No abstract

We investigated the ability of cadmium and mercury ions to cause endothelial dysfunction in bovine pulmonary artery endothelial cell monolayers. Exposure of monolayers for 48 h to metal concentrations greater than 3-5 microM produced profound cytotoxicity (increased lactate dehydrogenase leakage), a permeability barrier failure, depletion of glutathione and ATP and almost complete inhibition of the activity of key thiol enzymes, glucose-6-phosphate dehydrogenase (G6PDH) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In contrast, metal concentrations less than 1-2 microM induced increases in glutathione and thiol-enzyme activities with minimal changes in LDH leakage, barrier function and ATP content. At shorter incubation times (24 h or less), high concentrations of cadmium caused glutathione induction rather than depletion. Thus, oxidative stress and cytotoxicity induced by lower concentrations of the metal ions stimulate compensatory responses, including increased synthesis of glutathione, which presumably preserved the activity of key thiol enzymes, however these responses were not sustainable at higher metal ion concentrations. We conclude, while high concentrations of heavy metals are cytotoxic, lower concentration induce a compensatory protective response, which may explain threshold effects in metal-ion toxicity.

Background: Waniewski postulated a transient increase in peritoneal capillary surface area to fit their model predictions to experimental data of Heimburger measured in renal failure (RF) patients undergoing peritoneal dialysis (PD) but with only a 3.86% glucose dialysis fluid. The present aim is to propose a new mathematical model of the patient PD procedure that could closely fit the complete Heimburger measurement set without this postulate. Methods: The three-pore model of Rippe was used to describe transient changes in peritoneal volume and solute concentrations during a PD dwell. The predialysis, RF patient, plasma solute concentrations were assumed to remain constant during the dwell. The model was validated using the 3.86% glucose Heimburger measurements. Permeability surface area product parameters were chosen to match only the end-dwell peritoneal fluid glucose concentration and the end-dwell amounts of urea, creatinine, and Na+ removed from this simulated patient group. Then, this model was used to predict additional measurements by Heimburger on two other patient groups dialyzed with glucose concentrations of 2.27% and 1.36%, respectively. Parameters were unchanged when simulating these other patient groups. Results: To match the shape of the transient changes in drained volume and dialysis fluid glucose concentration for the 3.86% glucose group, it was necessary for only one parameter, the effective radius of glucose, to vary linearly in proportion to the dialysis fluid glucose concentration. This description was unchanged in the other two groups. Conclusion: Postulated transient increases in peritoneal capillary surface area were unnecessary to predict the entire Heimburger measurements.

The solvent-drag reflection coefficient (sigma f) was measured from plasma disappearance (integral-mass balance method) for native albumin and four fluorescent solutes of radii from 2 to 16 nm in the isolated, plasma-perfused cat hindlimb preparation. The data for the smallest solutes were measured > 2 h after tracer addition and at high filtration rates to avoid underestimation of sigma f due to tracer diffusion. A two-pore model was fit (small-pore and large-pore radii, approximately 3.5 and 23 nm, respectively, 84% of hydraulic capacity in small pores) to these data using an objective computer-based estimation procedure. In the model, membrane sigma f was determined by flow weighting the sigma f values for the two pathways. Also, the phenomenon of volume circulation among the pathways was included. In different limbs, the permeability-surface area (PS) product was measured for the smallest solute, alpha-lactalbumin, from its perfusate-disappearance transient and a linear diffusion model. The PS value estimated was 0.11 +/- 0.026 (95% confidence limits) ml.min-1 times 100 g muscle-1. These PS values were found to be coincident with those predicted using parameter sets derived from the multiparameter 95% confidence space consistent with the two-pore model fits. The two-pore model also closely predicted PS data for small solutes from other studies in skeletal muscle; however, it failed to adequately describe small-molecule transport data from osmotic transient studies. It was necessary to add a water-exclusive pathway (40% of total hydraulic capacity) to account for these latter data; however, the predictions with this addition were still consistent with the data measured in the present study. We conclude that pore models can describe both macromolecular and small solute reflection coefficient and PS data in skeletal muscle.

We developed mathematical models that predict equilibrium distribution of water and electrolytes (proteins and simple ions), metabolites, and other species between plasma and erythrocyte fluids (blood) and interstitial fluid. The models use physicochemical principles of electroneutrality in a fluid compartment and osmotic equilibrium between compartments and transmembrane Donnan relationships for mobile species. Across the erythrocyte membrane, the significant mobile species Cl⁻ is assumed to reach electrochemical equilibrium, whereas Na(+) and K(+) distributions are away from equilibrium because of the Na(+)/K(+) pump, but movement from this steady state is restricted because of their effective short-term impermeability. Across the capillary membrane separating plasma and interstitial fluid, Na(+), K(+), Ca²(+), Mg²(+), Cl⁻, and H(+) are mobile and establish Donnan equilibrium distribution ratios. In each compartment, attainment of equilibrium by carbonates, phosphates, proteins, and metabolites is determined by their reactions with H(+). These relationships produce the recognized exchange of Cl(-) and bicarbonate across the erythrocyte membrane. The blood submodel was validated by its close predictions of in vitro experimental data, blood pH, pH-dependent ratio of H(+), Cl⁻, and HCO₃⁻ concentrations in erythrocytes to that in plasma, and blood hematocrit. The blood-interstitial model was validated against available in vivo laboratory data from humans with respiratory acid-base disorders. Model predictions were used to gain understanding of the important acid-base disorder caused by addition of saline solutions. Blood model results were used as a basis for estimating errors in base excess predictions in blood by the traditional approach of Siggaard-Andersen (acid-base status) and more recent approaches by others using measured blood pH and Pco₂ values. Blood-interstitial model predictions were also used as a basis for assessing prediction errors of extracellular acid-base status values, such as by the standard base excess approach. Hence, these new models can give considerable insight into the physicochemical mechanisms producing acid-base disorders and aid in their diagnoses.