F. Disole et al., Naloxone inhibits A6 cell Na+/H+ exchange by activating protein kinase C via the mobilization of intracellular calcium, EXP NEPHROL, 9(5), 2001, pp. 341-348
The opioid receptor antagonist, naloxone, has been shown to have beneficial
effects in the kidney and to be implicated in renal salt and water balance
. In the present study the signal transduction pathways utilized by naloxon
e were studied in an epithelial cell line model of the cortical collecting
duct, A6 cells. We found that naloxone has a dual effect depending on the c
oncentration used: at a low concentration (10(-6) M) it antagonized the bet
a -endorphin-dependent increase in cytoplasmic calcium [Ca2+](i), while at
higher concentrations (> 10(-5) M) it increased [Ca2+](i) and intracellular
inositol phosphate levels. While naloxone-induced increases in [Ca2+](i) o
ccurred in the absence of external calcium, it was significantly stimulated
by increasing the external calcium concentration, suggesting that naloxone
increases [Ca2+](i) via both calcium release and calcium influx. In polari
zed A6 cell monolayers naloxone inhibited the activity of the Na+/H+ exchan
ger (NHE) only when added to the basolateral cell surface. This inhibition
of the NHE was prevented by pretreatment of the cells with either the intra
cellular calcium chelator, BAPTA or with the protein kinase C inhibitor, ca
lphostin C. These findings demonstrate that naloxone induces a rapid increa
se in intracellular calcium which inhibits the NHE via the calcium-dependen
t protein kinase C regulatory pathway. Copyright (C) 2001 S. Karger AG, Bas
el.