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Dextran modulates microvascular permeability: effect in isotonic and hypertonic solutions.

Hypertonic saline solutions with Dextran (HSD) have been advocated for rapid restoration of intravascular volume. Dextran is thought to increase the duration of action of hypertonic saline (HS) by selectively partitioning the water in the vascular space that has been drawn out of cells by HS. The goal of this study was to define the microvascular permeability modulating activity of Dextran in both isotonic and hypertonic solutions. We hypothesized that Dextran would decrease hydraulic permeability (Lp). Using the modified Landis micro-occlusion technique, single rat mesenteric venules were perfused with either normal Ringers (NR) with 135 mM NaCl or HS with 185 mM NaCl. In sequential cannulations of the venules, 1%, 2%, and 3% of Dextran was added to the NR perfusion (n = 6) and the HS perfusion (n = 6). The Lp was measured at baseline and after perfusion with each Dextran concentration. Baseline Lp measurements for NR and HS solutions were 1.01 +/- 0.034 and 5.14 +/- 1.02, respectively. In the NR group, the 2% and 3% Dextran decreased permeability below baseline levels to 0.79 +/- 0.028 (P < 0.0001) and 0.66 +/- 0.028 (P < 0.0001), respectively. In the HS group, the 2% and 3% Dextran decreased permeability to 1.65 +/- 0.53 (P < 0.0001) and 0.99 +/- 0.2 (P < 0.0001), respectively. All values for Lp are x10(-7) cm s(-1) x cm H2O(-1). The addition of Dextran to isotonic and hypertonic solutions results in a decrease in microvessel permeability. This effect is more pronounced with the perfusion of hypertonic solutions. The results demonstrate the oncotic potential of Dextran and its ability to hold water in the vascular space. Dextran may have a beneficial effect when used for resuscitation with HS by decreasing microvascular permeability and augmenting intravascular volume.

Animals↗

An explanation for the positive inotropic effect of hypertonic solutions.

Hypertonic solutions of mannitol and sucrose have positive inotropic effects on both cardiac and skeletal muscle in vivo and in vitro. By increasing the tonicity of dog plasma of 50 mOsm in vitro with sucrose or mannitol Ca++ activity. The negative results with calcium proteinate and simple salt solutions suggest that the increased activity increases of 20--50 percent can be measured with a calcium-specific electrode. Increased tonicity had no effect on calcium proteinate complexes. By increasing the tonicity of solutions of small molecular weight complexes, a 5--50 percent increase in Ca++ activity results, depending on the specific complex used. Increasing the tonicity of solutions of inorganic salts such as CaSO4 or CaCl2 did not increase Ca++ activity seen with small molecular weight complexes is caused by dissociation of the Ca++, not by an interaction of the sucrose or mannitol solutions with the electrode. The absolute change inducible in a 10(-3) M solution of a small molecular weight complex is in the range of 0.5 mEq/l, a physiologically significant range. Thus it is suggested that part of the positive inotropic effect of increase osmolarity is a result of increased Ca++ activity from small molecular weight complexes in plasma and interstitial fluid.

Animals↗

The impact of albumin on hydraulic permeability: comparison of isotonic and hypertonic solutions.

Hypertonic saline, Dextran, and albumin have been advocated for rapid restoration of intravascular volume. The goal of this study was to define how albumin impacts the effects of hypertonic saline and Dextran on hydraulic permeability. We hypothesized that albumin would decrease the hydraulic permeability (L(p)) of isotonic and hypertonic solutions containing Dextran. Using the modified Landis micro-occlusion technique, single rat mesenteric venules were perfused with either Ringer's + 1% albumin (RA) or hypertonic saline + 1% albumin (HSA). In sequential cannulations of the venules, 1%, 2%, and 3% Dextran was added to the RA perfusion (n = 6) and the HSA perfusion (n = 6). These results were compared with similar studies completed without albumin. Albumin significantly decreased L(p) with all HS solutions studied compared with HS without albumin. Baseline L(p) measurements for RA and HSA solutions were 1.08 +/- 0.07 and 0.51 +/- 0.03, respectively. In the RA group, 2% and 3% Dextran was associated with a lower L(p) of 0.83 +/- 0.04 (P = 0.002) and 0.67 +/- 0.05 (P = 0.002), respectively. In the HSA group, 2% and 3% Dextran was associated with a lower L(p) of 0.37 +/- 0.02 (P = 0.001) and 0.32 +/- 0.02 (P < 0.0001), respectively. All values for L(p) are x 10(-7) cm x s(-1) x cmH2O(-1). Albumin maintains low hydraulic permeability levels during perfusion with hypertonic saline. In the setting of sufficient of endothelial albumin levels, hypertonic saline and Dextran may be advantageous when used for resuscitation by decreasing trans-endothelial fluid flux and augmenting intravascular volume.

Albumins↗

Efflux of red cell water into buffered hypertonic solutions.

Buffered NaCl solutions hypertonic to rabbit serum were prepared and freezing point depressions of each determined after dilution with measured amounts of water. Freezing point depression of these dilutions was a linear function of the amount of water added. One ml. of rabbit red cells was added to each 4 ml. of the hypertonic solutions and after incubation at 38 degrees C. for 30 minutes the mixture was centrifuged and a freezing point depression determined on the supernatant fluid. The amount of water added to the hypertonic solutions by the red cells was calcuated from this freezing point depression. For each decrease in the freezing point of -0.093 degrees C. of the surrounding solution red cells gave up approximately 5 ml. of water per 100 ml. of red cells in the range of -0.560 to -0.930 degrees C. Beyond -0.930 degrees C. the amount of water given up by 100 ml. of red cells fits best a parabolic equation. The maximum of this equation occurred at a freezing point of the hypertonic solution of -2.001 degrees C. at which time the maximum amount of water leaving the red cells would be 39.9 ml. per 100 ml. of red cells. The data suggest that only about 43 per cent of the red cell water is available for exchange into solutions of increasing tonicity.

Buffers↗

Effects of hypertonic solutions on contraction of frog tonic muscle fibers.

The influence of solution hypertonicity on contraction was studied in small bundles of tonic muscle fibers from the iliofibularis muscle of the frog Rana pipiens. Muscles were activated with high-K+ solutions that had osmolalities which were increased with tris(hydroxymethyl)aminomethanepropionate. Peak potassium contracture force decreased monotonically with tonicity and was zero in solutions with 2.5 or 3 times the osmolality of control Ringer. Contracture force at all tonicities studied (less than or equal to 3 X Ringer) was increased by increasing Ca2+ in the media 10-fold (to 20 mM) and/or by adding caffeine (10-20 mM). Nevertheless, this potentiated force also was diminished as tonicity increased. Force of single, mechanically skinned tonic fibers taken from these bundles was activated by Ca2+ over the same concentration range as that of twitch fibers. Moreover, maximal Ca2+-activated force, normalized per cross-sectional area, was similar in skinned tonic and twitch fibers. As was shown previously in twitch fibers, maximal Ca2+-activated force was decreased when ionic strength was increased. These data suggest that, as with twitch fibers, increased tonicity depresses contraction of tonic fibers by increasing the intracellular ionic strength, which in turn inhibits the ability of the contractile apparatus to generate force. Unlike twitch fibers, however, disruption of the excitation-contraction coupling process probably plays a more significant role in the action of hypertonicity on tonic fibers.

Animals↗

Loss of the plateau of the cardiac action potential in hypertonic solutions.

The effect of hypertonicity on the electrical properties of vertebrate myocardial cells was studied in ventricular muscle fibers of guinea pig, cat, frog, and chicken. The latter two species do not have a T-tubule system, whereas the former two do. In hypertonic solutions (2 x isotonic) produced by addition of sucrose or excess of NaCl, cell diameter decreased and there was a slight hyperpolarization and decrease in action potential overshoot. In guinea pig and cat, the hypertonic solution caused a decrease in input resistance and the plateau of the action potential to disappear in some of the cells; contractions of the entire ventricle also became depressed. These effects were reversed by returning the muscle fibers to isotonic solution. Addition of 5 mM SrCl(2) to the hypertonic solution also caused the plateau component and contraction to reappear. In frog and chick cells, loss of the plateau component and contraction never occurred in hypertonic solution, and input resistance increased. Urea and glycerol hyperosmolarity (2 x) caused no loss of the plateau component or contraction. If the frog and chicken ventricular, and guinea pig atrial myocardial cells (all of which lack T tubules) were to serve as an adequate control for possible effects of hypertonicity on the surface membrane and on contractile proteins, then the results suggest that swelling of the T tubules of mammalian myocardial cells leads to loss of the plateau component.

Action Potentials↗

Caffeine- and potassium-induced contractures of frog striated muscle fibers in hypertonic solutions.

The effect of hypertonic solutions on the caffeine- and KCl-induced contractures of isolated fibers of frog skeletal muscle was tested. Hypertonic solutions, twice the normal osmotic strength, prepared by adding NaCl or sucrose, potentiate the caffeine-induced contractures. The fibers may develop tensions of 3.6 kg/cm(2) of fiber transverse section. The same hypertonic medium reduced the peak tension of KCl-induced contractures. Thus the hypertonic condition does not affect the contractile mechanism itself. These findings give further support to the view that the differential effect of hypertonic solution is on the excitation-contraction coupling mechanism. Extracellular calcium is not essentially required for the first few of a series of caffeine-induced contractures either in hypertonic or in isotonic solutions.

Animals↗

Volume and twitch tension changes in single muscle fibers in hypertonic solutions.

Single muscle fibers were exposed to solutions made hypertonic (approximately 460 milliosmols/kg water) by addition of either NaCl, glycerol, urea, acetamide, ethylene glycol, or propylene glycol. The changes in either the fiber twitch tension or the volume were measured. In the case of NaCl both fiber volume and twitch tension fall rapidly to 64 and 27% of the respective initial value. These two values were maintained for the duration of the exposure. In the case of the other substances, the fiber volume and twitch tension also decreased but in these cases the effect was transient and the fibers recovered their initial volume and twitch tension. The rate of recovery in the different hypertonic media increased in the order: glycerol < urea < ethylene glycol < propylene glycol < acetamide. In the cases of the last three substances, the initial twitch value was recovered in less than 5 min and even surpassed. However, on returning to normal Ringer the fibers' ability to twitch or to develop potassium contractures was lost. The return of the fibers to normal Ringer after exposure to these hypertonic solutions causes a transient swelling of the fibers. However, when fibers were swelled by exposure to hypotonic media, they did not lose their ability to twitch on return to the normal Ringer.

Action Potentials↗

Selective response of human airway epithelia to luminal but not serosal solution hypertonicity. Possible role for proximal airway epithelia as an osmolality transducer.

The response of cultured human nasal epithelia to hypertonic bathing solutions was tested using ion-selective microelectrode and quantitative microscopy. Raised luminal, but not serosal, osmolality (+/- 150 mM mannitol) decreased Na+ absorption but did not induce Cl- secretion. Raised luminal osmolality increased cell Cl- activity, Na+ activity, and transepithelial resistance and decreased both apical and basolateral membrane potentials and the fractional resistance of the apical membrane; equivalent circuit analysis revealed increases in apical, basolateral, and shunt resistances. Prolonged exposure (10 min) to 430 mosM luminal solution elicited no regulation of any parameter. Optical measurements revealed a reduction in the thickness of preparations only in response to luminal hypertonic solutions. We conclude that (a) airway epithelial cells exhibit asymmetric water transport properties, with the apical membrane water permeability exceeding that of the basolateral membrane; (b) the cellular response to volume loss is a deactivation of the basolateral membrane K+ conductance and the apical membrane Cl- conductance; (c) luminal hypertonicity slows the rate of Na+ absorption but does not induce Cl- secretion; and (d) cell volume loss increases the resistance of the paracellular path. We speculate that these properties configure human nasal epithelium to behave as an osmotic sensor, transducing information about luminal solutions to the airway wall.

Adult↗

Effect of salt solutions on radiosensitivity of mammalian cells. III. Treatment with hypertonic solutions.

V79 Chinese hamster cells were treated with hypertonic solutions of NaCl or KCl and irradiated rat various times before, during, or after exposure to the solution. In solutions of molarities between 0-2 and 0-5 M, the cellular radiosensitivity increases with the molarity of the bathing solution. At these molarities, the hypertonic solution need not be present during irradiation to sensitize cells. Furthermore, radiosensitivity of cells could be increased by exposing cells for longer times to the hypertonic solution before irradiation. At higher salt concentrations (at 1-5 to 1-8 M), significant radioprotection is observed. Survival curve data showed that this protection was characterized by an increase in DO and a decrease in n, while the survival curves of cells sensitized with 0-465 M NaCl or with lower concentrations exhibited mainly changes in DO. The 1-55 M NaCl solution must be present during radiation to give a protective effect. Prolonged exposure to the salt before irradiation reduced the amount of radioprotection afforded by the salt. The results are discussed in terms of the effects of ions on histones, cellular water structure and the cell-aging cycle.

Cell Survival↗

Tension in isolated frog muscle fibers induced by hypertonic solutions.

The effect of hypertonic solutions on the tension of isolated twitch muscle fibers of the frog has been investigated. Increased tonicity up to about 1.7 times normal (1.7 T) caused a very small, graded, maintained tension increase. Above about 1.7 T a large, transient contracture response was superimposed on the small tension. The contracture response was graded with tonicity and reached a maximum at 2.5 T of 108 +/- 25 mN.mm(2) a third of the maximum tetanic tension in isotonic solution. Contracture tension developed with a delay which decreased with increased tonicity. The contracture threshold was lower and the delay shorter in small fibers than in large. Contractures were obtained equally well in depolarized as in polarized fibers. They were completely suppressed by 0.1-0.5 mM tetracaine. The possible mechanism responsible for the tension-inducing effect of hypertonic solutions is discussed in terms of the close similarity between the properties of these contractures and those caused by caffeine, and it is suggested that the effect is due to a release of calcium from internal stores.

Animals↗

Responses to hypertonic solutions in guinea-pig atria: changes in action potentials, force of contraction and calcium content.

In left atria of guinea-pig hearts we studied the effects of Tyrode solution made hypertonic by the addition of mannitol (50 to 300 mosm/l). Electrical and mechanical performance were investigated at 0.1, 1 and 3 Hz. Up to 150 mosm/l a positive inotropic effect was observed, addition of 300 mosm/l caused a positive inotropic response followed by a long lasting negative inotropic effect. The positive inotropic effect depended on the frequency of stimulation: at the low frequency of 0.1 Hz the increase in force of contraction was so large, that in hypertonic solution the absolute value of developed tension at 0.1 Hz was actually larger than at 3 Hz. With 150 mosm/l mannitol the time to peak tension and the twitch duration were prolonged. These effects were also most prominent at 0.1 Hz. The action potential duration was shortened; the membrane hyperpolarized. The observed changes in action potential duration and the membrane hyperpolarization may reflect changes in cation concentration due to cellular dehydration. The propagation velocity of excitation was reduced in the absence of a detectable decrease in maximum rate of depolarization during the upstroke of the action potential. The cells did not behave as perfect osmometers because loss of tissue water as estimated from wet weight and dry weight measurements was smaller than expected for a 1.5-fold increase in tonicity. After having established complete exchange of tissue calcium with 45Ca, hypertonicity-induced changes in the cellular calcium content could be determined by changes in 45Ca content. At both frequencies of stimulation, the cellular calcium content increased to the same extent.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

[Prehospital use of hypertonic solutions for traumatic brain injury].

Hypertonic solutions efficaciously lower increased intracranial pressure and improve cerebral hemodynamics in particular at the level of microcirculation. Therefore hypertonic solutions have been introduced to the in-hospital intensive care treatment of brain-injured patients. In view of the disturbed cerebral perfusion and oxygenation in the acute phase following traumatic brain injury, early initiation of treatment is desirable to improve long-term outcome and to minimize secondary brain damage. Two different hypertonic isooncotic solutions are licensed in Germany for prehospital and in-hospital treatment of acute hypotension due to hypovolaemia and haemorrhagic shock. Both solutions offer interesting therapeutic options for treatment of patients with increased intracranial pressure. Limitation of license to the treatment of shock in Germany does not allow routine prehospital use in isolated head trauma at the moment. In other European countries, the approval for the prehospital use of hypertonic isooncotic solutions has been modified.

Animals↗

Increase in human intestinal permeability following ingestion of hypertonic solutions.

1. A simple oral loading technique involving the ingestion of solutions containing lactulose is described. Timed urinary excretion of lactulose, which is non-metabolizable, is used as an indicator of intestinal permeability, and measured by quantitative paper chromatography. 2. This technique has been used to investigate the intestinal permeability of apparently healthy adults following the ingestion of solutions made hypertonic by the addition of the solutes sucrose, glucose, mannitol, glycerol, urea and sodium chloride. 3. These experiments show that intestinal permeability to lactulose increases as the solute concentration in the ingested solution is increased. Susceptibility to this effect, though consistent for each individual, shows considerable variation between subjects. 4. Factors thought to be pernitent to the enhancement of intestinal permeability by hypertonic solutions, and some possible implications of this, are discussed.

Disaccharides↗

The sarcoplasmic reticulum and T-system of rat extensor digitorum longus muscles exposed to hypertonic solutions.

Excised rat extensor digitorum longus muscles were soaked in a Krebs solution made hypertonic with extra NaCl and fixed using a combination of acrolein and glutaraldehyde dissolved in the same hypertonic Krebs. Electron microscopic examination showed that the sarcoplasmic reticulum (S.R.) of these muscles occupied the same fraction of fibre volume as it did in control muscles soaked and fixed in normal Krebs solution, contradicting previous studies on frog muscle. It appears unlikely that the S.R. is the rapidly exchanging Na+-compartment of rat muscle which enlarges in hypertonic solutions, or that it is an extracellular compartment. The T-system of hypertonic muscles was swollen, but its volume is insufficient to form the rapidly exchanging Na+-compartment.

Animals↗

A study on the mechanism of twitch potentiation by hypertonic solution in the frog atrial muscle.

Hypertonic solutions were found to exhibit both positive and negative inotropic effects on the contraction of the isolated atrial myocardium of bullfrog. The optimum tonicity for twitch potentiation was about 1.5 T. The mechanism for the positive inotropic action was investigated. The possibility of involvement of an increase in calcium influx during each action potential was excluded, since both the overshoot and the plateau of action potential were strongly depressed by perfusion of hypertonic solution. The effect on the time course of twitch potentiation was similar to that of muscle shrinkage, regardless of the type solute (sucrose, NaCl or LiCl) used for elevating the tonicity, except that excess sodium showed an initial rapid inhibitory phase of contraction. A marked post-rest potentiation was observed even after "zero" calcium perfusion, provided that the tonicity of the bathing medium was elevated previously. Potassium contracture occurred during the prolonged hypertonic perfusion in "zero" calcium condition. In addition, caffeine contracture was strongly augmented in hypertonic solution. The results suggest that an elevation in both the [Ca2+]i and amount of calcium bound intracellularly may play an important role in the positive inotropic action.

Action Potentials↗