscle. Therefore, it appeared possible that NO may influence the development of neonatal skeletal muscle. The NO donator, sodium nitroprusside (SNP), was used to determine the effects of NO on proliferation, fusion and myotube development in primary neonatal rat cultures and the mouse skeletal muscle cell line, C2C12. SNP treatment led to inhibition of fusion in both C2C12 and primary rat myoblast cultures. In addition, SNP reduced DNA synthesis in proliferating C2C12 cells and led to disintegration of rat primary myotubes. These effects of SNP were attenuated by preaddition of the guanylate cyclase inhibitor, methylene blue (MB) suggesting that NO release from SNP was influencing myogenesis via a cGMP-dependent pathway. In contrast, addition of 8-bromo-cGMP, a cell permeable analogue of cGMP was unable to mimic the effect of SNP treatment indicating that cGMP was not involved in the SNP response. Further investigation using oxyhamemoglobin as chelator of free NO did not reverse the effects of SNP Also, the effect of photolysed SNP on myogenesis was identical to that of freshly prepared SNP. These findings together suggested that the action of SNP was not via NO but was possibly an artifactual effect of metabolite(s) of SNP. Further investigation indicated that SNP treatment was toxic to myogenic cells, possibly via production of cyanide. In addition, the observation that MB could attenuate the toxic effects of SNP suggests that there is an interaction between these two compounds which is not dependent on NO activating guanylate cyclase.

Dietary nitrate (NO3-) supplementation, in the form of NO3- -rich beetroot juice, can elicit a number of biological and physiological effects within the human body, which improve exercise performance and indices of cardiovascular health. The purpose of this thesis was to investigate further the potential ergogenic and therapeutic benefits that dietary nitrate supplementation may evoke. Specific questions addressed in this thesis include whether supplementation can influence the power-duration relationship for severe-intensity exercise, and if supplementation can be effective in an older population and in varying environmental conditions. The thesis also strives to develop our understanding of the physiological mechanisms that underpin effective supplementation. Healthy, adult human subjects volunteered for all investigations presented in this thesis. A number of physiological variables were assessed in each experimental chapter, following nitrate supplementation. Chapter 4: Short term dietary NO3- supplementation reduced systolic blood pressure by 4mmHg (BR: 118 ± 5 vs. PL: 122 ± 5mmHg) and improved exercise tolerance during exercise at 60%Δ (BR: 696 ± 120 vs. PL: 593 ± 68 s), 70%Δ (BR: 452 ± 106 vs. PL: 390 ± 86 s), 80%Δ (BR: 294 ± 50 vs. PL: 263 ± 50 s) but not 100% peak power (BR: 182 ± 37 vs. PL: 166 ± 26 s) but did not significantly alter either critical power (BR: 221 ± 27 vs. PL: 218 ± 26 W) or W′ (BR: 19.3 ± 4.6 vs. PL: 17.8 ± 3 kJ). The V̇O2 phase II time constant was significantly shorter in BR compared to PL (BR: 22.8 ± 7.4 vs. PL: 25.4 ± 7.2 s) when considered irrespective of exercise intensity. Chapter 5: The metabolism of [NO2-] during exercise and recovery is altered by NO3- supplementation and, to a lesser extent, FIO2. End exercise V̇O2 was significantly lower during moderate-intensity exercise in Hypoxia-BR (H-BR) compared to Hypoxia-PL (H-PL) (H-BR: 1.91 ± 0.28 vs. H-PL: 2.05 ± 0.25 L∙min-1) and Normoxia-PL (N-PL) (1.97 ± 0.25 L∙min-1). V̇O2 kinetics were faster in H-BR compared to H-PL (phase II τ, H-BR: 24 ± 13 vs. H-PL: 31 ± 11 s). Tolerance to severe-intensity exercise was improved by NO3- supplementation in hypoxia (H-PL: 197 ± 28 vs. H-BR: 214 ± 43 s), but not normoxia (N-PL: 431 ± 124 vs. N-BR: 412 ± 139 s). Chapter 6: In a healthy older population, NO3- supplementation significantly reduced resting systolic (BR: 115 ± 9 vs. PL: 120 ± 6 mmHg) and diastolic (BR: 70 ± 5 vs. PL: 73 ± 5 mmHg) blood pressure. Supplementation also resulted in a speeding of the V̇O2 mean response time (BR: 25 ± 7 vs. PL: 28 ± 7 s) in the transition from standing rest to treadmill walking, although the O2 cost of exercise remained unchanged. Functional capacity (6-minute walk test), the muscle metabolic response to low-intensity exercise, brain metabolite concentrations and cognitive function were not altered. Chapter 7: On average, muscle tissue [NO3-] across the entire exercise protocol was significantly elevated by 72% following BR. At the group level, V̇O2 and muscle metabolic responses during exercise were unchanged between conditions and tolerance to severe-intensity exercise was unaltered. However, further analyses revealed the existence of ‘responders’ and ‘non responders’ with the changes in steady-state V̇O2 and muscle [NO3-] being correlated with severe-intensity exercise tolerance. The results of this thesis demonstrate that dietary NO3- supplementation has the potential to elicit ergogenic and therapeutic benefits in varying populations and environmental conditions. However, the presented data also clearly outline that supplementation may not always be effective. While the underlying mechanisms and parameters which may influence its effectiveness are not yet fully understood, supplementation should be carefully considered, monitored and tailored specifically for individuals and their particular requirements.

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

This thesis describes a series of experiments using the technique of microelectrophoresis. The aim of the experiments was to investigate the pharmacological actions of noradrenaline on single cerebral cortical neurones, and to study the interaction between noradrenaline and tricyclic antidepressant drugs.

No description available.