REG OF NITRIC OXIDE PRODUCT IN THE HEPATIC CIRCULATION

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Nitric oxide (NO) plays an important role in the regulation of hepatic vasodilator tone. Intrahepatic vasoconstriction contributes to the development of an increase in portal pressure in hepatic cirrhosis. The source of this vasoconstriction appears to be an alteration in the sinusoidal endothelial cell (SEC), a unique microvascular cell which lines the resistance vessels in the hepatic sinusoids and expresses NO synthase (NOS) III. Shear stress is a physiologic biomechanical force which has been found to modulate regional blood flow through the regulation of endothelial cell production of vasodilator substances such as NO. Preliminary studies suggest that shear stress activates a tyrosine phosphorylation cascade and additionally causes a subcellular redistribution of NO synthase (NOS) III, two events which are novel mechanisms of regulation of NOS III. The long term objective of these studies is to elucidate the mechanisms of regulation of NO production in the hepatic microcirculation by shear stress and to examine how they may contribute to the hemodynamic alterations seen in cirrhosis. Understanding the mechanisms that regulate portal pressure is vital as the development of portal hypertension is the single most important factor that determines which patients with cirrhosis will develop complications. Defining the mechanisms that regulate nitric oxide production in SEC may lead to therapeutic options whereby NO activity may be pharmacologically or genetically modulated and benefit patients with cirrhosis and portal hypertension.