Hypotheses & Aims Clause Samples

Hypotheses & Aims. 1.1 The nitric oxide signalling cascade and the cardiovascular system‌ Since the discovery that the Endothelium-Derived Relaxing Factor (EDRF) was nitric oxide (NO)[1, 2], over the last four decades NO has been identified as a key signalling molecule in the cardiovascular system and multiple other organ systems. The importance of the discovery and identification of NO as EDRF is reflected by the award of the 1998 Nobel Prize in Medicine to Furchgott, ▇▇▇▇▇, and ▇▇▇▇▇▇▇[3]. NO is a free radical gas, with a half-life in the circulation of ~20ms[4]. In humans, it is produced via two key mechanisms: the “L-arginine-nitric oxide pathway” as originally described by ▇▇▇▇▇▇▇[5] and the more recently discovered nitrate-nitrite- NO pathway[6]. The L-arginine-nitric oxide pathway involves the generation of NO via the conversion of L-arginine to L-citrulline by haem- and ▇▇▇▇▇▇-containing nitric oxide synthase (NOS) enzymes[7] in a process that requires dimerism of the NOS enzyme and the presence of the co-factors tetrahydrobiopterin (BH4), nicotinamide adenine dinucleotide phosphate (NADPH) and O2[8]. Three NOS isoenzymes have been identified in humans; endothelial (▇▇▇▇), neuronal (nNOS) and inducible (iNOS). As will be discussed in detail below, ▇▇▇▇ and nNOS are constitutively expressed and have distinct roles in the regulation of cardiovascular function. By contrast, the role of iNOS is in relation to host response to infection and inflammation. While the production of NO by ▇▇▇▇ and nNOS is Ca2+/calmodulin-dependent, production of NO by iNOS will continue until the enzyme is degraded, resulting in higher local concentrations of NO[9]. The nitrate-nitrite-NO pathway (also known as the enterosalivary pathway) describes the two-step process by which orally ingested inorganic nitrate (NO -) is reduced to NO via inorganic nitrite (NO -). The discovery of the nitrate-nitrite-NO pathway significantly altered the understanding of the role of inorganic nitrate and nitrite in relation to the cardiovascular system. Previously, they were considered to be inert by-products of NO oxidation. However, it is now recognised that dietary nitrate is converted, via nitrite, to NO[10, 11]. Due to the half-life of nitrite being significantly longer than NO in the blood, nitrite therefore represents a circulating pool of potentially bioavailable NO. NO signalling in the vasculature‌ NO’s role as a signalling molecule in the vasculature occurs primarily in a paracrine fashion i.e. NO prod...