A possible role of circulating Na⁺, K⁺-pump inhibitors in the pathogenesis of multi-organ failure in acute hepatic failure

Abstract

In an attempt to elucidate one of possible mechanisms of multi-organ failure (MOF) in acute hepatic failure (AHF), we investigated in vitro effects of circulating substances, which levels elevated in AHF, on the Na⁺, K⁺-pump function in rat brain and kidney as well as human leukocyte. Bile acids [CDCA, GCDCA, DCA], short-chain fatty acids (SCFA) [iC₅, nC₆ and C₈], endotoxin (LPS), and α-palmitoyl lysolecithin showed inhibitory effects on the rat brain and kidney Na⁺, K⁺-ATPase activities in a dose-dependent manner. At lower concentrations, inhibitory effects of DCA, C₈ and LPS were observed to be synergistic. In addition, CDCA and C₈ also inhibited human leukocyte Na⁺, K⁺-pump activity. In summary, bile acids and SCFA were shown to be potent Na⁺, K⁺-pump inhibitors and suggested to play an important role, at least in part, in the pathogenesis of MOF (particularly brain edema, renal failure and infection) in AHF, by presumably damaging the sodium pumping of cell membranes in these organs. A PGI₂ analog, OP-2507, recovered the leukocyte Na⁺, K⁺-pump activity reduced by C₈, possibly by exerting a membrane stabilizing action.