Functional Significance of Cell Volume Regulatory Mechanisms

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LANG ET AL. Volume 78
activated by Ca 2/ (542, 675). Thus an increase of intracel- noic acids (818), indicating that the inhibitory effect on
lular Ca osmolyte flux is not due to inhibition of epoxygenase.
2/ concentration during cell swelling could participate
in the activation of these two enzymes during cell Similarly, in Necturus gallbladder, ketoconazole does not
swelling. Along these lines, LTD4 may overcome the inhib- prevent regulatory KCl efflux but stimulates NaCl entry,
itory effect of the calmodulin antagonist pimozide on cell leading to cell swelling (615).
volume regulation, suggesting that LTD4 is a signal down- In addition to their influence on volume-sensitive ion
stream of Ca 2/ (673). channels, phospholipase A2 and a cytochrome P-450 prod-
Arachidonic acid has been shown to inhibit glial cell uct of arachidonic acid have been invoked in mediating
volume regulation (1052) and to inhibit volume regulatory the swelling-induced cellular release of sorbitol (354).
Cl The fatty acid composition of the cell membrane can
0 channels (403, 673, 679, 1047). On the other hand, it
may increase Ca 2/ concentration in renal collecting duct be modulated by dietary polyunsaturated fatty acids,
and activate K which lead to enhanced formation of leukotrienes and
/ channels in neurons (622, 1213). Moreover,
the 15-lipoxygenase product of arachidonic acid thus to acceleration of RVD in Ehrlich ascites tumor cells
(712).
hepoxilin A3 activates volume regulatory K / channels in
platelets (798–801), and the 5-lipoxygenase product LTD4
activates volume regulatory K / and Cl 0 channels (547,
592, 674, 675, 679) and volume regulatory taurine release L. pH in Acidic Cellular Compartments
(592, 678) in Ehrlich ascites tumor cells, as well as taurine
release in fish erythrocytes (1207). 5-Lipoxygenase prod- As evidenced from acridine orange and fluorescein
ucts similarly appear to mediate regulatory cell volume isothiocyanate-dextran fluorescence, hepatocyte swelling
decrease in colonic epithelium (277, 281, 282), chromaffin leads to alkalinization of acidic cellular compartments,
cells (287), MDCK cells (947), and human fibroblasts whereas cell shrinkage enhances the acidity in those com-
(808). However, in most of these cell types, the evidence partments (156, 683, 1088, 1089, 1279, 1280).
comes largely from effects of 5-lipoxygenase inhibitors The lysosomal proteases are known to have their pH
such as nordihydroguaiaretic acid (NDGA). In Ehrlich as- optimum in the acidic range, and alkalinization of the
cites tumor cells (679) and proximal renal tubules (Völkl lysosomes is well known to inhibit hepatic proteolysis
and Lang, unpublished observations), on the other hand, (859, 860). Thus the alkalinizing effect on acidic cellular
the inhibitory effect of NDGA was not overcome by the compartments could at least in theory contribute to the
addition of LTD4, pointing to an additional effect of the antiproteolytic action of cell swelling. Along these lines,
drug not related to 5-lipoxygenase inhibition. It may more alkalinization of acidic cellular compartments parallels
directly inhibit the volume regulatory Cl 0 channels (438) the cell swelling and antiproteolytic effect of transforming
or be effective by increasing arachidonic acid concentra- growth factor-b1 on LLC-PK1 cells (752). However, the
tion (1052). contribution of vesicular alkalinization to the antiproteo-
The enhanced formation of leukotrienes in swollen lytic effect of cell swelling remains to be proven. At least
Ehrlich ascites tumor cells parallels a decreased forma- in liver cells, swelling alkalinizes prelysosomal rather than
tion of PGE2, an effect possibly accounting for the inhibi- lysosomal compartments (766, 1090). Moreover, inhibition
tion of Na / channels (679). Those channels are thought of tyrosine kinase by erbstatin interferes with prelyso-
to be stimulated by PGE2 (679). On the other hand, in somal alkalinization but not with inhibition of proteolysis
ciliary epithelial cells, PGE2 was thought to mediate the (S. vom Dahl and D. Häussinger, unpublished observaactivation
of volume regulatory K tions), pointing to some antiproteolytic mechanisms inde-
/ channels during cell
swelling (191). Prostaglandin E2 similarly activates K /
pendent of lysosomal pH.
channels in MDCK cells (1153) and erythrocytes (743). The alkalinization of acidic cellular compartments in
In collecting duct principal cells, inhibition of phos- hepatocytes occurs not only if cell swelling is due to de-
pholipase A2 with quinacrine blunted the activation of crease of extracellular osmolarity but also if cell swelling
volume regulatory Ca 2/ -sensitive K / channels, which, on is caused by inhibition of K / channels and by concentra-
the other hand, were activated by arachidonic acid (751). tive uptake of amino acids (1279).
In LLC-PK1 cells, however, volume regulatory rubidium It appears that the influence of cell volume on pH of
flux was not modified by arachidonic acid, even though acidic cellular compartments is not confined to prelyso-
it was inhibited by an arachidonic acid antagonist (262). somes in hepatocytes but involves a number of distinct
Ketoconazole, an inhibitor of epoxygenase (cyto- compartments in a great variety of cells, such as pancrechrome
P-450), impedes volume regulatory efflux of os- atic b-cells, glial cells, neurons, vascular smooth muscle
molytes, such as sorbitol, betaine, myo-inositol, or amino cells, proximal renal tubules, MDCK cells, alveolar cells,
acids from renal papillary cells (354), MDCK cells (38), macrophages, and fibroblasts (153–157, 684, 1090, 1283).
and C6 glioma cells (818, 1171). However, the inhibitory Accordingly, the functions of these compartments may be
effect is not reversed by addition of hydroxyeicosatetrae- modified by alterations of cell volume.
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