Dopamine Impairs Functional Integrity of Rat Hepatocytes Through Nuclear Factor Kappa B Activity Modulation: An In Vivo, Ex Vivo, and In Vitro Study

摘要

Dopamine (DA) is commonly used to maintain the hemodynamic stability of brain-dead donors despite its controversial effects on organ functions. This study aimed at examining the hemodynamic effect of DA in a rat brain-dead model in vivo, alteration of hepatocyte integrity in liver grafts after ex vivo preservation, and changes in cultured clone-9 hepatocytes including cellular viability, cell cycle, apoptotic regulators, and lipopolysaccharide (LPS)-stimulated nuclear factor kappa B (NF-kappa B) signaling machinery. Although in vivo findings demonstrated enhanced portal venous blood flow and hepatic microcirculatory perfusion after DA infusion, no apparent advantage was noted in preserving hepatocyte integrity ex vivo. In vitro, prolonged exposure to high-dose DA reduced proliferation and induced G(1) growth arrest of clone-9 hepatocytes with concomitant decreases in B cell lymphoma 2 (BCL2)/B cell lymphoma 2-associated X protein (BAX) and heat shock protein 70/BAX protein ratios and intracellular NF-kappa B p65. Moreover, DA pretreatment suppressed LPS-elicited inhibitor of kappa B alpha phosphorylation and subsequent NF-kappa B nuclear translocation, suggesting that DA may down-regulate NF-kappa B signaling, thereby reducing expression of antiapoptotic regulators, such as BCL2. In conclusion, despite augmentation of hepatic perfusion, DA infusion failed to preserve hepatocyte integrity both in vivo and ex vivo. In vitro findings demonstrated that high-dose DA may hamper the function of NF-kappa B signaling machinery and eventually undermine functional integrity of hepatocytes in liver grafts. (C) 2015 AASLD.