Pathophysiology of Diet-Induced Acid Stress.

Diets can influence the body's acid-base status because specific food components yield acids, bases, or neither when metabolized. Animal-sourced foods yield acids and plant-sourced food, particularly fruits and vegetables, generally yield bases when metabolized. Modern diets proportionately contain more animal-sourced than plant-sourced foods, are, thereby, generally net acid-producing, and so constitute an ongoing acid challenge. Acid accumulation severe enough to reduce serum bicarbonate concentration, i.e., manifesting as chronic metabolic acidosis, the most extreme end of the continuum of "acid stress", harms bones and muscles and appears to enhance the progression of chronic kidney disease (CKD). Progressive acid accumulation that does not achieve the threshold amount necessary to cause chronic metabolic acidosis also appears to have deleterious effects. Specifically, identifiable acid retention without reduced serum bicarbonate concentration, which, in this review, we will call "covert acidosis", appears to cause kidney injury and exacerbate CKD progression. Furthermore, the chronic engagement of mechanisms to mitigate the ongoing acid challenge of modern diets also appears to threaten health, including kidney health. This review describes the full continuum of "acid stress" to which modern diets contribute and the mechanisms by which acid stress challenges health. Ongoing research will develop clinically useful tools to identify stages of acid stress earlier than metabolic acidosis and determine if dietary acid reduction lowers or eliminates the threats to health that these diets appear to cause.

Sensitizing methicillin-resistant Staphylococcus aureus (MRSA) to cefuroxime: the synergic effect of bicarbonate and the wall teichoic acid inhibitor ticlopidine.

Methicillin-resistant Staphylococcus aureus (MRSA) strains are a major challenge for clinicians due, in part, to their resistance to most ß-lactams, the first-line treatment for methicillin-susceptible S. aureus. A phenotype termed "NaHCO3-responsiveness" has been identified, wherein many clinical MRSA isolates are rendered susceptible to standard-of-care ß-lactams in the presence of physiologically relevant concentrations of NaHCO3, in vitro and ex vivo; moreover, such "NaHCO3-responsive" isolates can be effectively cleared by ß-lactams from target tissues in experimental infective endocarditis (IE). One mechanistic impact of NaHCO3 exposure on NaHCO3-responsive MRSA is to repress WTA synthesis. This NaHCO3 effect mimics the phenotype of tarO-deficient MRSA, including sensitization to the PBP2-targeting ß-lactam, cefuroxime (CFX). Herein, we further investigated the impacts of NaHCO3 exposure on CFX susceptibility in the presence and absence of a WTA synthesis inhibitor, ticlopidine (TCP), in a collection of clinical MRSA isolates from skin and soft tissue infections (SSTI) and bloodstream infections (BSI). NaHCO3 and/or TCP enhanced susceptibility to CFX in vitro, by both minimum inhibitor concentration (MIC) and time-kill assays, as well as in an ex vivo simulated endocarditis vegetations (SEV) model, in NaHCO3-responsive MRSA. Furthermore, in experimental IE (presumably in the presence of endogenous NaHCO3), pre-exposure to TCP prior to infection sensitized the NaHCO3-responsive MRSA strain (but not the non-responsive strain) to enhanced clearances by CFX in target tissues. These data support the notion that NaHCO3 is acting similarly to WTA synthesis inhibitors, and that such inhibitors have potential translational applications in the treatment of certain MRSA strains in conjunction with specific ß-lactam agents.

Drug-free and multifunctional sodium bicarbonate/hyaluronic acid hybrid dressing for synergistic healing of infected wounds.

Skin wounds are susceptible to microbial infections which commonly lead to the delayed wound healing. Rapid clearance of pathogens from the wound is of great significance and importance for efficient healing of the infected wounds. Herein, we report a multifunctional hybrid dressing, which simply combines sodium bicarbonate (NaHCO3) and hyaluronic acid (HA) for the synergistic wound healing. Addition of NaHCO3 allows the hybrid dressing to have the great antibacterial and antioxidant activity, while maintaining the intrinsic skin repair function of HA. As a result, NaHCO3/HA hybrid dressing showed the great antibacterial activity against both Gram-positive (S. aureus) and Gram-negative (E. coli) pathogens, the ability to improve the fibroblasts proliferation and migration, the cell-protection capacity under H2O2-induced oxidative stress, and most importantly, the great healing efficacy for the mice wound infected by S. aureus. We further found that the epidermal regeneration, the collagen deposition and the angiogenesis were enhanced by NaHCO3/HA hybrid dressing. All these effects were NaHCO3 concentration-dependent. Since the NaHCO3/HA hybrid dressing is drug-free, easily fabricated, biocompatible, and efficient for wound healing, it may have great potentials for clinical management of infected wounds.

Effects of bathing in different hot spring types on Japanese gut microbiota.

Hot springs have been used for a variety of purposes, including the treatment and amelioration of illness and recreation. Japan has ten different types of therapeutic springs (described here as spa types), which are traditionally believed to have different efficacy. However, more research must be conducted to determine how they affect healthy people. Therefore, this study focused on the gut microbiota and aimed to investigate changes in the gut microbiota in healthy people after bathing in different spa types. Using Beppu's hot springs (simple, chloride, bicarbonate, sulfur, and sulfate types), 136 healthy Japanese adults living in the Kyushu area participated in the study and bathed in the same hot spring for seven days. Fecal samples were collected before and after the 7-day bathing period, and the relative abundance of the gut microbiota was determined by 16S rRNA sequencing. The results showed that the relative abundance of Bifidobacterium bifidum increased significantly after seven consecutive days of bathing in the bicarbonate spring. Significant increases in other gut microbiota were also observed after bathing in simple, bicarbonate, and sulfur springs. These results suggest that bathing in different hot springs may affect the gut microbiota in healthy individuals differently.

Bicarbonate and BSA increase the capacitation pattern and acrosomal exocytosis in boar sperm after 120 min of incubation.

Sperm capacitation is a crucial step towards the acquisition of fertilizing capacity. Despite the attempts to mimic the in vivo situation, there is still a lack of standardization in vitro techniques. Bicarbonate and serum albumin (BSA) are routinely used, although controversial results are reported regarding the optimal concentration of each compound. In addition, whether caffeine is needed on in vitro capacitation media in boar sperm remains to be elucidated. Here, 18 boar commercial artificial insemination doses were used to test different concentrations of bicarbonate (19, 37 or 56 mM) in experiment 1, BSA (1.5, 3, 4.5 mg/mL) in experiment 2 and the presence or absence of caffeine (5.15 mM) experiment 3. We analysed at 0, 30 and 120 min of incubation at 38.5°C, 5% CO2 : Total motility (TMOT), membrane integrity (VIAB), acrosomal exocytosis (rAcro; H33342/PI/PNA), capacitation status (chlortetracycline staining CTC) and mitochondrial membrane potential (JC-1). The higher concentrations of bicarbonate (37 and 56 mM) decreased TM and VIAB (p < .01) but increased rAcro (p < .01) after 120 min of incubation compared to the fresh control. In contrast, only the BSA concentration of 3 mg/mL reduced the VIAB at 120 min, but all the concentrations tested increased the average of JC-1 and decreased TM (p < .01) throughout incubation compared to the fresh control. Finally, in experiment 3, when boar sperm were incubated in the capacitating media with bicarbonate, BSA and with or without caffeine, the capacitated pattern measured by the CTC technique and rAcro increased after 120 min of incubation (p < .01) compared to fresh control, either in the presence or in the absence of caffeine. In summary, our results suggested that the combination of capacitating components, like bicarbonate and BSA, contributed to increasing the proportion of capacitated boar spermatozoa, mitochondrial membrane potential as well as acrosomal exocytosis. However, caffeine did not significantly influence in vitro sperm capacitation in this species.

Blood Pressure Stability and Plasma Aldosterone Reduction: The Effects of a Sodium and Bicarbonate-Rich Water - A Randomized Controlled Intervention Study.

Objective: Hypertension is a recognized risk factor for cardiovascular disease (CVD), and dietary sodium intake has been linked to its development. However, mineral water high in bicarbonate and sodium does not appear to have adverse effects on blood pressure.This study examines the effects of consuming a mineral water high in bicarbonate and sodium (HBS) compared to a low bicarbonate and sodium (LBS) mineral water on blood pressure and related factors.Methods: A randomized controlled intervention was conducted with 94 healthy participants, consuming 1,500 - 2,000 mL daily of either mineral water high in bicarbonate and sodium (HBS water, n = 49) or low in bicarbonate and sodium (LBS water, n = 45). Blood pressure, anthropometrics, and urinary calcium and sodium excretion were assessed at baseline and after 28 days. 3-day food protocols were assessed to evaluate possible dietary changes.Results: Blood pressure changes did not differ between the groups. Both normotensive and hypertensive subjects showed similar changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) in response to the different test waters. Serum aldosterone decreased significantly in both groups, with a greater reduction in the HBS group. Urinary calcium excretion significantly decreased (p = 0.002) and sodium excretion increased in the HBS group. Multiple linear regression analyses indicated no association between urinary sodium excretion and systolic blood pressure increase in the HBS group (B = 0.046, p = 0.170). Changes in urinary sodium excretion did not correlate with changes in serum aldosterone in the same group (r=-0.146, p = 0.350).Conclusions: The study revealed no significant differences in blood pressure changes between individuals consuming HBS water and LBS water. Notably, the additional sodium intake from the test water was effectively excreted.Trial registration: This trial was registered in the German Clinical Trials Register (DRKS00025341, https://drks.de/search/en).

What is the context? High blood pressure is a risk factor for heart diseases, one of the leading causes of illness and death worldwide. Too much sodium in the diet has been linked to the development of high blood pressure. However, some high-sodium mineral waters appear to have a different effect on blood pressure. Researchers have demonstrated that mineral waters high in both sodium and bicarbonate may not have harmful effects on blood pressure.What is the study about? In this study, 94 healthy participants between the ages 30 to 65 were divided into two groups. One group drank high-bicarbonate, high-sodium mineral water, and the other group drank low-bicarbonate, low-sodium mineral water for four weeks. Blood pressure was measured before and at the end of the study. The participants were asked not to change their usual diet and physical activity during the study.What are the results? Blood pressure did not change differently between the two groups. Consumption of high-sodium, high-bicarbonate mineral water increased sodium intake, but sodium was effectively excreted in the urine. Moreover, aldosterone, a blood pressure regulating hormone, decreased with mineral water consumption. Its reduction is good for maintaining stable blood pressure.

Structural mechanism of Escherichia coli cyanase.

Cyanase plays a vital role in the detoxification of cyanate and supplies a continuous nitrogen source for soil microbes by converting cyanate to ammonia and carbon dioxide in a bicarbonate-dependent reaction. The structures of cyanase complexed with dianion inhibitors, in conjunction with biochemical studies, suggest putative binding sites for substrates. However, the substrate-recognition and reaction mechanisms of cyanase remain unclear. Here, crystal structures of cyanase from Escherichia coli were determined in the native form and in complexes with cyanate, bicarbonate and intermediates at 1.5-1.9 Šresolution using synchrotron X-rays and an X-ray free-electron laser. Cyanate and bicarbonate interact with the highly conserved Arg96, Ser122 and Ala123 in the active site. In the presence of a mixture of cyanate and bicarbonate, three different electron densities for intermediates were observed in the cyanase structures. Moreover, the observed electron density could explain the dynamics of the substrate or product. In addition to conformational changes in the substrate-binding pocket, dynamic movement of Leu151 was observed, which functions as a gate for the passage of substrates or products. These findings provide a structural mechanism for the substrate-binding and reaction process of cyanase.

Sperm Capacitation and Kinematics in Phodopus Hamsters.

This study was designed to analyze changes in the spermatozoa of three species of Phodopus hamsters incubated under different conditions. Cauda epididymal sperm were incubated for 4 h in modified Tyrode's medium containing albumin, lactate, pyruvate, and Hepes (mTALP-H), in the same medium with the addition of bicarbonate (mTALP-BH), or with bicarbonate and 20 ng/mL of progesterone (mTALP-BH+P4). Media with bicarbonate are believed to promote capacitation in rodent species. Sperm motility, viability, capacitation patterns, and kinematics were assessed at different times. Capacitation in live cells was quantified after staining with Hoechst 33258 and chlortetracycline. Patterns believed to correspond to non-capacitated cells (F pattern), capacitated, acrosome-intact cells (B pattern), and acrosome-reacted cells (AR pattern) were recognized. Kinematics were examined via computer-assisted sperm analysis (CASA). The results showed a decrease in total motility in all three species in different media, with a sharp decrease in progressive motility in bicarbonate-containing media (without or with progesterone), suggesting hyperactivated motion. However, none of the other signs of hyperactivation described in rodents (i.e., decrease in STR or LIN, together with an increase in ALH) were observed. F pattern cells diminished with time in all media and were generally lower in P. roborovskii and higher in P. campbelli. B pattern cells increased in mTALP-BH media in all species. Progesterone did not enhance the percentage of B pattern cells. Finally, AR pattern cells increased in all species incubated in different media, showing the highest percentage in P. roborovskii and the lowest in P. campbelli. Comparisons between media revealed that there were higher percentages of F pattern cells and lower percentages of B pattern cells over time in medium without bicarbonate (mTALP-H) in comparison to media containing bicarbonate (mTALP-BH; mTALP-BH+P4). Overall, changes consistent with the acquisition of capacitation and development of hyperactivated motility were found; however, further studies are required to better characterize media necessary to support the pathways involved in these processes in Phodopus species.

Trafficking of carbonic anhydrase 12 and bicarbonate transporters by histamine stimulation mediates intracellular acidic scenario in lung cancer cells.

Carbonic anhydrase 12 is considered an oncogenic and acidic microenvironmental factor in cancer cells. To verify the role of histamine signalling as an anti-cancer signal, we determined the roles of CA12 and its associated bicarbonate transporters. In this study, histamine stimulation mediated mislocalization of CA12 in lung cancer cells. Histamine receptor activation-mediated CA12 endocytosis and pH were restored by CaMKII inhibition. CA12-associated AE2 expression was enhanced, whereas NBCn1 expression and its activity were reduced by histamine stimulation. Histamine receptor activation-mediated acidification was induced by internalised CA12 and NBCn1 and, at the same time by increased bicarbonate efflux through enhanced AE2 expression. Inhibition of protein trafficking by bafilomycin restored CA12 and AE2 localisation and diminished cellular acidosis. Thus, we verified that histamine stimulation induced an acidic scenario, which revealed trafficking of CA12 and its associated bicarbonate transporters in lung cancer cells and its dysregulated pH modulation may be involved in the histamine signalling-mediated anti-cancer process.

Boar sperm motility is modulated by CCK at a low concentration of bicarbonate under capacitation conditions.

In a previous study, our group detected the cholecystokinin (CCK) protein in the porcine oviduct. This fact, together with the involvement of CCK in the regulation of sperm protein tyrosine phosphorylation by the modulation of HCO3 - uptake (in mice and humans) suggests a role for CCK during sperm capacitation. Therefore, on the one hand, the expression of CCK receptors (CCK1R and CCK2R) on boar testes has been investigated and probed; on the other hand, boar spermatozoa (from seminal doses of 1-day and 5-day storage) were exposed to different concentrations of CCK (0-control, 25 or 50 µM) in a medium supporting capacitation supplemented with 0, 5 or 25 mmol/L of HCO3 - for 1 h at 38.5°C. Sperm motion (total and progressive motility), kinetic parameters, viability, acrosome status, and mitochondrial activity were determined. No differences between groups (0, 25 or 50 µM of CCK) were observed when HCO3 - was absent in the media (p > .05). However, the results showed that when the media was supplemented with 5 mmol/L HCO3 - in 1-day seminal dose storage, the linearity index (LIN, %), straightness index (STR, %) and oscillation index (WOB, %) (sperm kinetics parameters) increased in the presence of CCK regardless the concentration (p < .05). Nevertheless, CCK in sperm from 5-day storage only increased the WOB parameter in comparison to the control (p < .05). Furthermore, the average amplitude of the lateral displacement of the sperm head (ALH, µm) and curvilinear velocity (VCL, µm/s) decreased when CCK was present, depending on its concentration and sperm aging (1-day vs. 5-days) (p < .05). In the case of the media supporting capacitation supplemented with 25 mmol/L HCO3 - , any differences were observed except for sperm viability in the 5-day seminal doses, which increased in the 50 µM-CCK group compared to the control (p < .05). In conclusion, these data suggest an implication of CCK protein during sperm capacitation under low bicarbonate concentration increasing the sperm linear trajectory.

The 13C-bicarbonate technique as a tool for measurement of energy expenditure in overweight dogs undergoing body weight reduction and the effect of different dietary composition.

Changes in body size and composition, i.e., body weight (BW) gain or loss, affect the daily energy expenditure (EE). To ensure an appropriate BW reduction and to find an efficient strategy to reduce and maintain a target BW, regular evaluations and adjustments of energy allowance are important. This study aimed to provide a detailed knowledge about the possible changes in resting EE using the oral 13C-bicarbonate technique (o13CBT) as a research tool in 16 overweight pet dogs undergoing BW reduction. Dietary composition (i.e., in % of dry matter [DM] being a high protein [33.3], low fat [9.6], and high crude fiber [18.0] diet [LFHFibre], and a high protein [37.9], high fat [52.0], carbohydrate-free diet [HFat]) during 16 wk of energy restriction were evaluated regarding effects on resting EE, rate of BW reduction, body composition, and plasma concentrations of metabolic hormones involved in energy metabolism and appetite regulation. The mean BW loss was higher (P < 0.05) for the dogs fed the LFHFibre diet (1.1%/wk) than that for dogs fed the HFat diet (0.8%/wk), but the total BW reduction of 14.6% and 12.0% of initial BW did not differ significantly (P > 0.05). Resting EE was lower (P < 0.02) after the BW reduction; 414 kJ (99 kcal)/kg BW0.75/d at the start (week 0) and 326 kJ (78 kcal)/kg BW0.75/d at the end (week 16) of the study. The BW reduction in both groups (P > 0.05) consisted of both fat mass (FM) and fat-free mass (FFM). Energy expenditure, calculated in relation to amount of FFM, was not significantly (P > 0.05) affected by BW reduction. Dietary composition did not significantly affect (P > 0.05) plasma concentrations of insulin, leptin, and ghrelin, and no effect (P > 0.05) of BW reduction was observed on hormone concentrations. In conclusion, the o13CBT proved to be a useful research method for studying short-term EE in overweight dogs. Even though all dogs lost BW, most dogs were still overweight at the end of the study. Due to a high individual variation among dogs, a longer experimental period with a larger sample size would be desirable.

The most common nutritional disorder in dogs is overweight, and knowledge about dogs' energy requirement is therefore important to adjust daily feed allowance. Changes in body weight may affect energy expenditure (EE) and, thereby, energy requirement. This study aimed to measure such potential changes under resting conditions in overweight dogs. It was found that the minimally invasive 13C-bicarbonate technique was a useful research method for studies regarding EE during weight loss (WL) in dogs. EE decreased when the dogs lost weight, and energy allowance needed to be reduced to maintain WL. The second objective of this study was to evaluate the effects of feeding diets with different macronutrient compositions on EE, rate of WL, body composition, and plasma concentrations of hormones involved in energy metabolism and appetite regulation. The mean WL rate was slightly higher for dogs fed a diet with high protein, low fat, and high crude fiber contents than those fed a carbohydrate-free diet with a high protein and fat contents. However, diet did not affect the resting EE, measured plasma hormone concentrations, or the total WL at the end of the study.

Mathematical modelling of bicarbonate supplementation and acid-base chemistry in kidney failure patients on hemodialysis.

Acid-base regulation by the kidneys is largely missing in end-stage renal disease patients undergoing hemodialysis (HD). Bicarbonate is added to the dialysis fluid during HD to replenish the buffers in the body and neutralize interdialytic acid accumulation. Predicting HD outcomes with mathematical models can help select the optimal patient-specific dialysate composition, but the kinetics of bicarbonate are difficult to quantify, because of the many factors involved in the regulation of the bicarbonate buffer in bodily fluids. We implemented a mathematical model of dissolved CO2 and bicarbonate transport that describes the changes in acid-base equilibrium induced by HD to assess the kinetics of bicarbonate, dissolved CO2, and other buffers not only in plasma but also in erythrocytes, interstitial fluid, and tissue cells; the model also includes respiratory control over the partial pressures of CO2 and oxygen. Clinical data were used to fit the model and identify missing parameters used in theoretical simulations. Our results demonstrate the feasibility of the model in describing the changes to acid-base homeostasis typical of HD, and highlight the importance of respiratory regulation during HD.

Evaluation of eleven kiwifruit genotypes for bicarbonate tolerance and characterization of two tolerance-contrasting genotypes.

Screening bicarbonate-tolerant genotypes is an environmentally-friendly and long-term effective strategy to cope with bicarbonate-induced chlorosis in fruit crops grown on calcareous soils. We investigated eleven genotypes from four kiwifruit species (Actinidia chinensis, A. macrosperma, A. polygama, and A. valvata) for differences in bicarbonate tolerance. We also characterized the physiological and molecular differences in two contrasting genotypes of this group. In the first experiment, bicarbonate-treated plantlets were irrigated with 3.0 g L-1 CaCO3 and 5.04 g L-1 NaHCO3 in peat and perlite medium culture. Based on principal component analysis, weight-based membership function method and cluster analysis, the tested genotypes were classified into three groups: (1) tolerant, including YX, Av-1, Acd, Ap, Av-2, and QM; (2) moderately tolerant, including Av-3, Am, Av-4, and HWD; and (3) sensitive, including only QH. In the second experiment, QH (bicarbonate-sensitive) and YX (bicarbonate-tolerant) were grown in sand culture with 4.0 g L-1 CaCO3 and 0.84 g L-1 or 1.26 g L-1 NaHCO3. Compared with QH, YX showed a better ability to take up iron (Fe) by roots and to transport Fe from roots to shoots in the bicarbonate treatments, probably due to a better capacity to protect from oxidative damage and to excrete protons, and a differential expression of genes associated with Fe uptake and translocation, including HA8, IRT1, YSL3 and NRAMP3. The results can facilitate identifying potential resources for bicarbonate tolerance and breeding new rootstocks, and contribute to the elucidation of the bicarbonate tolerance mechanisms in the genus Actinidia.

Diet and phytogenic supplementation substantially modulate the salivary proteome in dairy cows.

Phytogenic compounds may influence salivation or salivary properties. However, their effects on the bovine salivary proteome have not been evaluated. We investigated changes in the bovine salivary proteome due to transition from forage to high-concentrate diet, with and without supplementation with a phytogenic feed additive. Eight non-lactating cows were fed forage, then transitioned to a 65% concentrate diet (DM basis) over a week. Cows were control (n = 4, CON) or supplemented with a phytogenic feed additive (n = 4, PHY). Proteomic analysis was conducted using liquid chromatography coupled with mass spectrometry. We identified 1233 proteins; 878 were bovine proteins, 189 corresponded to bacteria, and 166 were plant proteins. Between forage and high-concentrate, 139 proteins were differentially abundant (P < 0.05), with 48 proteins having a log2FC difference > |2|. The salivary proteome reflected shifts in processes involving nutrient utilization, body tissue accretion, and immune response. Between PHY and CON, 195 proteins were differently abundant (P < 0.05), with 37 having a log2FC difference > |2|; 86 proteins were increased by PHY, including proteins involved in smell recognition. Many differentially abundant proteins correlated (r > |0.70|) with salivary bicarbonate, total mucins or pH. Results provide novel insights into the bovine salivary proteome using a non-invasive approach, and the association of specific proteins with major salivary properties influencing rumen homeostasis. SIGNIFICANCE: Phytogenic compounds may stimulate salivation due to their olfactory properties, but their effects on the salivary proteome have not been investigated. We investigated the effect of high-concentrate diets and supplementation with a phytogenic additive on the salivary proteome of cows. We show that analysis of cows' saliva can be a non-invasive approach to detect effects occurring not only in the gut, but also systemically including indications for gut health and immune response. Thus, results provide unique insights into the bovine salivary proteome, and will have a crucial contribution to further understand animal response in terms of nutrient utilization and immune activity due to the change from forage to a high-energy diet. Additionally, our findings reveal changes due to supplementation with a phytogenic feed additive with regard to health and olfactory stimulation. Furthermore, findings suggest an association between salivary proteins and other components like bicarbonate content.

Impact of Acetate versus Citrate Dialysates on Intermediary Metabolism-A Targeted Metabolomics Approach.

Acetate is widely used as a dialysate buffer to avoid the precipitation of bicarbonate salts. However, even at low concentrations that wouldn't surpass the metabolic capacity of the Krebs tricarboxylic acid (TCA) cycle, other metabolic routes are activated, leading to undesirable clinical consequences by poorly understood mechanisms. This study aims to add information that could biologically explain the clinical improvements found in patients using citrate dialysate. A unicentric, cross-over, prospective targeted metabolomics study was designed to analyze the differences between two dialysates, one containing 4 mmol/L of acetate (AD) and the other 1 mmol/L of citrate (CD). Fifteen metabolites were studied to investigate changes induced in the TCA cycle, glycolysis, anaerobic metabolism, ketone bodies, and triglyceride and aminoacidic metabolism. Twenty-one patients completed the study. Citrate increased during the dialysis sessions when CD was used, without surpassing normal values. Other differences found in the next TCA cycle steps showed an increased substrate accumulation when using AD. While lactate decreased, pyruvate remained stable, and ketogenesis was boosted during dialysis. Acetylcarnitine and myo-inositol were reduced during dialysis, while glycerol remained constant. Lastly, glutamate and glutarate decreased due to the inhibition of amino acidic degradation. This study raises new hypotheses that need further investigation to understand better the biochemical processes that dialysis and the different dialysate buffers induce in the patient's metabolism.

Mechanisms of bicarbonate secretion in the equine colon ex vivo.

OBJECTIVE: To examine bicarbonate (HCO3-) secretion ex vivo in the equine large colon to determine any differences between the right dorsal colon (RDC) and right ventral colon (RVC). The effect of phenylbutazone (PBZ) on HCO3- secretion was examined in the RDC. ANIMALS: 14 healthy horses. PROCEDURES: In anesthetized horses (n = 10), segments of mucosa from RDC and RVC were harvested to measure HCO3- secretion ex vivo with the pH Stat method. The effect of PBZ on HCO3- secretion in the RDC was studied in 4 additional horses. RESULTS: Three distinct mechanisms of HCO3- secretion previously described in a murine model were confirmed in the equine colon. The RDC had a greater capacity for electrogenic, Cl--independent HCO3- secretion than the RVC (P = 0.04). In the RDC, all HCO3- secretion was decreased by PBZ (P < 0.02) but was not studied in the RVC because of low baseline secretion. CLINICAL RELEVANCE: Secretion of HCO3- by the RDC could play a pivotal role in equine colon physiology, because intense microbial fermentation in this site could require HCO3- secretion to buffer short-chain fatty acids. Inhibition of this secretion by PBZ could interfere with mucosal buffering and predispose to changes associated with right dorsal colitis.

Neurotensin and xenin stimulates pancreatic exocrine secretion through the peripheral cholinergic nerves in conscious sheep.

The present study aimed to clarify the effects of neurotensin and xenin on pancreatic exocrine secretion in conscious sheep and their mechanism of actions. The animals were equipped with two silastic cannulae in the common bile duct to separately collect pancreatic fluid and bile, and a silastic cannula in the proximal duodenum to continuously return the mixed fluids. NT and xenin were intravenously injected at range of 0.01-3.0 nmol/kg during the phase I of duodenal migrating motor complex. A single intravenous NT injection significantly and dose-dependently increased pancreatic fluid, protein, and bicarbonate outputs. The effect of NT at 1 nmol/kg was completely inhibited by a background intravenous infusion of atropine methyl nitrate at a dose of 10 nmol/kg/min, however, the effect was not altered by a prior injection of the neurotensin receptor subtype (NTR)-1 antagonist SR 48692 at 60 nmol/kg. Moreover, a single intravenous xenin-25 injection significantly and dose-dependently increased pancreatic fluid and protein output, whereas the effect of xenin-25 did not clearly show dose-dependence. The prior SR 48692 injection at 30 nmol/kg did not significantly alter the effects of xenin-25 at 0.3 nmol/kg, while the atropine infusion significantly inhibited the increase in fluid secretion. Under the atropine infusion, xenin-25 at 0.3 nmol/kg did not increase protein and bicarbonate outputs, whereas the inhibitory effect of the atropine was not significant compared to that of the single injection of xenin-25. A single intravenous injection of NTR-2 agonist levocabastine at 0.1-3 nmol/kg did not alter pancreatic exocrine secretion. These results suggest that both NT and xenin-25 effectively stimulates pancreatic exocrine secretion through the peripheral cholinergic system in sheep and that NTR-2 is not involved in the regulation of pancreatic exocrine secretion, however, we did not precisely determine the role of NTR-1 in the actions of both the peptides on pancreatic exocrine secretion.

Vasorelaxant effect of monoterpene carvacrol on isolated human umbilical artery.

Carvacrol (CRV) is the main compound of essential oils extracted primarily from Thymus and Origanum species. Its various biological activities were confirmed: antioxidant, anti-inflammatory, antibacterial, antifungal, anti-tumour, antinematodal, and vasorelaxant action. Although vasodilation mediated by CRV was previously described, the exact mechanism of its action has not yet been established. Hence, the aim of this study was to investigate CRV vasoactivity on human umbilical arteries (HUA) and the different pathways involved in its mechanism of action using the tissue bath methodology. CRV caused a significant decrease in vascular tension of 5-HT-pre-contracted umbilical arteries, with EC50 of 442.13 ± 33.8 µmol/L (mean ± standard error of the mean-SEM). At 300 µmol/L, CRV shifted downward the 5-HT concentration-response curve with a statistical significance of p < 0.001 obtained for the four highest concentrations. At a concentration of 1 mmol/L, CRV completely abolished BaCl2-induced contraction in Ca2+-free Krebs-Ringer bicarbonate solution and the BAY K 8644-induced contraction in Krebs-Ringer bicarbonate solution (p < 0.001). Isopentenyl pyrophosphate, the antagonist of TRPV3 channel, was able to decrease the efficacy of CRV (p < 0.001). The blocking of L-type Ca2+ channels on smooth muscle cells is the most probable mechanism of CRV-induced vasorelaxation. However, the role of TRPV3 channels in CRV-induced vasodilation of HUA cannot be excluded either.

Making Antimicrobial Susceptibility Testing More Physiologically Relevant with Bicarbonate?

Azithromycin is a clinically important drug for treating invasive salmonellosis despite poor activity in laboratory assays for MIC. Addition of the main buffer in blood, bicarbonate, has been proposed for more physiologically relevant and more predictive testing conditions. However, we show here that bicarbonate-triggered lowering of azithromycin MIC is entirely due to alkalization of insufficiently buffered media. In addition, bicarbonate is unlikely to be altering efflux pump activity.

Acute Effects of Sodium Bicarbonate in Children with Congenital Heart Disease with Biventricular Circulation in Non-cardiac Arrest Situations.

Despite the controversy, sodium bicarbonate is a commonly used medication in critically ill patients of all ages. There is a lack of data on the acute impact on hemodynamic parameters, biomarker indicators of cardiac output, and changes in vasoinotropic support after sodium bicarbonate therapy. In our retrospective study on children with biventricular circulation in pediatric cardiac intensive care unit receiving bicarbonate therapy: we analyzed its effects on arterial blood gases, heart rate, blood pressure (BP), central venous pressures (CVP), cerebral and renal near-infrared spectroscopy (NIRS), changes in vasoinotropic and ventilator changes before and after sodium bicarbonate administration. Thirty-one administrations of sodium bicarbonate in 23 patients with congenital heart disease without residual shunts were analyzed. The average age was 15.4 months, weight 7.7 kg, and the average bicarbonate dose was 1 meq/kg. There was an increase in arterial pH from 7.24 to 7.30 (p = 0.14) and bicarbonate changed from 18 to 20 mEq/L (p = 0.23). No clinically significant changes were found in the following parameters: heart rate (141 ± 20.1 to 136 ± 19), systolic BP (84 ± 17 to 86 ± 14 mmHg), diastolic BP (48 ± 12 to 49 ± 12 mmHg), cerebral NIRS (64 ± 12 to 65 ± 12), renal NIRS (80 ± 10 to 81 ± 7), CVP (9 ± 3 to 10 ± 4 mmHg), paCO2 (45 ± 26 to 42 ± 7 mmHg), paO2 (143 ± 78 to 127 ± 59 mmHg), serum lactate (2.2 ± 2.7 to 3.6 ± 3.8 mmol/L), and vasoinotropic score (7.5 ± 5.0 to 7.7 ± 4.7). Outside of a change in serum pH and bicarbonate levels no other significant changes were noted after sodium bicarbonate administration in children with congenital heart disease with fully septated, biventricular circulation. There was no improvement in systemic oxygen delivery.