In perfused rat liver, hypoosmotic exposure (225 mosmol/L) leads to a volume-regulatory decrease by release of K+, Cl- and HCO3- through Ba2+-, DIDS- and quinidine-sensitive ion channels. The underlying signal transduction mechanisms, however, are unknown. As hypoosmotic hepatocyte swelling leads to a rapid activation of extracellular signal regulated kinases (Erks) and of p38MAPK, the role of mitogen-activated protein kinases (MAPK) and PI-3-kinase in mediating the RVD in perfused rat liver was studied. The presence of the MEK inhibitor PD 098 059, which blocks the hypoosmotic activation of Erks, had no effect on the extent and time course of cell volume regulatory K+ efflux. However, inhibitors of p38MAPK such as SB 203 580 and PD 169 316, but not their inactive analogue SB 202 474, significantly delayed and diminished the volume-regulatory K+ efflux. Accordingly, in presence of these p38MAPK inhibitors, the hepatocytes remained in a more swollen state after completion of RVD. Inhibition of hypoosmotic Erk activation by pertussis or cholera toxin, erbstatin or genistein had no effect on RVD by hypoosmolarity. Likewise, neither inhibition of PI-3-kinase by wortmannin or LY 294 002 nor inhibition of S 6 phosphorylation by rapamycin nor protein kinase inhibition by H-7, H-89 or KT 5823 led to a significant change of RVD upon hypoosmolarity. The amount and time course of K+ release by oxidative stress upon addition of t-BOOH or H2O2 remained unaffected by inhibition of p38MAPK by SB 203 580, suggesting a specific inhibition of RVD-dependent K+ release by this inhibitor. The findings suggest that swelling-induced activation of p38MAPK, but not of Erks and PI-3-kinase, is involved in RVD in liver, whereas p38MAPK is apparently not involved in the net K+ release induced by oxidative stress.

© 2001 S. Karger AG, Basel
2001
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