Effect of hypoxia on the hepatic metabolism of lidocaine in the isolated perfused pig liver

Mets, Berend; Hickman, Rosemary; Allin, R.; Dyk, Jean van; Lotz, Zoë

doi:10.1002/hep.1840170422

Cited by 29 publications

(14 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…7. For these studies, the standard pipette (intracellular) solution was modified by ϩ efflux is an early and characteristic feature of liver cell injury that precedes loss of cell viability (4,7,8). The principal findings in this model cell line are that K ϩ efflux is regulated through a Ca 2ϩ -and PKC-dependent mechanism and involves opening of apamin-sensitive SK Ca channels.…”

Section: Role Of Ca 2ϩmentioning

confidence: 99%

See 1 more Smart Citation

Metabolic Stress Opens K+ Channels in Hepatoma Cells through a Ca2+- and Protein Kinase Cα-dependent Mechanism

Wang

Sostman

Roman

et al. 1996

Journal of Biological Chemistry

View full text Add to dashboard Cite

K ϩ efflux through ion channels represents a key point for regulation of liver cell transport and metabolism. Under physiologic conditions, opening of K ϩ channels by glucagon and closure by insulin modulates many liver cell functions including solute uptake, gluconeogenesis, and intracellular pH regulation through effects on membrane potential difference (1, 2). However, these regulatory pathways are disrupted by metabolic stress associated with exposure to toxins including ethanol (3) or by ischemia related to hypoperfusion or organ preservation which can result in liver cell injury and necrosis (4). Many of the effects of ischemia result from hypoxia which inhibits oxidative phosphorylation and depletes cellular ATP stores. Pharmacologic agents including 2,4-dinitrophenol (DNP) 1 which uncouples oxidative metabolism and 2-deoxy-Dglucose (2-DG) which impairs glycolysis have been useful models of ATP depletion because in liver cells they produce biochemical changes similar to those caused by hypoxia (5).At the cellular level, one of the earliest effects of oxidative stress is dissipation of transmembrane cation gradients (6) and sustained release of K ϩ ions (7). In isolated livers, oxidative stress stimulates K ϩ efflux, increasing the concentration of K ϩ in perfusate from 5.6 to 13.1 mM (8). Efflux of K ϩ appears early, preceding release of aminotransferases, and correlates closely with the fall in ATP levels (8). Net loss of K ϩ ions is related in part to inhibition of Na ϩ /K ϩ pump activity (4, 6). However, studies of other cell types have identified an additional and quantitatively important pathway for hypoxia-induced K ϩ efflux mediated by opening of K ϩ channels. In cardiovascular tissues, K ϩ channel opening represents an important adaptive response to stress since membrane hyperpolarization results in vasodilation and restoration of blood flow (9). Two modes of regulation have been identified, including opening of glibenclamide-sensitive K ATP channels where ATP itself is responsible for channel gating (9 -11) and opening of Ca 2ϩ -sensitive K ϩ channels in tissues where metabolic inhibition increases intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) (12, 13). It is notable that metabolic inhibition releases Ca 2ϩ from intracellular stores of liver cells (6,14,15), and the resulting increase in [Ca 2ϩ ] i is characteristic of many forms of liver cell injury (4).The purpose of the current studies was to evaluate the relationship between cellular metabolism and membrane K ϩ permeability in HTC cells, a model liver cell line. Different models of metabolic inhibition increased K ϩ conductance 30-fold or more through activation of apamin-sensitive SK Ca channels. Channel opening appears to occur through a mechanism distinct from cardiovascular tissues and involves translocation of protein kinase C␣ (PKC␣) from cytosol to membrane. Moreover, intracellular perfusion with purified PKC␣ activates currents in the absence of metabolic inhibition, suggesting that the ␣ isoform of PKC may be selectively ...

show abstract

Section: Role Of Ca 2ϩmentioning

confidence: 99%

“…In isolated livers, oxidative stress stimulates K ϩ efflux, increasing the concentration of K ϩ in perfusate from 5.6 to 13.1 mM (8). Efflux of K ϩ appears early, preceding release of aminotransferases, and correlates closely with the fall in ATP levels (8).…”

mentioning

confidence: 99%

Metabolic Stress Opens K+ Channels in Hepatoma Cells through a Ca2+- and Protein Kinase Cα-dependent Mechanism

Wang

Sostman

Roman

et al. 1996

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…In isolated liver, hypoxia stimulates an increase in the concentration of K ϩ in the perfusate from 5.6 to 13.1 mM (9). K ϩ efflux appears early, preceding release of aminotransferases, and correlates closely with the fall in cellular ATP levels (9).…”

Section: Introductionmentioning

confidence: 99%

Cytosolic Ca2+ and protein kinase Calpha couple cellular metabolism to membrane K+ permeability in a human biliary cell line.

Wang¹,

Roman²,

Schlenker³

et al. 1997

J. Clin. Invest.

View full text Add to dashboard Cite

Cholangiocytes represent an important target of injury during the ischemia and metabolic stress that accompanies liver preservation. Since K ϩ efflux serves to minimize injury during ATP depletion in certain other cell types, the purpose of these studies was to evaluate the effects of ATP depletion on plasma membrane K ϩ permeability of Mz-ChA-1 cells, a model human biliary cell line. Cells were exposed to dinitrophenol (

show abstract

“…7 Both propranolol and lidocaine are metabolized in the liver by the cytochrome-P450 system. Cytochrome P450 3A4 catalyzes the oxidation of lidocaine to its metabolite monoethylglycinxylidide (MEGX), a process susceptible to hypoxia, 8 and the serum concentration of MEGX after intravenous injection of lidocaine (MEGX test) has been suggested as a marker of microsomal liver function. 9 Adenosine is a potent vasodilatator of the hepatic artery and hepatic arterial flow reserve (adenosine-induced hepatic arterial vasodilatation) is related to Child-Pugh class in patients with cirrhosis.…”

mentioning

confidence: 99%

Functional significance of hepatic arterial flow reserve in patients with cirrhosis

et al. 2003

View full text Add to dashboard Cite

Effect of hypoxia on the hepatic metabolism of lidocaine in the isolated perfused pig liver

Cited by 29 publications

References 27 publications

Metabolic Stress Opens K+ Channels in Hepatoma Cells through a Ca2+- and Protein Kinase Cα-dependent Mechanism

Metabolic Stress Opens K+ Channels in Hepatoma Cells through a Ca2+- and Protein Kinase Cα-dependent Mechanism

Cytosolic Ca2+ and protein kinase Calpha couple cellular metabolism to membrane K+ permeability in a human biliary cell line.

Functional significance of hepatic arterial flow reserve in patients with cirrhosis

Contact Info

Product

Resources

About