Pharmacokinetics and Pharmacodynamics of Lansoprazole/Sodium Bicarbonate Immediate-release Capsules in Healthy Chinese Subjects: An Open, Randomized, Controlled, Crossover, Single-, and Multiple-dose Trial.

Proton pump inhibitors (PPIs) differ in onset of action and bioavailability. This trial was conducted to investigate the pharmacokinetics and pharmacodynamics of an immediate-release capsule formulation containing lansoprazole 30 mg and sodium bicarbonate 1100 mg (T preparation) in healthy Chinese subjects. This was an open, single-center, randomized, single and multiple oral doses, and two-period crossover study in 30 healthy subjects. After single- and multiple-dose oral administration, blood samples were obtained and lansoprazole concentration in serum was measured for pharmacokinetic analysis. Meanwhile, the intragastric pH was monitored continuously to evaluate the pharmacodynamics of the investigational drugs. The Tmax of the T preparation was 0.5 hours, while the Tmax of the R preparation was 1.5 hours after multiple doses, which indicated that the absorption speed of the T preparation was significantly faster than that of the R preparation. The same characteristics also existed after single-dose administration. The area under the curve (AUC)ss of the T preparation was bio-equivalent to that of the R preparation under steady state. The time percentage of intragastric pH > 4.0 for the T preparation was higher than that of the R preparation after 1 hour for both single- and multiple-dose. It suggested compared with R preparation, the time percentage of intragastric pH > 4.0 met the criteria for superiority after 1 hour administration for the T preparation. In addition, no serious adverse events occurred in this study. Across this study, the T preparation was better than the R preparation at improving drug absorption and increasing intragastric pH, and had a favorable safety profile.

The effects of bathing in neutral bicarbonate ion water.

Percutaneously absorbed carbon dioxide enhances blood flow. The mechanism by which it does so is unclear, but we hypothesized that it involves bicarbonate ions. BALB/c mice were bathed in neutral bicarbonate ionized water (NBIW) and showed increased blood bicarbonate levels and blood flow via phosphorylation of peripheral vascular endothelial nitric oxide synthase (eNOS) and production of nitric oxide (NO). Phosphorylation of eNOS and NO production were also increased in human umbilical vein endothelial cells cultured in medium containing NBIW, and NBIW showed reactive oxygen species scavenging activity. In a double-blind, randomized study in men and women aged 30 to 59 years with subjective cold intolerance, bathing in NBIW elevated body temperature faster than bathing in a control solution and improved chills and sleep quality. Taken together, our results show that percutaneously absorbed carbon dioxide changes to bicarbonate ions, which act directly on endothelial cells to increase NO production by phosphorylation of eNOS and thus improve blood flow.

Bicarbonate Resensitization of Methicillin-Resistant Staphylococcus aureus to ß-Lactam Antibiotics.

Endovascular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major health care concern, especially infective endocarditis (IE). Standard antimicrobial susceptibility testing (AST) defines most MRSA strains as "resistant" to ß-lactams, often leading to the use of costly and/or toxic treatment regimens. In this investigation, five prototype MRSA strains, representing the range of genotypes in current clinical circulation, were studied. We identified two distinct MRSA phenotypes upon AST using standard media, with or without sodium bicarbonate (NaHCO3) supplementation: one highly susceptible to the antistaphylococcal ß-lactams oxacillin and cefazolin (NaHCO3 responsive) and one resistant to such agents (NaHCO3 nonresponsive). These phenotypes accurately predicted clearance profiles of MRSA from target tissues in experimental MRSA IE treated with each ß-lactam. Mechanistically, NaHCO3 reduced the expression of two key genes involved in the MRSA phenotype, mecA and sarA, leading to decreased production of penicillin-binding protein 2a (that mediates methicillin resistance), in NaHCO3-responsive (but not in NaHCO3-nonresponsive) strains. Moreover, both cefazolin and oxacillin synergistically killed NaHCO3-responsive strains in the presence of the host defense antimicrobial peptide (LL-37) in NaHCO3-supplemented media. These findings suggest that AST of MRSA strains in NaHCO3-containing media may potentially identify infections caused by NaHCO3-responsive strains that are appropriate for ß-lactam therapy.

Positron Emission Tomography Imaging of Lesions pH Using 11C-Labeled Bicarbonate.

OBJECTIVES: As acid-base imbalance is involved in many pathological processes, the capability to image tissue pH alterations in the clinic could offer new ways to detect disease and respond to treatment. In this study, the authors show that tissue pH can be imaged in vivo with 11C-labeled bicarbonate (H11CO3-) buffer and positron emission tomography (PET). METHODS: H11CO3- was produced by on-column NaOH adsorption. Biodistribution of H11CO3- in normal mice was determined. In addition, uptake studies and inhibition experiments of H11CO3- in the S180 fibrosarcoma-bearing mice and the inflammatory mice were investigated with PET imaging. The tumor and inflammatory interstitial pH was measured by a needle pH microelectrode. RESULTS: PET imaging demonstrated the high uptake of H11CO3- in mice tumor tissues and inflammatory tissues, which showed that the average tumor or inflammatory interstitial pH was significantly lower than the surrounding tissue. Administration of sodium bicarbonate in the drinking water increased the measured tumor pH, while the uptake of H11CO3- in mice model tissues had no change. Similarly, administration with ammonium chloride (NH4Cl) decreased the pH, whereas the unchanged uptake of H11CO3- in mice model tissues was also found. However, after administration of acetazolamide, the low uptake of H11CO3- in mice model tissues was observed. CONCLUSIONS: H11CO3- solution is an endogenous bicarbonate buffer tracer that can be injected into patients without toxicity. H11CO3- PET can be used clinically to image pathological processes that are associated with acid-base imbalance, such as cancer and inflammation.

NIR responsive liposomal system for rapid release of drugs in cancer therapy.

To design a rapid release liposomal system for cancer therapy, a NIR responsive bubble-generating thermosensitive liposome (BTSL) system combined with photothermal agent (Cypate), doxorubicin (DOX), and NH4HCO3 was developed. Cypate/DOX-BTSL exhibited a good aqueous stability, photostability, and photothermal effect. In vitro release suggested that the amounts of DOX released from BTSL were obviously higher than that of (NH4)2SO4 liposomes at 42°C. After NIR irradiation, the hyperthermic temperature induced by Cypate led to the decomposition of NH4HCO3 and the generation of a large number of CO2 bubbles, triggering a rapid release of drugs. Confocal laser scanning microscope and acridine orange staining indicated that Cypate/DOX-BTSL upon irradiation could facilitate to disrupt the lysosomal membranes and realize endolysosomal escape into cytosol, improving the intracellular uptake of DOX clearly. MTT and trypan blue staining implied that the cell damage of Cypate/DOX-BTSL with NIR irradiation was more severe than that in the groups without irradiation. In vivo results indicated that Cypate/DOX-BTSL with irradiation could dramatically increase the accumulation of DOX in tumor, inhibit tumor growth, and reduce systemic side effects of DOX. These data demonstrated that Cypate/DOX-BTSL has the potential to be used as a NIR responsive liposomal system for a rapid release of drugs in thermochemotherapy.

Combining different types of multifunctional liposomes loaded with ammonium bicarbonate to fabricate microneedle arrays as a vaginal mucosal vaccine adjuvant-dual delivery system (VADDS).

To develop effective mucosal vaccines, two types of multifunctional liposomes, the mannosylated lipid A-liposomes (MLLs) with a size of 200nm and the stealth lipid A-liposomes (SLLs) of 50nm, both loaded with a model antigen and NH4HCO3, were fabricated together into microneedles, forming the proSLL/MLL-constituted microneedle array (proSMMA), which upon rehydration dissolved rapidly recovering the initial MLLs and SLLs. Mice vaccinated with proSMMAs by vaginal mucosa patching other than conventional intradermal administration established robust antigen-specific humoral and cellular immunity at both systemic and mucosal levels, especially, in the reproductive and intestinal ducts. Further exploration demonstrated that the MLLs reconstituted from the administered proSMMAs were mostly taken up by vaginal mucosal dendritic cells, whereas the recovered SLLs trafficked directly to draining lymph nodes wherein to be picked up by macrophages. Moreover, the antigens delivered by either liposomes were also cross-presented for MHC-I displaying by APCs thanks to lysosome escape and ROS (reactive oxygen species) stimulation, both of which occurred when lysosomal acidifying the liposome-released NH4HCO3 into CO2 and NH4+/NH3 to rupture lysosomes by gas expansion and to cause ROS production by excessive ammonia induction, resulting in a mixed Th1/Th2 type response which was also promoted by liposomal lipid A via activation of TLR4. In addition, vaginal vaccination of the engineered HSV2 antigen gD-loaded proSMMAs successfully protected mice from the virus challenge. Thus, the proSMMAs are in fact a vaccine adjuvant-dual delivery system capable of eliciting robust humoral and cellular immunity against the invading pathogens, especially, the sexually transmitted ones.

In vivo pH mapping of injured lungs using hyperpolarized [1-13 C]pyruvate.

PURPOSE: To optimize the production of hyperpolarized 13 C-bicarbonate from the decarboxylation of hyperpolarized [1-13 C]pyruvate and use it to image pH in the lungs and heart of rats with acute lung injury. METHODS: Two forms of catalysis are compared calorimetrically to maximize the rate of decarboxylation and rapidly produce hyperpolarized bicarbonate from pyruvate while minimizing signal loss. Rats are injured using an acute lung injury model combining ventilator-induced lung injury and acid aspiration. Carbon images are obtained from both healthy (n = 4) and injured (n = 4) rats using a slice-selective chemical shift imaging sequence with low flip angle. pH is calculated from the relative HCO3- and CO2 signals using the Henderson-Hasselbalch equation. RESULTS: It is demonstrated that base catalysis is more effective than metal-ion catalysis for this decarboxylation reaction. Bicarbonate polarizations up to 17.2% are achieved using the base-catalyzed reaction. A mean pH difference between lung and heart of 0.14 pH units is measured in the acute lung injury model. A significant pH difference between injured and uninjured lungs is also observed. CONCLUSION: It is demonstrated that hyperpolarized 13 C-bicarbonate can be efficiently produced from the base-catalyzed decarboxylation of pyruvate. This method is used to obtain the first regional pH image of the lungs and heart of an animal. Magn Reson Med 78:1121-1130, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Ranking of factors determining potassium mass balance in bicarbonate haemodialysis.

BACKGROUND: One of the most important pathogenetic factors involved in the onset of intradialysis arrhytmias is the alteration in electrolyte concentration, particularly potassium (K(+)). METHODS: Two studies were performed: Study A was designed to investigate above all the isolated effect of the factor time t on intradialysis K(+) mass balance (K(+)MB): 11 stable prevalent Caucasian anuric patients underwent one standard (∼4 h) and one long-hour (∼8 h) bicarbonate haemodialysis (HD) session. The latter were pair-matched as far as the dialysate and blood volume processed (90 L) and volume of ultrafiltration are concerned. Study B was designed to identify and rank the other factors determining intradialysis K(+)MB: 63 stable prevalent Caucasian anuric patients underwent one 4-h standard bicarbonate HD session. Dialysate K(+) concentration was 2.0 mmol/L in both studies. Blood samples were obtained from the inlet blood tubing immediately before the onset of dialysis and at t60, t120, t180 min and at end of the 4- and 8-h sessions for the measurement of plasma K(+), blood bicarbonates and blood pH. Additional blood samples were obtained at t360 min for the 8 h sessions. Direct dialysate quantification was utilized for K(+)MBs. Direct potentiometry with an ion-selective electrode was used for K(+) measurements. RESULTS: Study A: mean K(+)MBs were significantly higher in the 8-h sessions (4 h: -88.4 ± 23.2 SD mmol versus 8 h: -101.9 ± 32.2 mmol; P = 0.02). Bivariate linear regression analyses showed that only mean plasma K(+), area under the curve (AUC) of the hourly inlet dialyser diffusion concentration gradient of K(+) (hcgAUCK(+)) and AUC of blood bicarbonates and mean blood bicarbonates were significantly related to K(+)MB in both 4- and 8-h sessions. A multiple linear regression output with K(+)MB as dependent variable showed that only mean plasma K(+), hcgAUCK(+) and duration of HD sessions per se remained statistically significant. Study B: mean K(+)MBs were -86.7 ± 22.6 mmol. Bivariate linear regression analyses showed that only mean plasma K(+), hcgAUCK(+) and mean blood bicarbonates were significantly related to K(+)MB. Again, only mean plasma K(+) and hcgAUCK(+) predicted K(+)MB at the multiple linear regression analysis. CONCLUSIONS: Our studies enabled to establish the ranking of factors determining intradialysis K(+)MB: plasma K(+) → dialysate K(+) gradient is the main determinant; acid-base balance plays a much less important role. The duration of HD session per se is an independent determinant of K(+)MB.

Deletion of Slc26a6 alters the stoichiometry of apical Cl-/HCO-3 exchange in mouse pancreatic duct.

To define the stoichiometry and molecular identity of the Cl(-)/HCO(3)(-) exchanger in the apical membrane of pancreatic duct cells, changes in luminal pH and volume were measured simultaneously in interlobular pancreatic ducts isolated from wild-type and Slc26a6-null mice. Transepithelial fluxes of HCO(3)(-) and Cl(-) were measured in the presence of anion gradients favoring rapid exchange of intracellular HCO(3)(-) with luminal Cl(-) in cAMP-stimulated ducts. The flux ratio of Cl(-) absorption/HCO(3)(-) secretion was ∼0.7 in wild-type ducts and ∼1.4 in Slc26a6(-/-) ducts where a different Cl(-)/HCO(3)(-) exchanger, most likely SLC26A3, was found to be active. Interactions between Cl(-)/HCO(3)(-) exchange and cystic fibrosis transmembrane conductance regulator (CFTR) in cAMP-stimulated ducts were examined by measuring the recovery of intracellular pH after alkali-loading by acetate prepulse. Hyperpolarization induced by luminal application of CFTRinh-172 enhanced HCO(3)(-) efflux across the apical membrane via SLC26A6 in wild-type ducts but significantly reduced HCO(3)(-) efflux in Slc26a6(-/-) ducts. In microperfused wild-type ducts, removal of luminal Cl(-), or luminal application of dihydro-4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid to inhibit SLC26A6, caused membrane hyperpolarization, which was abolished in Slc26a6(-/-) ducts. In conclusion, we have demonstrated that deletion of Slc26a6 alters the apparent stoichiometry of apical Cl(-)/HCO(3)(-) exchange in native pancreatic duct. Our results are consistent with SLC26A6 mediating 1:2 Cl(-)/HCO(3)(-) exchange, and the exchanger upregulated in its absence, most probably SLC26A3, mediating 2:1 exchange.

Influence of bicarbonate/low-GDP peritoneal dialysis fluid (BicaVera) on in vitro and ex vivo epithelial-to-mesenchymal transition of mesothelial cells.

BACKGROUND: Peritoneal membrane damage induced by peritoneal dialysis (PD) is largely associated with epithelial-to-mesenchymal transition (EMT) of mesothelial cells (MCs), which is believed to be a result mainly of the glucose degradation products (GDPs) present in PD solutions. OBJECTIVES: This study investigated the impact of bicarbonate-buffered, low-GDP PD solution (BicaVera: Fresenius Medical Care, Bad Homburg, Germany) on EMT of MCs in vitro and ex vivo. IN VITRO STUDIES: Omentum-derived MCs were incubated with lactate-buffered standard PD fluid or BicaVera fluid diluted 1:1 with culture medium. Ex vivo studies: From 31 patients randomly distributed to either standard or BicaVera solution and followed for 24 months, effluents were collected every 6 months for determination of EMT markers in effluent MCs. RESULTS: Culturing of MCs with standard fluid in vitro resulted in morphology change to a non-epithelioid shape, with downregulation of E-cadherin (indicative of EMT) and strong induction of vascular endothelial growth factor (VEGF) expression. By contrast, in vitro exposure of MCs to bicarbonate/low-GDP solution had less impact on both EMT parameters. Ex vivo studies partially confirmed the foregoing results. The BicaVera group, with a higher prevalence of the non-epithelioid MC phenotype at baseline (for unknown reasons), showed a clear and significant trend to gain and maintain an epithelioid phenotype at medium- and longer-term and to show fewer fibrogenic characteristics. By contrast, the standard solution group demonstrated a progressive and significantly higher presence of the non-epithelioid phenotype. Compared with effluent MCs having an epithelioid phenotype, MCs with non-epithelioid morphology showed significantly lower levels of E-cadherin and greater levels of fibronectin and VEGF. In comparing the BicaVera and standard solution groups, MCs from the standard solution group showed significantly higher secretion of interleukin 8 and lower secretion of collagen I, but no differences in the levels of other EMT-associated molecules, including fibronectin, VEGF, E-cadherin, and transforming growth factor ß1. Peritonitis incidence was similar in both groups. Functionally, the use of BicaVera fluid was associated with higher transport of small molecules and lower ultrafiltration capacity. CONCLUSIONS: Effluent MCs grown ex vivo from patients treated with bicarbonate/low-GDP BicaVera fluid showed a trend to acquire an epithelial phenotype, with lower production of proinflammatory cytokines and chemokines (such as interleukin 8) than was seen with MCs from patients treated with a lactate-buffered standard PD solution.

Calcium mass balances during standard bicarbonate hemodialysis and long-hour slow-flow bicarbonate hemodialysis.

BACKGROUND: Dialysate calcium (Ca) concentration should be viewed as part of the integrated therapeutic regimen to control renal osteodystrophy and maintain normal mineral metabolism. Thus, a correct ionized calcium mass balance (Ca++MB) during hemodialysis (HD) is crucial in the treatment of renal osteodystrophy. The GENIUS single-pass batch dialysis system (Fresenius Medical Care, Germany) consists of a closed dialysate tank of 90 L; it offers the opportunity of effecting mass balances of any solute in a very precise way. METHODS: The present study has a crossover design: 11 stable anuric HD patients underwent 2 bicarbonate HD sessions, 1 of 4 hours (4h) and the other of 8 hours (8h) in a random sequence, always at the same interdialytic interval, at least 1 week apart. The GENIUS system and high-flux FX80 dialyzers (Fresenius Medical Care, Germany) were used. The volume of blood and dialysate processed, volume of ultrafiltration and dialysate Ca concentrations (1.50 mmol/L) were prescribed to be the same. Trends of plasma Ca++, blood pH and bicarbonates during dialysis, as well as Ca++MBs were determined. Plasma parathyroid hormone (PTH) levels at the start and end of the 2 treatments were measured. RESULTS: Ca++MBs (mean ± SD) were +284.6 ± 137.4 mg and +297.7 ± 131.6 mg (p=0.307) in the 4h and 8h treatments, respectively. No single session out of the 22 had a negative Ca++MB for the patient. Mean plasma Ca++, blood pH and bicarbonate levels were not statistically significantly different when comparing the start and end of the sessions of the 2 treatments. Mean plasma Ca++, blood pH and bicarbonate levels increased significantly along the time points in both 4h and 8h HD sessions (repeated measures ANOVA: p<0.0001). Mean plasma PTH levels were not statistically significantly different when comparing the start and end of the sessions of the 2 treatments. The differences between predialysis and postdialysis plasma PTH levels were not statistically significantly different either in 4h or 8h sessions (Wilcoxon's test: p=NS), even though a trend toward lower postdialysis plasma PTH levels was observed in both 4h and 8h treatments. CONCLUSIONS: Our data show incontrovertibly that, when dialyzing with a dialysate Ca concentration of 1.50 mmol/L, 4h standard bicarbonate HD and 8h slow-flow bicarbonate HD always achieve a quite similar positive Ca++MB for the patients.

Bicarbonate transport by the human pancreatic ductal cell line HPAF.

OBJECTIVES: The human pancreatic duct cell line, HPAF, has been shown previously to secrete Cl(-) in response to Ca(2+)-mobilizing stimuli. Our aim was to assess the capacity of HPAF cells to transport and secrete HCO3(-). METHODS: HPAF cells were grown as confluent monolayers on permeable supports. Short-circuit current was measured by voltage clamp. Intracellular pH (pHi) was measured by microfluorometry in cells loaded with 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF). RESULTS: In HCO3(-)-free solutions, ATP-evoked changes in short-circuit current were inhibited by bumetanide, and the recovery of pHi from acid loading was abolished by 5-(N-ethyl-N-isopropyl)-amiloride (EIPA). In the presence of HCO3(-), ATP-evoked secretion was no longer inhibited by bumetanide, and there was a strong EIPA-insensitive recovery from acid loading, which was inhibited by 4,4'-diisothiocyanatodihydrostilbene-2,2'-disulfonate (H2DIDS). ATP, but not forskolin, stimulated HCO3(-) efflux from the cells. CONCLUSIONS: In the absence of HCO3(-), ATP-evoked Cl(-) secretion is driven by a basolateral Na(+)-K(+)-2Cl(-) cotransporter, and pH(i) is regulated by apical and basolateral Na(+)/H(+) exchangers. In the presence of HCO3(-), ATP-evoked secretion is sustained in the absence of Na(+)-K(+)-2Cl(-) cotransporter activity and is probably driven by basolateral Na(+)-HCO3(-) cotransport.

Ability of sat-1 to transport sulfate, bicarbonate, or oxalate under physiological conditions.

Tubular reabsorption of sulfate is achieved by the sodium-dependent sulfate transporter, NaSi-1, located at the apical membrane, and the sulfate-anion exchanger, sat-1, located at the basolateral membrane. To delineate the physiological role of rat sat-1, [(35)S]sulfate and [(14)C]oxalate uptake into sat-1-expressing oocytes was determined under various experimental conditions. Influx of [(35)S]sulfate was inhibited by bicarbonate, thiosulfate, sulfite, and oxalate, but not by sulfamate and sulfide, in a competitive manner with K(i) values of 2.7 +/- 1.3 mM, 101.7 +/- 9.7 microM, 53.8 +/- 10.9 microM, and 63.5 +/- 38.7 microM, respectively. Vice versa, [(14)C]oxalate uptake was inhibited by sulfate with a K(i) of 85.9 +/- 9.5 microM. The competitive type of inhibition indicates that these compounds are most likely substrates of sat-1. Physiological plasma bicarbonate concentrations (25 mM) reduced sulfate and oxalate uptake by more than 75%. Simultaneous application of sulfate, bicarbonate, and oxalate abolished sulfate as well as oxalate uptake. These data and electrophysiological studies using a two-electrode voltage-clamp device provide evidence that sat-1 preferentially works as an electroneutral sulfate-bicarbonate or oxalate-bicarbonate exchanger. In kidney proximal tubule cells, sat-1 likely completes sulfate reabsorption from the ultrafiltrate across the basolateral membrane in exchange for bicarbonate. In hepatocytes, oxalate extrusion is most probably mediated either by an exchange for sulfate or bicarbonate.

Cl- is required for HCO3- entry necessary for sperm capacitation in guinea pig: involvement of a Cl-/HCO3- exchanger (SLC26A3) and CFTR.

Our previous study demonstrated the involvement of cystic fibrosis transmembrane conductance regulator (CFTR) in transporting bicarbonate that is necessary for sperm capacitation; however, whether its involvement is direct or indirect remains unclear. The present study investigated the possibility of a Cl-/HCO3- exchanger (solute carrier family 26, number 3 [SLC26A3]) operating with CFTR during guinea pig sperm capacitation. Incubating sperm in media with various concentrations of Cl- resulted in varied percentages of capacitated sperm in a concentration-dependent manner. Depletion of Cl-, even in the presence of HCO3-, abolished sperm capacitation and vice versa, indicating the involvement of both anions in the process. Capacitation-associated HCO3--dependent events, including increased intracellular pH, cAMP production, and protein tyrosine phosphorylation, also depend on Cl- concentrations. Similar Cl- dependence and inhibitor sensitivity were observed for sperm-hyperactivated motility and for sperm-egg fusion. The expression and localization of CFTR and SLC26A3 were demonstrated using immunostaining and Western blot analysis. Taken together, our results indicate that Cl- is required for the entry of HCO3- that is necessary for sperm capacitation, implicating the involvement of SLC26A3 in transporting HCO3-, with CFTR providing the recycling pathway for Cl-.

Comparison between bicarbonate/lactate and standard lactate dialysis solution in peritoneal transport and ultrafiltration: a prospective, crossover single-dwell study.

OBJECTIVE: It has been proposed that biocompatible bicarbonate/lactate based (Bic/Lac), physiologic-pH peritoneal dialysis (PD) solutions will be beneficial in long-term PD. However, we do not yet have detailed knowledge concerning the comparative physiology of buffer transport for these new solutions and their impact on underlying peritoneal transport of solutes and ultrafiltration (UF). The purpose of this study was to investigate the profile of buffer handling and peritoneal membrane transport characteristics during a single dwell of the new Bic/Lac-based versus standard lactate-based (Lac) PD solution. METHODS: In this prospective crossover study, we compared a 25 mmol/L bicarbonate/15 mmol/L lactate buffered, physiologic pH, low glucose degradation product (GDP) solution (Physioneal; Baxter Healthcare, McGaw Park, Illinois, USA) with a standard lactate buffered, acidic pH, conventional solution (Dianeal; Baxter). 18 patients underwent two peritoneal equilibration tests (PETs) with 2.5% Dianeal and 2.5% Physioneal separated by 1 week. Buffer transport, mass transfer area coefficients (MTACs), solute transport, and UF were determined for the two PETs. All bags were weighed by a nurse before instillation and after drainage to assess the net UF in each dwell. RESULTS: 18 patients that met the inclusion criteria were enrolled in this study. Whereas intraperitoneal pH remained constant at 7.52 +/- 0.11 throughout the dwell with the Bic/Lac solution, pH was still in the acidic range with the Lac solution after 1 hour (7.29 +/- 0.13, p < 0.001); this difference disappeared after the second hour of dwell. The MTACs for creatinine (10.68 +/- 3.66 vs 10.73 +/- 2.96 mL/minute/1.73 m(2), p > 0.05) and urea (27.94 +/- 10.50 vs 27.62 +/- 6.95 mL/min/1.73 m(2), p > 0.05), for Bic/Lac versus Lac respectively, did not differ between these two solutions; transport of glucose and other solutes was also similar. However, after a 4-hour dwell with Bic/Lac solution, net UF was significantly lower than that observed with Lac solution (274.2 +/- 223.3 mL vs 366.1 +/- 217.3 mL, p = 0.026). CONCLUSIONS: Compared to standard Lac-based solution, Bic/Lac based, pH neutral, low-GDP solution avoids intraperitoneal acidity. Peritoneal mass transport kinetics are similar for small solutes. Net UF is significantly lower with Bic/Lac solution; the mechanism for this is unclear.

Efecto de un incremento en la diuresis sobre la absorción y retención de algunos nutrientes en ratas / Effect of an increase in diuresis on absorption and retention of some nutrients in rats

Estudios previos en ratas han demostrado que la administración del diurético furosemida aumenta la pérdida urinaria de electrolitos y nutrientes, causando un efecto negativo sobre las reservas de los mismos. Una alternativa para proteger esas reservas es incrementar la absorción intestinal. Así, se evaluó la absorción, pérdidas urinarias y reservas corporales de nitrógeno, calcio, magnesio, sodio, potasio y cinc, en cuatro grupos de ratas: control, y tres grupos experimentales que consumieron furosemida en concentraciones de 0,5; 1,0 y 1,5 mg/g de dieta, durante 23 días. El diurético causó poliuria dosis dependiente, disminución en el consumo de alimento, la eficiencia y el crecimiento. También, provocó un aumento en las pérdidas urinarias del nitrógeno y minerales. La absorción de nitrógeno, calcio y cinc no se modificó, mientras que la del magnesio, sodio y potasio aumentó ligeramente. Se determinó que la absorción no compensó las pérdidas urinarias. Así, la furosemida afectó negativamente la retención de nutrientes y electrolitos, provocando una reducción en las reservas corporales de los mismos. Este diurético tiene un efecto negativo sobre el estado nutricional en ratas, causado por la reducción en el consumo de alimento, así como en la utilización de los nutrientes consumidos. La reducción en la utilización de los nutrientes asociada con este diurético, puede ser explicada en parte, por una pobre retención de nutrientes por el riñón, que no puede ser compensada por un incremento en la absorción intestinal.

Previous studies have shown that, in rats, the administration of the diuretic furosemide increases diuresis as well as urinary loss of electrolytes and essential nutrients. This loss has a negative effect on electrolytes and nutrient reserves. Since one alternative to help protect these reserves is to increase intestinal absorption, the purpose of this study was to evaluate the absorption, urinary loss and tissue reserves of nitrogen, calcium, magnesium, sodium, potassium and zinc in rats offered 0, 0.5, 1.0 and 1.5 mg furosemide per g diet, daily during 23 days. The diuretic caused a dose dependent polyuria, a reduction in food intake, growth and feed efficiency. In addition, those rats had increased urinary loss of nitrogen and minerals. Nitrogen, calcium and zinc absorption were not affected, but magnesium, sodium and potassium increased slightly. Intestinal absorption could not compensate for urinary loss. In general, this study showed that in rats, this diuretic had a negative effect on nutritional status caused by a reduction in food intake and also in the utilization of the nutrients consumed. The reduction in nutrient utilization associated with this diuretic may be partly explained by a poor nutrient retention by the kidney which was not compensated by an increase in intestinal absorption.

Transport of acetate and sodium in sheep omasum: mutual, but asymmetric interactions.

We have studied the transport of acetate across the isolated epithelium of sheep omasum; no net transport was observed (J(ms) approximately = J(sm)) under Ussing chamber conditions. Low mucosal pH (pH 6.4) significantly enhanced J(ms) acetate and the transport rates of acetate increased linearly and significantly (r2=0.99) with the luminal acetate concentration. The presence of another short chain fatty acid (propionate) did not affect J(ms) acetate significantly. Neither addition of 1 mmol l(-1) DIDS to the mucosal side nor HCO3 replacement caused changes of J(ms) acetate; this does not support the assumption of acetate transport via anion exchange. Addition of 1 mmol l(-1) amiloride to the mucosal side significantly decreased acetate fluxes at high mucosal acetate concentration (100 mmol l(-1)) and low pH (6.4) indicating interaction between acetate uptake in the undissociated form, intracellular release of protons and activation of Na+/H+ exchange (NHE). However, the mutual interaction between Na transport via NHE and acetate transport is asymmetric. Stimulation or inhibition of Na transport via NHE is much more pronounced than the corresponding changes of acetate fluxes. Thus, the obtained results support the conclusion that acetate is transported via simple diffusion and probably predominantly in the protonated form, thereby explaining the positive and mutual interaction between Na transport and short chain fatty acids.

Axial flow modulates proximal tubule NHE3 and H-ATPase activities by changing microvillus bending moments.

We have previously demonstrated that mouse proximal tubules in vitro respond to changes in luminal flow with proportional changes in Na+ absorption (Du Z, Duan Y, Yan Q, Weinstein AM, Weinbaum S, and Wang T. Proc Natl Acad Sci USA 101: 13068-13073, 2004). It was hypothesized that brush-border microvilli function as a sensor to detect and amplify luminal hydrodynamic forces and transmit them to the actin cytoskeleton. In the present study we examine whether 1) flow-dependent HCO3- transport is proportional to flow-dependent variations in microvillous torque (bending moment); 2) both luminal membrane Na(+)/H+ exchange (NHE3) and H(+)-ATPase activity are modulated by axial flow; and 3) paracellular permeabilities contribute to the flux perturbations. HCO3- absorption is examined by microperfusion of mouse S2 proximal tubules in vitro, with varying perfusion rates, and in the presence of the Na/H-exchange inhibitor EIPA, the H(+)-ATPase inhibitor bafilomycin, and the actin cytoskeleton inhibitor cytochalasin D. Paracellular permeability changes are assessed with measurements of epithelial HCO3- permeability and transepithelial potential difference (PD). It is found that 1) an increase in perfusion rate enhances HCO3- absorption and microvillous torque, and the fractional changes of each are nearly identical; 2) inhibition of NHE3 by EIPA, or H(+)-ATPase by bafilomycin, produced only partial inhibition of flow-stimulated bicarbonate transport; 3) disruption of the actin cytoskeleton by cytochalasin D blocked the increment of HCO3- absorption by high flow; and 4) HCO3- permeability and transepithelial PD are not modulated by flow. We conclude that flow-dependent modulation of proximal tubule HCO3- reabsorption is due to changes in both NHE3 and H(+)-ATPase activity within the luminal cell membrane and this requires an intact actin cytoskeleton. Paracellular permeability changes do not contribute to this flow dependence. Perfusion-absorption balance in the proximal tubule is a direct effect of flow-induced torque on brush-border microvilli to regulate luminal cell membrane transporter activity.