| Nitric oxide (NO) is a powerful vasodilator that plays an important role in normal physiological and pathophysiological conditions. The primary goal of this research was to advance the understanding of the interacting mechanisms between NO, O2, hemoglobin, blood flow, and multiple chemical species in the microcirculation under steady state and non-steady conditions. The general approach was to develop and validate a non-linear cylindrical diffusion-reaction mass transport model based on experimental data to analyze these factors. Different from prior studies in the literature, this study simulates the effects of multiple cylindrical vessel layers, coupled NO and O2 transport, O2-dependent production from different NOS isoforms, time-dependent transport and chemical reactions, convective transport, arteriole-venule pairing, dynamic changes in vessel diameter, and multiple chemical species including superoxide and peroxynitrite. In addition, numerous factors affecting NO and O2 availability such as viscosity, hematocrit, the Fähraeus effect, oxygen saturation, pH, and CO2 were modeled.; Specific findings from this study suggest: that NO and O2 transport are fundamentally intertwined; that NO can help enhance O2 delivery to distal tissue regions, particularly at low PO2 values; that NO production from nNOS can help augment normal vasodilatory functions; that production of NO from iNOS and nNOS could act as a protective mechanism in pathological conditions; that the Fähraeus effect is significant in vessels less than 30 μm in diameter and leads to higher predicted NO concentrations; that arteriole-venule pairing acts to increase peak endothelial and tissue NO concentrations; that, due to differences in reaction times for different chemical species, non-steady state conditions should be included to capture any transient effects; convective transport significantly influences axial NO gradients and downstream vessel concentrations; and that, at even relatively low production rates, superoxide is a potent scavenger of NO. Overall, this study illustrates how mathematical modeling can be used as a powerful tool to understand interactive mechanisms affecting NO transport that often cannot be analyzed experimentally. This holds great promise for understanding disease processes associated with NO dysfunction and can assist in the development of novel treatment strategies or clinical therapeutics. |
