Hepatic and extra-hepatic stimulation of glutathione release into plasma by norepinephrine in vivo

Studies were conducted to determine the effect of norepinephrine (NE) on reduced glutathione (GSH) and oxidized glutathione (GSSG) export from hepatic and extra-hepatic tissues in vivo. Anesthetized Single Comb White Leghorn (SCWL) males were implanted with cannulae in the carotid artery, hepatic vein (HV) and hepatic portal veins (PV), and the left bile duct. In Experiment 1, GSH and GSSG in hepatic and portal venous plasma and bile were determined prior to, during, and following two 20-min infusions of NE (2 and 10 microg/min per kg BW) into the hepatic PV. The lower NE infusion rate increased hepatic venous GSH (indicative of increased GSH export into liver sinusoids) without affecting systemic or hepatic vascular pressures; however, it had no affect on portal venous GSH. The higher NE infusion rate increased GSH in the HV and hepatic PV (indicative of extra hepatic export of glutathione) as well as systemic pressure, hepatic and portal venous pressures, and the transhepatic pressure gradient. Biliary secretion of GSH and GSSG was unaffected by either rate of NE infusion in Experiment 1. In Experiment 2, pretreatment of birds with phentolamine, an alpha-adrenergic receptor blocker (alpha-block), abolished sinusoidal export GSH as well as the ability of NE to stimulate GSH release from hepatic and extra-hepatic tissue. Although HV and PV pressures were lower in alpha-block birds compared with controls, there were no differences in the transhepatic pressure gradient between groups. Plasma GSSG was below the limits of detection in Experiments 1 and 2. The combined results of Experiments 1 and 2 indicate that hepatic export of GSH was independent of changes in systemic or hepatic vascular pressures or changes in the transhepatic pressure gradient. The results of these studies are the first to demonstrate that export of GSH into plasma in vivo is mediated by an alpha-receptor-mediated mechanism in hepatic and extra-hepatic tissues. The findings may be particularly important with regard to antioxidant homeostasis of animals during periods of stress.