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Loss of absorptive capacity for sodium chloride as a cause of diarrhea following partial ileal and right colon resection.

Previous studies have emphasized the role of bile acid and fat malabsorption as the cause of the diarrhea that may follow ileal and right colon resection; unabsorbed bile acids and fat are believed to reduce sodium chloride and water absorption in the remaining colon. In this paper we report studies in eight patients with severe postresection diarrhea, in search of a more basic defect in sodium chloride absorption, ie, a loss of sodium chloride absorptive capacity as a direct consequence of resection of sodium chloride absorption sites. First, we determined whether or not diarrhea persisted during a 48-hr fast; in all patients diarrhea and large fecal electrolyte losses continued during a fast. Second, we measured sodium chloride and water absorption rates during total gut perfusion with a balanced electrolyte solution; compared to normal controls, the patients absorbed 23-31% less water, sodium, and chloride. In three patients who could be studied further, the absorptive defect was markedly accentuated when the perfusing solution was such that sodium chloride absorption had to take place against a concentration gradient. These observations indicate that postresection diarrhea patients have a reduced capacity to absorb sodium chloride, particularly when there is a concentration gradient between lumen and plasma. Although all of these patients had malabsorption of radiolabeled taurocholic acid, there was only a modest and statistically insignificant reduction in daily stool weight during treatment with large doses of cholestyramine, suggesting that bile acid malabsorption was not responsible for a major part of their diarrhea.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Effect of chloride withdrawal on the geometry of the T-tubules in amphibian and mammalian muscle.

The relative chloride permeabilities of the T-tubule membranes in mammalian (rat sternomastoid) and amphibian (toad sartorius) skeletal muscle fibers have been assessed from the change in volume of the T-tubules during chloride withdrawal from fibers exposed to low extracellular chloride concentrations. A 3.5- to 4.2-fold increase in T-tubule volume was found in mammalian fibers, and this was shown to be independent of the composition of the low chloride solution or the nature of the fixative used in preparation for electron microscopy. The increase in T-tubule volume was transient and was inhibited by factors which block chloride conductance, i.e., low pH, 2,4-dichlorophenoxyacetic acid, and nitrate ions. A small increase (1.48-fold) in T-tubule volume was seen in amphibian fibers when chloride ions were replaced by sulphate ions. No increase in volume was observed in amphibian T-tubules when methyl sulphate ions replaced chloride ions. The results support the idea that the chloride permeability of the T-tubule membrane is significantly higher in mammalian fibers than in amphibian fibers.

2,4-Dichlorophenoxyacetic Acid↗

Dietary chloride as a possible determinant of the severity of exercise-induced asthma.

Dietary sodium chloride (NaCl) has been shown to alter the severity of exercise-induced asthma, but it is not known if the sodium and chloride ions have independent effects in this regard. The hypothesis tested in the present study was that both a low sodium, low chloride diet and a high sodium, low chloride diet would improve post-exercise pulmonary function in subjects with exercise-induced asthma (EIA) compared to a normal NaCl diet (NSD); but that neither of these diets would have an effect on post-exercise pulmonary function in control (non-EIA) subjects. Eight subjects who suffered from EIA and eight subjects who did not (control) took part in a double-blind crossover study. Pre- and post-exercise pulmonary function was assessed after 2 weeks on a NSD, a low NaCl diet (LSD, low sodium, low chloride) or a sodium bicarbonate diet (NaHCO3 diet, high sodium, low chloride). A 1 week washout period occurred between diets. Altering dietary sodium or chloride had no effect on pre-exercise (baseline) pulmonary function in either group or on post-exercise pulmonary function in control subjects. However, both the LSD and the NaHCO3 diet lessened the deterioration in post-exercise pulmonary function in EIA subjects. Comparing results from pre- to post-exercise, forced expiratory volume in 1 s (FEV1) at 15 min post-exercise differed significantly (P < 0.05) between diets [mean (SEM) 7 (4)% on the LSD, 14 (4)% on the NaHCO3 diet, and 19 (2)% on the NSD]. Similar patterns were observed for forced vital capacity (FVC), forced expiratory flow rate at 25%-75% FVC and peak expiratory flow rate. The NaHCO3 diet lessened the deterioration of post-exercise pulmonary function, but not to the extent of LSD. These data suggest that both sodium and chloride contribute to the worsening of EIA symptoms seen after consuming a normal or high NaCl diet.

Acidosis↗

Insulin restores the calcium-activated chloride conductance in dedifferentiated renal glomerular mesangial cells from the H-2KB-TSA58 [corrected] transgenic mouse.

The effects of duration in culture were assessed in mesangial cells from the H-2Kb-tsA58 transgenic mouse using the whole-cell configuration of the patch clamp technique. The whole-cell potassium conductance remained constant in cells from passages 8-17 while the chloride conductance was found to decrease in cells after passage 15. This reduction of the chloride conductance, indicating cell dedifferentiation, was the result of complete loss of the calcium-activated component of the conductance and loss of part of the calcium-insensitive component. Insulin, which increases the calcium-sensitivity of the calcium-activated component of the chloride conductance in early passage cells, restored part of the calcium-sensitive component of the chloride conductance in dedifferentiated cells. Vasoactive agonists such as arginine vasopressin and angiotensin II stimulate a chloride-dependent depolarization in mesangial cells that initiates cell contraction. In view of the importance of the chloride flux it is possible that the loss of a significant magnitude of chloride conductance may underlie mesangial cell pathology to some degree. This is supported by data that show insulin can reverse many of the early renal changes observed in diabetic nephropathy and, as shown in this study, that insulin enhances the chloride conductance in dedifferentiated, cultured mesangial cells.

Animals↗

Neuronal transmembrane chloride electrochemical gradient: a key player in GABA A receptor activation physiological effect.

It has long been accepted that GABA is the main inhibitory neurotransmitter in the mammalian brain, acting via GABA(A) or GABA(B) receptors. However, new evidences have shown that it may work as an excitatory transmitter, especially in the brain of newly-born animals and acting via GABA(A) receptors. The difference in the end results of GABA(A) receptors activation in the two cases is not due to the receptor associated channels, which in both cases are chloride channels. The different physiological effect in the two cases is due to different electrochemical gradients for chloride. When GABA acting via GABA(A) receptors is inhibitory, either there is no transmembrane electrochemical gradient for chloride or there is one forcing such negative ions into the nerve cell, once chloride channels are open. Viceversa, GABA is excitatory when the electrochemical gradient is such to make chloride ions flow outside the cell, upon opening of the GABA activated chloride channels.In this review this concept is discussed in details and evidence in the scientific literature for the existence of different types of chloride pumps (either internalizing or extruding chloride) is compiled.

Animals↗

Role of chloride ion as an allosteric activator of angiotensin-converting enzyme.

The nature of chloride ion as an activator of angiotensin-converting enzyme was studied by a series of kinetic experiments with hog plasma enzyme preparation. The enzyme required the presence of chloride ion for its full catalytic activity, but its requirement of monovalent anion was not absolute. The KA value for the enzyme-chloride binding was estimated to be about 150 mM in all cases regardless of the peptide substrates employed. In the presence of chloride ion, the activity of the enzyme was increased, but its optimum pH was shifted gradually to the alkaline region up to pH 8.2 depending on the concentration of chloride ion. In addition, in the presence of chloride ion, the apparent Km values were reduced markedly while the Vmax values were not much altered; for example, for the hydrolysis of angiotensin I decapeptide, the Km value decreased by a factor of 50 while only an 18% increase in Vmax was observed when the enzyme was saturated with chloride ion. The result suggests that chloride ion acts as a conformational modifier inducing the affinity of synergistic binding of substrate.

Allosteric Regulation↗

Intracellular chloride activity and membrane potential in stripped frog skin (Rana temporaria).

The regulation of cell chloride activity in frog skin was investigated using double barrelled Cl--microelectrodes to measure cell membrane potentials and chloride activity in the isolated frog epidermis. Experiments were done under short-circuit conditions, impaling cells from the serosal side. The basic electrophysiological parameters of the isolated skin were similar to those reported in the literature for whole preparations. Intracellular chloride activity was on average 21.9 mM and membrane potential was about 57 mV, implying that chloride was distributed away from its electrochemical equilibrium (i.e., concentrated inside the cells). Chloride activity decreased after removal of either Cl- or Na+ from the serosal bathing solution, with no change in membrane potential. The chloride permeability of the serosal membrane was calculated to be 2.6 X 10(-6) cm X s-1 which represents about 1/4 of the total conductance of the serosal membrane. We suggest that an electrically silent sodium-dependent uphill transport of chloride is present at the basolateral membrane of the frog skin, which accounts for the non-passive distribution of chloride.

Animals↗

Chloride current induced by alcohols in rat dorsal root ganglion neurons.

We have recently demonstrated that ethanol and longer-chain alcohols (n-alcohols) enhance gamma-aminobutyric acid (GABA)-induced chloride currents before desensitization takes place. The potencies of n-alcohols increase with lengthening of the carbon chain. We now report that n-alcohols induce chloride currents by themselves in rat dorsal root ganglion neurons in primary culture. The whole cell variation of the patch clamp techniques was used to record currents as induced by external application of alcohols and other test compounds. Ethanol, n-butanol, n-hexanol and n-octanol induced inward currents with their potencies increasing in that order. The potencies were approximately one order of magnitude less than those to augment GABA-induced currents. The maximum amplitudes of currents induced by the alcohols were less than those produced by GABA. The n-octanol-induced currents were carried largely by chloride ions because the reversal potentials were changed according to the Nernst chloride potential as the internal chloride concentration was changed. Bicuculline and picrotoxin suppressed the n-octanol-induced current, and chlordiazepoxide and pentobarbital augmented the n-octanol-induced current. Therefore, the alcohol-induced chloride currents flow through the chloride channels associated with the GABAA receptors. When applied after the GABA-induced current was desensitized to a lower level, n-octanol suppressed rather than augmented the current. Thus, n-alcohols mimic barbiturates in augmenting the GABA-induced currents and in generating chloride currents by themselves. These actions of both agents may play a role in causing anxiolytic, sedative and/or anesthetic effects.

Alcohols↗

Mass spectrometry of oligosaccharides by chloride-attachment reactions: the origin of fragment loss.

The direct exposure, negative chemical ionisation, chloride-attachment mass spectrometry of trehalose and sucrose gave abundant chloride-attached molecular ions. The same feature was observed when these sugars were subjected to fast-atom bombardment (f.a.b.) in a glycerol matrix containing ammonium chloride. No characteristic fragment ion was found when trehalose was analysed by either method. In contrast, sucrose gave intense chloride-containing fragments, arising by glycosidic cleavage, when analysed by the first method, whereas such cleavage was not detectable by f.a.b.-ammonium chloride analysis. However, the mass-analysed ion kinetic energy (m.i.k.e.) spectra of the (M + Cl)- ions from either trehalose and sucrose, generated under f.a.b.-ammonium chloride conditions, showed glycosidic cleavage reactions in addition to a large loss of HCl. These cleavage reactions might be attributed to SN2-like reactions on the acetal carbon atom and to base-induced eliminations, and they were enhanced by collision-induced dissociations. However, the relative abundance of such glycosidic cleavages from the ionic state would be too weak to explain the presence of the large chloride-containing fragments in the direct exposure spectra of sucrose. Thus, these ions were mainly produced by a thermal cleavage followed by chloride-attachment reactions.

Chlorides↗

Inhibition of chloride secretion by BaCl2 in the rectal gland of the spiny dogfish, Squalus acanthias.

In the rectal gland of the spiny dogfish (Squalus acanthias), chloride enters the cell via a cotransport system together with sodium and potassium in a 2 Cl-: 1 Na+: 1 K+ stoichiometry. The system is energized by the electrochemical potential for sodium directed into the cell. Sodium is extruded from the cell by Na-K-ATPase located on the basolateral cell membrane. Chloride leaks into the lumen following a favorable electrical gradient. Potassium is thought to recirculate across the basolateral cell membrane. Since barium ions inhibit the efflux of potassium from cells we used barium chloride to explore the role of potassium in the process of stimulated secretion of chloride by the gland. The secretion of chloride was stimulated with theophylline 2.5 X 10(-4)M and dibutyryl cyclic AMP 5 X 10(-5)M. Ba++ inhibited the secretion of chloride in a way that was reversible and dose dependent. The reduction in secretion was associated with a parallel fall in transglandular electrical potential. Inhibition was half maximal at a concentration of Ba++ of 10(-3)M. The reduction in efflux of potassium produced by Ba++ presumably decreases the potassium diffusion potential, thus reducing the electronegativity of the cell and dissipating the driving force for chloride across the apical cell membrane. Recirculation of K+ across the basolateral border of the cell would thus be essential for the maintenance of chloride secretion by the gland.

Animals↗

Rat hepatic vinyl chloride metabolites induce gene conversion in the yeast strain D7RAD in vitro and in vivo.

We have tested the genetic activity of gaseous vinyl chloride in vitro and in vivo using the gene-conversion system (trp5-12/trp5-27 leads to TRP+) in the yeast strain D7RAD. To induce, in vitro, TRP+ convertants with 2.5% gaseous vinyl chloride, a rat-liver microsomal system for metabolic activation of the vinyl chloride and dividing yeast cells are required. Neither a deficiency in excision repair (rad3) nor in the error-prone repair pathway (rad6) increased the vinyl-chloride-induced conversion frequencies compared with the repair-competent D7RAD strain. When logarithmically growing cells of the D7RAD strain were injected intravenously into male Wistar rats which inhaled 1% vinyl chloride in air for 24 h, a significant enhancement of the TRP+ conversion frequencies was found compared with that in cells re-isolated from untreated rats. These results indicate that vinyl chloride metabolites from the metabolizing hepatocytes diffuse into yeast cells, which accumulate in the liver capillaries. This supports the hypothesis that the endothelial cells of the liver sinuses, which have hardly any metabolic activity, but give rise to vinyl-chloride-induced hemangiotheliomas (rare type of liver tumor), are transformed by diffusible metabolites of the procarcinogen vinyl chloride.

Animals↗

Pharmacokinetics of vinyl chloride in the rat.

When rats are exposed to [14C]vinyl chloride in a closed system, the vinyl chloride present in the atmosphere equilibrates with the animals' organism within 15 min. The course of equilibration could be determined using rats which had been given 6-nitro-1,2,3-benzothiadiazole. This compound completely blocks metabolism of vinyl chloride. The enzymes responsible for metabolism of vinyl chloride are saturated at an atmospheric concentration of vinyl chloride of 250 ppm. Pharmacokinetic analysis shows that no significant cumulation of vinyl chloride or its major metabolites is to be expected on repeated administration of vinyl chlorides. This may be consistent with the theory that a reactive, shortly living, metabolite which occurs in low concentration only, may be responsible for the toxic effects of vinyl chloride.

Animals↗

Nuclear Magnetic resonance quadrupole relaxation studies of chloride binding to the isolated hemoglobins from trout (Salmo irideus).

NMR studies of chloride binding to the main components of trout blood, Hb Trout I and Hb Trout IV, indicate that although the affinity of chloride is high for both hemoglobins, the characteristics of the binding process are markedly differnet. In Hb Trout IV chemical exchange at the chloride binding site(s) is fast and quadrupole effects determine the linewidth; chloride binding has a definite pH dependence, but there is no significant oxygen linkage. In contrast Hb Trout I represents a unique case of slow chemical exchange, which may depend on unusual stereoche mical characteristics of the chloride binding site; chloride binding is pH independent, but shows a significant oxygen linkage, which may be attributed to changes of the lifetime of chloride at the binding site. The chloride binding properties displayed by Hb Trout I and IV have been compared with those of normal and modified human hemoglobins and discussed in terms of the structural differences in the C- and N-terminal regions of the alpha- and beta-chains.

Animals↗

Effect of dietary chloride on aldosterone synthase induction and angiotensin II receptors in rat adrenals.

Effects of dietary chloride ions on the levels of both cytochrome P-450aldo (CYP11B2) and angiotensin II receptors were examined in rat adrenals. Capsular adrenal CYP11B2 protein levels significantly increased in previously chloride-depleted animals treated with either ammonium- or choline chloride. No changes in CYP11B2 protein levels were detected in previously chloride-depleted rats replenished with either ammonium acetate or choline bromide. The induction of CYP11B2 by chloride-repletion was not concurrent with either increased plasma renin activity or elevated serum potassium levels. None of the above dietary manipulations affected angiotensin II receptor number and affinity, respectively. Treatment of chloride-repleted animals with an angiotensin II receptor antagonist (TCV116) significantly attenuated the increase of CYP11B2 protein levels. In addition, chloride-repletion of previously chloride-depleted animals increased mRNA levels encoding angiotensin II type 1B receptor, but decreased mRNA levels encoding the type 1A form of the receptor. Thus, the presented data are supportive of the notion that the regulation of CYP11B2 expression in the capsular portion of the rat adrenal is, in part, mediated via induction of the angiotensin II type 1B receptor.

Adrenal Glands↗

Methylene chloride poisoning: a paradigmatic review.

The incidence of reported cases of toxicity resulting from methylene chloride exposure has increased within the last decade. A vast majority of these reports involve acute episodes, and the prevalence of domestic poisoning is relatively high. Diverse pathologic sequelae attributed to methylene chloride or its metabolites have been reported, although a distinct bias for central nervous system effects is evident. paradoxically, detoxification of methylene chloride via the mixed-function oxidase pathway is an inherently intoxicating event. Although the anomalous conversion of methylene chloride into carbon monoxide has increased the popular awareness of methylene chloride poisoning among medical personnel, lack of experience in diagnosis and treatment of methylene chloride poisoning is widespread. This review of 26 cases spanning 50 years reveals that the industrial and domestic use of methylene chloride is equally widespread. A compendium of the clinical experience with methylene chloride poisoning is presented.

Animals↗

Chloride concentration affects Kv channel voltage-gating kinetics: Importance of experimental anion concentrations.

Chloride concentration has been shown to have a dramatic impact on protein folding and subsequent tertiary conformation [K.D. Collins, Ions from the Hofmeister series and osmolytes: effects on proteins in solution and in the crystallization process, Methods 34 (2004) 300-311; I. Jelesarov, E. Durr, R.M. Thomas, H.R. Bosshard, Salt effects on hydrophobic interaction and charge screening in the folding of a negatively charged peptide to a coiled coil (leucine zipper), Biochemistry 37 (1998) 7539-7550]. As it is known that Kv channel gating is linked to the stability of the cytoplasmic T1 multimerization domain conformation [D.L. Minor, Y.F. Lin, B.C. Mobley, A. Avelar, Y.N. Jan, L.Y. Jan, J.M. Berger, The polar T1 interface is linked to conformational changes that open the voltage-gated potassium channel, Cell 102 (2000) 657-670; B.A. Yi, D.L. Minor Jr., Y.F. Lin, Y.N. Jan, L.Y. Jan, Controlling potassium channel activities: interplay between the membrane and intracellular factors, Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 11016-11023] and that intracellular chloride concentration has been linked to Kv channel kinetics [L.K. Bekar, W. Walz, Intracellular chloride modulates A-type potassium currents in astrocytes, Glia 39 (2002) 207-216; W.B. Thoreson, S.L. Stella, Anion modulation of calcium current voltage dependence and amplitude in salamander rods, Biochim. Biophys. Acta 1464 (2000) 142-150], the objective of the present study was to address how chloride concentration changes affect Kv channel kinetics more closely in an isolated expression system. Initially, no significant chloride concentration-dependent effects on channel steady-state gating kinetics were observed. Only after disruption of the cytoskeleton with cytochalasin-D did we see significant chloride concentration-dependent shifts in gating kinetics. This suggests that the shift in gating kinetics is mediated through effects of intracellular chloride concentration on cytoplasmic domain tertiary conformation as cytoskeletal interaction appears to mask the effect. Furthermore, as cytoskeletal disruption only impacts channel gating kinetics at low physiological intracellular chloride concentrations, these studies highlight the importance of paying close attention to anion concentrations used under experimental conditions.

Cell Line↗

Uptake of chloride ion from aqueous solution by calcined layered double hydroxides: equilibrium and kinetic studies.

Layered double hydroxides (LDH) calcined within a certain temperature range (denoted as CLDH) have been shown to recover their original layered structure in the presence of appropriate anions. In the light of this so-called "memory effect", uptake of chloride ion from aqueous solution by calcined MgAl-CO3 LDH was investigated in batch mode. The equilibrium isotherm showed that the uptake of chloride ion by CLDH was consistent with the Langmuir and Freundlich equations and that the Langmuir model gave a better fit to the experimental data than the Freundlich model. The maximum uptake capacity of CLDH for chloride ion was 149.5 mg/g, close to the stoichiometric uptake (168 mg/g). The influence of varying pH of solution, initial chloride concentration, adsorbent quantity, and temperature on the kinetics of chloride removal has also been explored. Four kinetic models were used to fit the experimental data, and it was found that the pseudo-second-order kinetics model could be used to describe the uptake process satisfactorily. The calculated value of Ea was found to be 56.8 kJ/mol, which suggests that the process of uptake of chloride ion is controlled by the rate of reaction of chloride ion with the CLDH rather than diffusion. A mechanism for removal of chloride ion has been confirmed by X-ray diffraction, FT-IR spectroscopy and TG-MS measurements.

Adsorption↗

Regulation of human placental chloride channel by arachidonic acid and other cis unsaturated fatty acids.

OBJECTIVE: Arachidonic acid has been implicated in the modulation of various transport processes, including conductive chloride transport in brush border membranes in the human placenta. The purpose of this work was to explore the effects of some cis unsaturated fatty acids on the electrophysiologic properties of the maxi chloride channels present in apical membranes from human placenta. STUDY DESIGN: Apical membrane chloride channels from human term placentas were reconstituted in giant liposomes. These cell-sized liposomes, generated by a cycle of dehydration and rehydration, are suitable for electrophysiologic studies by the patch-clamp method. RESULTS: Low micromolar concentrations of arachidonic acid reversibly inhibit maxi chloride channels in excised patches. Other cis unsaturated fatty acids, such as oleic and linoleic acids, show similar blockade. The inhibition was dose dependent. The maxi chloride channel can also be inhibited by 4,4 -diisothiocyanatostilbene-2,2 -disulfonic acid, a known chloride channel inhibitor. CONCLUSIONS: Our results identify the apical membrane maxi chloride channel as a possible electrophysi ologic counterpart of 4,4 -diisothiocyanatostilbene-2, 2 -disulfonic acid and cis unsaturated fatty acid-inhibited conductance previously described in brush border membranes of the human placenta. From a functional point of view the control of these channels by arachidonic acid may be of great importance in placental physiologic characteristics. Regulation of chloride channels could be important in the control of electrolyte and fluid transfer across the placenta. In addition, if these channels contribute to setting the membrane potential their regulation could have consequences for nutrient transport and delivery to the fetus. The electrophysiologic identification of these channels and their regulation might help to unravel their possible role in transplacental transport in normal and pathologic placental tissue.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗