Functional Significance of Cell Volume Regulatory Mechanisms

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260 LANG ET AL. Volume 78 molarity may approach values exceeding isotonicity by a 858, 1142). Causes include excessive sweating, osmotic factor of ú4 (1033). Any blood cell passing the kidney diuresis, lack of ADH or defective renal response to ADH, medulla experiences exposure to this high ambient osmo- and drinking of seawater (553). larity and subsequent return to isosmolarity within sec- Even though extracellular osmolarity increases due onds. Medullary cells have not only to cope with this to accumulation of urea in uremia (803), urea easily pasexcessive extracellular osmolarity for prolonged periods ses cell membranes and does thus not usually cause os- but encounter rapid changes of osmolarity during transi- motic gradients across the cell membrane. Nevertheless, tion from antidiuresis to diuresis, when medullary osmo- as shown in several cell types, high extracellular urea larity rapidly decreases toward isosmolarity (63). concentrations may trigger cell shrinkage by modifying Less dramatic alterations of extracellular osmolarity the set point for volume regulatory mechanisms (see sect. occur during intestinal absorption, which exposes intesti- IIIA). Cell shrinkage may be the signal for increase of nal cells to anisosmotic luminal fluid and may modify osmolyte concentration in the brain, which has been ob- portal blood osmolarity and liver cell volume (460). served to parallel enhanced urea concentration in uremia Other tissues are exposed to altered extracellular os- (1223). molarity during a variety of disorders. Although moderate, Rapid correction of chronically enhanced osmolarity these alterations are still highly relevant challenges to cell may lead to cell swelling, namely, to cerebral edema (28, volume control. 1157). Chronic increases of extracellular osmolarity are Because Na compensated by cells through accumulation of osmolytes, / salts (mainly NaCl) contribute ú90% to extracellular osmolarity, a significant decrease of extra- which may not be rapidly readjusted. Cerebral betaine, cellular osmolarity is necessarily paralleled by hypona- inositol, and glycerophosphorylcholine, for instance, may tremia. A variety of clinical conditions can lead to hypona- remain enhanced for days after correction of extracellular tremia (20, 21, 90, 816, 905, 1265). Hyponatremia may re- hypertonicity (746, 1208). Conversely, rapid correction of flect an excess of water, either due to excessive oral load or due to impaired renal elimination, or a deficit of Na hyponatremia may prove similarly harmful (1141, 1156). / due to renal or extrarenal loss (90, 606, 1264). In both cases, the hyponatremia reflects a decreased extracellular osmolarity, leading to cell swelling. Excessive water in- B. Alterations of Extracellular Ion Composition take is seen in psychiatric disorders (22). Causes for im- Even at constant extracellular osmolarity, cell vol- paired renal water elimination include inappropriate antiume constancy may be challenged by altered extracellular diuretic hormone (ADH) secretion, glucocorticoid defi- ion composition (see Table 2). Most importantly, an increase of extracellular K / ciency, hypothyroidism, and renal and hepatic failure. con- Renal and/or extrarenal loss of Na / may result from min- centration depolarizes the cell membrane and eventually leads to cellular uptake of K / eralocorticoid deficiency, salt losing kidney, nephrotic with accompanying anions syndrome, osmotic diuresis, vomiting, and diarrhea (90). (mainly Cl 0 and HCO 0 3 ) and subsequent cell swelling. Con- versely, a decrease of extracellular K / Moreover, a wide variety of drugs including diuretics, could result in cell cyclooxygenase inhibitors, and certain central nervous shrinkage due to cellular loss of KCl (see Table 2). An increase of extracellular HCO 0 system active drugs may lead to hyponatremia due to 3 concentration loss of Na / and/or to retention of water (90). Hyposmolar could swell cells by electrogenic entry, hyperpolarization, reduced driving force for K / hyponatremia is further observed after burns, pancreati- exit, and subsequent accumutis, and crush syndrome (90). lation of KHCO3 (976). During correction of extracellular Hyponatremia does not necessarily indicate hypos- acidosis in the course of the treatment of diabetic ketoacimolarity but may occur in isosmolar or even hyperosmolar dosis, increasing extracellular pH allows the cells to extrude H / through the Na / /H / states (90). Extracellular osmolarity may be enhanced de- exchanger, similarly leading spite normal or even decreased extracellular Na / concen- to cell swelling (1255). tration during hyperglycemia in uncontrolled diabetes Several organic anions such as acetate, lactate, and mellitus (27) and ethanol poisoning (1010). Moreover, hy- proprionate swell cells by entry of the unionized acid, intracellular dissociation, stimulation of Na / /H / ponatremia cannot be equated with cell swelling. As de- exchange tailed in section IVF, cell swelling or cell shrinkage may by cytosolic acidosis, and subsequent accumulation of Na / prevail in diabetes mellitus. Burns, pancreatitis, and se- and organic anions (see Table 2). A similar effect is vere trauma, all conditions associated with hyponatremia exerted by CO2. In general, acidosis favors cell swelling, (see above), may actually lead to muscle cell shrinkage whereas cellular alkalosis has the opposite effect (see rather than cell swelling (507). Table 2). Along these lines, the cellular accumulation of Extracellular osmolarity is increased in hyperna- lactate in muscle exercise triggers volume regulatory tremia, due to excessive oral intake and/or renal retention mechanisms (1048). Isotonic replacement of Cl 0 of Na with gluconate leads to / and/or renal and extrarenal loss of water (325, 553, / 9j07$$ja07 P18-7 12-30-97 09:41:42 pra APS-Phys Rev
January 1998 FUNCTIONAL SIGNIFICANCE OF CELL VOLUME 261 cell shrinkage due to cellular loss of Cl 0 (and K / ) (see An increase of cell volume appears to be required for cell Table 2). proliferation (see sect. VI). Activation of Na / channels or nonselective cation channels by excitatory neurotransmitters such as gluta- C. Energy Depletion mate tends to swell neurons, whereas activation of K / As pointed out in section IIB, the maintenance of a channels or anion channels by inhibitory neurotransmitters such as GABA tends to shrink neurons (see Table 2). constant cell volume requires the expenditure of energy Secretagogues may stimulate transepithelial trans- to fuel the Na port by enhancing cellular ion entry, ion exit, or both. If / -K / -ATPase, which is required to establish the ionic gradients across the cell membrane. Inhibition of stimulation of ion entry prevails, the cells swell, whereas Na if ion exit is preferentially activated, the cells shrink. Thus / -K / -ATPase by ouabain or during ischemia eventually leads to cell swelling. In cardiac myocytes, the swelling secretagogues may either swell (e.g., epinephrine) or is preceded by transient cell shrinkage due to increase of shrink (e.g., acetylcholine) the cells (see Table 2). intracellular Ca 2/ and hypercontraction (31, 174, 1131). In kidney medulla, ADH enhances extracellular os- As would be expected, ischemia leads to swelling of molarity and thus forces the medullary cells to accumu- the brain (347, 1229) by impairment of Na / -K / -ATPase and late osmolytes (1033, 1075). Furthermore, ADH may more subsequent accumulation of NaCl (347, 593). However, ac- directly trigger the formation or accumulation of osmocording to in vitro studies on glial and neuronal cells, energy depletion alone does not result in cell swelling (35, lytes (880). 613, 775, 1396). Rather, additional factors such as the intracellular acidosis (91, 578, 611, 1299) may account for cell E. Substrate Transport swelling observed during ischemia (625). Furthermore, cell swelling in cerebral ischemia is favored by an increase of The transport and cellular accumulation of amino acids lead to cell swelling (Table 2). Especially Na / extracellular K -cou- / concentration (612) and by extracellular accumulation of glutamate (42, 1396), which stimulates cationic channels through N-methyl-D-aspartate (NMDA) re- pled transport processes can generate large chemical gradients across the cell membrane, due to the steep electrochemical gradient for Na / ceptors and leads to subsequent accumulation of Na . For instance, cellular gluta- / , depolarization, and uptake of Cl mine has been observed to increase by ú30 mM after the 0 (185, 186). In the heart, recovery from ischemia is facilitated in the presence of the Na addition of 3 mM glutamine to portal blood (502). As listed in Table 2, transport of several other sub- / /H / exchange inhibitor 3-methylsulfonyl-4-piperidinobenzoyl-guanidine-mesilate (HOE-694) (1085). strates such as glucose, taurine, and taurocholeate similarly increases cell volume. Alterations of cell volume are encountered during cryopreservation of organs (366, 394, 681). Low temperatures inhibit the Na / -K / -ATPase and may thus be ex- F. Metabolism pected to eventually result in cell swelling. In theory, any reaction resulting in an increase of osmotically active substances, such as degradation of pro- D. Ion Transport Altered by Hormones teins to amino acids, glycogen to glucose phosphate, or and Transmitters triglycerides to glycerol and fatty acids, may be expected As listed in Table 2, a wide variety of hormones has to create intracellular osmolarity. However, very little is known about the influence of metabolism on cell volume. been shown to alter cell volume. Exercising muscle may lead to cellular accumulation Most importantly, insulin swells hepatocytes by acti- of lactate and thus may increase cell volume (1048). The vation of both Na / /H / exchange and Na / -K / -2Cl 0 cotrans- developing intracellular acidosis may compound cell swelling by activation of the Na / /H / port (4, 472, 953), and glucagon shrinks hepatocytes, pre- exchanger. sumably by activation of ion channels (473, 1286, 1287). Diabetic ketoacidosis may cause cell swelling (125, The effect of these hormones on cell volume accounts for 197, 646, 1388) due to cellular uptake of acids and en- several of the effects on hepatocyte metabolism (504, 506, hanced Na / /H / exchange activity in compensation for cellular H / 1286, 1287). It should be pointed out that insulin and glu- generation (1255). More importantly, high glucose cagon modify cell volume at hormone concentrations well concentrations favor cellular formation and accumulation encountered under physiological conditions. This is not of sorbitol through aldose reductase (143, 180, 559, 748, necessarily true for all hormones listed in Table 2. Similar 990, 1196). As a consequence, cells decrease other osmo- to insulin, several growth factors increase cell volume in lytes such as myo-inositol (143, 411, 1079, 1158, 1222, a variety of cells by stimulation of Na / /H / exchange and 1386, 1387), an effect which can be reversed by inhibition in some cases of Na of aldose reductase with sorbinil (303, 326, 1218). On the / -K / -2Cl 0 cotransport (see Table 2). / 9j07$$ja07 P18-7 12-30-97 09:41:42 pra APS-Phys Rev
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