The Role of Hematocrit and Nitric Oxide in Regulation in the Microcirculation /

Nitric oxide is a critical signaling molecule in the microcirculatory control of vascular resistance. It enables the maintenance of blood pressure and cardiac output at optimal levels, via flow mediated endothelial nitric oxide production which serves to modulate vascular tone. Understanding nitric oxide production and bioavailability in the vasculature facilitates a number of theoretical models and clinical applications. Hematocrit influences the vaso-active role of nitric oxide, since both blood viscosity and shear stress increase with red blood cell concentrations. Moreover, increases in hematocrit cause cell free layer thickness to decrease and hemoglobin scavenging of nitric oxide in red blood cells to increase. To capture this behavior at the scale of an individual blood vessel, we construct a model of the autoregulatory response of blood vessels. The model incorporates coupled models of blood flow and nitric oxide transport, thereby explaining how changes in hematocrit influence vascular response. We also develop a model that captures the effects of changing hematocrit on blood rheology, velocity profiles and wall shear stress measurements. This model accounts for the non-Newtonian, shear-thinning properties of blood. A clinical application of these ideas is demonstrated by showing how changes in the blood rheology via plasma expanders can result in the restoration of cardiac performance. These individual- vessel models inform our analysis of the structure of microvascular networks. Specifically, we examine how hematocrit, pressure and shear stress are distributed in optimally configured model networks. Our approach allows for simulation of vascular networks which exhibit the broad characteristics of networks observed in-vivo. At the cellular level, we examine the biochemistry of nitric oxide production inside endothelial cells. We construct a model which simulates the endothelial nitric oxide production cycle, following application of shear stress. Our model predictions for both steady and transient shear induced nitric oxide production are shown to be in broad agreement with experimental data. Collectively, this dissertation significantly enhances our understanding of the dual and often competing roles of nitric oxide and hematocrit in the microcirculatio