Alkalosis increases muscle K+ release, but lowers plasma [K+] and delays fatigue during dynamic forearm exercise

Alkalosis enhances human exercise performance, and reduces K⁺ loss in contracting rat muscle. We investigated alkalosis effects on K⁺ regulation, ionic regulation and fatigue during intense exercise in nine untrained volunteers. Concentric finger flexions were conducted at 75% peak work rate (-3 W) until fatigue, under alkalosis (Alk, NaHCO₃, 0.3 g kg⁻¹) and control (Con, CaCO₃) conditions, 1 month apart in a randomised, double-blind, crossover design. Deep antecubital venous (v) and radial arterial (a) blood was drawn at rest, during exercise and recovery, to determine arterio-venous differences for electrolytes, fluid shifts, acid–base and gas exchange. Finger flexion exercise barely perturbed arterial plasma ions and acid–base status, but induced marked arterio-venous changes. Alk elevated [HCO₃⁻] and P^CO2, and lowered [H+] (P < 0.05). Time to fatigue increased substantially during Alk (25 ± 8%, P < 0.05), whilst both [K⁺]_a and [K⁺]_v were reduced (P < 0.01) and [K⁺]_a-v during exercise tended to be greater (P= 0.056, n= 8). Muscle K⁺ efflux at fatigue was greater in Alk (21.2 ± 7.6 µmol min⁻¹, 32 ± 7%, P < 0.05, n= 6), but peak K⁺ uptake rate was elevated during recovery (15 ± 7%, P < 0.05) suggesting increased muscle Na⁺,K^+-ATPase activity. Alk induced greater [Na⁺]_a, [Cl⁻]_v, muscle Cl⁻ influx and muscle lactate concentration ([Lac⁻]) efflux during exercise and recovery (P < 0.05). The lower circulating [K⁺] and greater muscle K⁺ uptake, Na⁺ delivery and Cl⁻ uptake with Alk, are all consistent with preservation of membrane excitability during exercise. This suggests that lesser exercise-induced membrane depolarization may be an important mechanism underlying enhanced exercise performance with Alk. Thus Alk was associated with improved regulation of K⁺, Na⁺, Cl⁻ and Lac⁻.

Induced alkalosis and caffeine supplementation : effects on 2,000-m rowing performance

Introduction: The purpose of this investigation was to determine the effect of ingested caffeine, sodium bicarbonate, and their combination on 2,000-m rowing performance, as well as on induced alkalosis (blood and urine pH and blood bicarbonate concentration [HCO3 -]), blood lactate concentration ([La-]), gastrointestinal symptoms, and rating of perceived exertion (RPE). Methods: In a double-blind, crossover study, 8 well-trained rowers performed 2 baseline tests and 4 × 2,000-m rowing-ergometer tests after ingesting 6 mg/kg caffeine, 0.3 g/kg body mass (BM) sodium bicarbonate, both supplements combined, or a placebo. Capillary blood samples were collected at preingestion, pretest, and posttest time points. Pairwise comparisons were made between protocols, and differences were interpreted in relation to the likelihood of exceeding the smallest-worthwhile- change thresholds for each variable. A likelihood of >75% was considered a substantial change. Results: Caffeine supplementation elicited a substantial improvement in 2,000-m mean power, with mean (± SD) values of 354 ± 67 W vs. placebo with 346 ± 61 W. Pretest [HCO3 -] reached 29.2 ± 2.9 mmol/L with caffeine + bicarbonate and 29.1 ± 1.9 mmol/L with bicarbonate. There were substantial increases in pretest [HCO3 -] and pH and posttest urine pH after bicarbonate and caffeine + bicarbonate supplementation compared with placebo, but unclear performance effects. Conclusions: Rowers' performance in 2,000-m efforts can improve by ~2% with 6 mg/kg BM caffeine supplementation. When caffeine is combined with sodium bicarbonate, gastrointestinal symptoms may prevent performance enhancement, so further investigation of ingestion protocols that minimize side effects is required. ABSTRACT FROM AUTHOR

Effects of acute alkalosis and acidosis on performance

Ingestion of agents that modify blood buffering action may affect high-intensity performance. Here we present a meta-analysis of the effects of acute ingestion of three such agents - sodium bicarbonate, sodium citrate and ammonium chloride - on performance and related physiological variables (blood bicarbonate, pH and lactate). A literature search yielded 59 useable studies with 188 observations of performance effects. To perform the mixed- model meta-analysis, all performance effects were converted into a percentage change in mean power and were weighted using standard errors derived from exact p-values, confidence limits (CLs) or estimated errors of measurement. The fixed effects in the meta-analytic model included the number of performance-test bouts (linear), test duration (log linear), blinding (yes/no), competitive status (athiete/nonathlete) and sex (male/female). Dose expressed as buffering mmoL/kg/body mass (BM) was included as a strictly proportional linear effect interacted with all effects except blinding. Probabilistic inferences were derived with reference to thresholds for small and moderate effects on performance of 0.5% and 1.5%, respectively. Publication bias was reduced by excluding study estimates with a standard error >2.7%. The remaining 38 studies and 137 estimates for sodium bicarbonate produced a possibly mod- erate performance enhancement of 1.7% (90% CL ± 2.0%) with a typical dose of 3.5mmoL/kg/BM (-0.3g/kgIBM) in a single 1-minute sprint, following blinded consumption by male athletes. In the 16 studies and 45 estimates for sodium citrate, a typical dose of l.SmmoL/kgIBM (-0.5gIkgJBM) had an unclear effect on performance of 0.0% (±1.3%), while the five studies and six estimates for ammonium chloride produced a possibly moderate impairment of 1.6% (±1.9%) with a typical dose of 5.5mmoL/kgIBM (-0.3glkg/BM). Study and subject characteristics had the following modifying small effects on the enhancement of performance with sodium bicarbonate: an increase of 0.5% (±0.6%) with a 1 mmoL/kg/BM increase in dose; an increase of 0.6% (±0.4%) with five extra sprint bouts; a reduction of 0.6% (±0.9%) for each 10-fold increase in test duration (e.g. 1-10 minutes); reductions of 1.1% (± 1 .1%) with nonathletes and 0.7% (±1.4%) with females. Unexplained variation in effects between research settings was typically ± 1.2%. The only noteworthy effects involving physiological variables were a small correlation between performance and pre-exercise increase in blood bicarbonate with sodium bi- carbonate ingestion, and a very large correlation between the increase in blood bicarbonate and time between sodium citrate ingestion and exercise. The approximate equal and opposite effects of sodium bicarbonate and am- monium chloride are consistent with direct performance effects of pH, but sodium citrate appears to have some additional metabolic inhibitory effect. Important future research includes studies of sodium citrate ingestion several hours before exercise and quantification of gastrointestinal symptoms with sodium bicarbonate and citrate. Although individual responses may vary, we recommend ingestion of 0.3-0.5 glkg/BM sodium bicarbonate to improve mean power by 1.7% (±2.0%) in high-intensity races of short duration. ABSTRACT FROM AUTHOR

Rising serum sodium levels are associated with a concurrent development of metabolic alkalosis in critically ill patients

PURPOSE Changes in electrolyte homeostasis are important causes of acid-base disorders. While the effects of chloride are well studied, only little is known of the potential contributions of sodium to metabolic acid-base state. Thus, we investigated the effects of intensive care unit (ICU)-acquired hypernatremia on acid-base state. METHODS We included critically ill patients who developed hypernatremia, defined as a serum sodium concentration exceeding 149 mmol/L, after ICU admission in this retrospective study. Data on electrolyte and acid-base state in all included patients were gathered in order to analyze the effects of hypernatremia on metabolic acid-base state by use of the physical-chemical approach. RESULTS A total of 51 patients were included in the study. The time of rising serum sodium and hypernatremia was accompanied by metabolic alkalosis. A transient increase in total base excess (standard base excess from 0.1 to 5.5 mmol/L) paralleled by a transient increase in the base excess due to sodium (base excess sodium from 0.7 to 4.1 mmol/L) could be observed. The other determinants of metabolic acid-base state remained stable. The increase in base excess was accompanied by a slight increase in overall pH (from 7.392 to 7.429, standard base excess from 0.1 to 5.5 mmol/L). CONCLUSIONS Hypernatremia is accompanied by metabolic alkalosis and an increase in pH. Given the high prevalence of hypernatremia, especially in critically ill patients, hypernatremic alkalosis should be part of the differential diagnosis of metabolic acid-base disorders.

Evaporation of free water causes concentrational alkalosis in vitro

BACKGROUND The development of metabolic alkalosis was described recently in patients with hypernatremia. However, the causes for this remain unknown. The current study serves to clarify whether metabolic alkalosis develops in vitro after removal of free water from plasma and whether this can be predicted by a mathematical model. MATERIALS AND METHODS Ten serum samples of healthy humans were dehydrated by 29 % by vacuum centrifugation corresponding to an increase of the contained concentrations by 41 %. Constant partial pressure of carbon dioxide at 40 mmHg was simulated by mathematical correction of pH [pH(40)]. Metabolic acid-base state was assessed by Gilfix' base excess subsets. Changes of acid-base state were predicted by the physical-chemical model according to Watson. RESULTS Evaporation increased serum sodium from 141 (140-142) to 200 (197-203) mmol/L, i.e., severe hypernatremia developed. Acid-base analyses before and after serum concentration showed metabolic alkalosis with alkalemia: pH(40): 7.43 (7.41 to 7.45) vs 7.53 (7.51 to 7.55), p = 0.0051; base excess: 1.9 (0.7 to 3.6) vs 10.0 (8.2 to 11.8), p = 0.0051; base excess of free water: 0.0 (- 0.2 to 0.3) vs 17.7 (16.8 to 18.6), p = 0.0051. The acidifying effects of evaporation, including hyperalbuminemic acidosis, were beneath the alkalinizing ones. Measured and predicted acid-base changes due to serum evaporation agreed well. CONCLUSIONS Evaporation of water from serum causes concentrational alkalosis in vitro, with good agreement between measured and predicted acid-base values. At least part of the metabolic alkalosis accompanying hypernatremia is independent of renal function.

Clinical presentation of metabolic alkalosis in an adult patient with cystic fibrosis

In subtropical and tropical climates, dehydration is common in cystic fibrosis patients with respiratory exacerbations. This may lead to a clinical presentation of metabolic alkalosis with associated hyponatraemia and hypochloraemia. An adult cystic fibrosis patient who presented with a severe respiratory exacerbation accompanied by metabolic alkalosis is presented and the effects of volume correction are reported.

Effect of magnesium depletion and potassium and chlorothiazide on intracellular pH in the rat, studied by 31P NMR

1. Both dietary magnesium depletion and potassium depletion (confirmed by tissue analysis) were induced in rats which were then compared with rats treated with chlorothiazide (250 mg/kg diet) and rats on a control synthetic diet. 2. Brain and muscle intracellular pH was measured by using a surface coil and [31P]-NMR to measure the chemical shift of inorganic phosphate. pH was also measured in isolated perfused hearts from control and magnesium-deficient rats. Intracellular magnesium status was assessed by measuring the chemical shift of β-ATP in brain. 3. There was no evidence for magnesium deficiency in the chlorothiazide-treated rats on tissue analysis or on chemical shift of β-ATP in brain. Both magnesium and potassium deficiency, but not chlorothiazide treatment, were associated with an extracellular alkalosis. 4. Magnesium deficiency led to an intracellular alkalosis in brain, muscle and heart. Chlorothiazide treatment led to an alkalosis in brain. Potassium deficiency was associated with a normal intracellular pH in brain and muscle. 5. Magnesium depletion and chlorothiazide treatment produce intracellular alkalosis by unknown mechanism(s).

Long-term outcome and extraintestinal manifestations in congenital chloride diarrhea

The rare autosomal recessive disease congenital chloride diarrhea (CLD) is caused by mutations in the solute carrier family 26 member 3 (SLC26A3) gene on chromosome 7q22.3-31.1. SLC26A3 encodes for an apical epithelial chloride-bicarbonate exchanger, the intestinal loss of which leads to profuse chloride-rich diarrhea, and a tendency to hypochloremic and hypokalemic metabolic alkalosis. Although untreated CLD is usually lethal in early infancy, the development of salt substitution therapy with NaCl and KCl in the late 1960s made the disease treatable. While the salt substitution allows normal childhood growth and development in CLD, data on long-term outcome have remained unclarified. One of the world s highest incidences of CLD 1:30 000 to 1:40 000 occurs in Finland, and CLD is part of the Finnish disease heritage. We utilized a unique sample of Finnish patients to characterize the long-term outcome of CLD. Another purpose of this study was to search for novel manifestations of CLD based on the extraintestinal expression of the SLC26A3 gene. This study on a sample of 36 patients (ages 10-38) shows that the long-term outcome of treated CLD is favorable. In untreated or poorly treated cases, however, chronic contraction and metabolic imbalance may lead to renal injury and even to renal transplantation. Our results demonstrate a low-level expression of SLC26A3 in the human kidney. Although SLC26A3 may play a minor role in homeostasis, post-transplant recurrence of renal changes shows the unlikelihood of direct transporter modulation in the pathogenesis of CLD-related renal injury. Options to resolve the diarrheal symptoms of CLD have been limited. Unfortunately, our pilot trial indicated the inefficacy of oral butyrate as well. This study reveals novel manifestations of CLD. These include an increased risk for hyperuricemia, inguinal hernias, and probably for intestinal inflammation. The most notable finding of this study is CLD-associated male subfertility. This involves a low concentration of poorly motile spermatozoa with abnormal morphology, high seminal plasma chloride with a low pH, and a tendency to form spermatoceles. That SLC26A3 immunoexpression appeared at multiple sites of the male reproductive tract in part together with the main interacting proteins cystic fibrosis transmembrane conductance regulator (CFTR) and sodium-hydrogen exchanger 3 (NHE3) suggests novel sites for the cooperation of these proteins. As evidence of the cooperation, defects occurring in any of these transporters are associated with reduced male fertility. Together with a finding of high sweat chloride in CLD, this study provides novel data on extraintestinal actions of the SLC26A3 gene both in the male reproductive tract and in the sweat gland. These results provide the basis for future studies regarding the role of SLC26A3 in different tissues, especially in the male reproductive tract. Fortunately, normal spermatogenesis in CLD is likely to make artificial reproductive technologies to treat infertility and even make unassisted reproduction possible.

Genetics of Type III Bartter Syndrome in Spain, Proposed Diagnostic Algorithm

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Biological impacts of enhanced alkalinity in Carcinus maenas

Further steps are needed to establish feasible alleviation strategies that are able to reduce the impacts of ocean acidification, whilst ensuring minimal biological side-effects in the process. Whilst there is a growing body of literature on the biological impacts of many other carbon dioxide reduction techniques, seemingly little is known about enhanced alkalinity. For this reason, we investigated the potential physiological impacts of using chemical sequestration as an alleviation strategy. In a controlled experiment, Carcinus maenas were acutely exposed to concentrations of Ca(OH)2 that would be required to reverse the decline in ocean surface pH and return it to pre-industrial levels. Acute exposure significantly affected all individuals' acid-base balance resulting in slight respiratory alkalosis and hyperkalemia, which was strongest in mature females. Although the trigger for both of these responses is currently unclear, this study has shown that alkalinity addition does alter acid-base balance in this comparatively robust crustacean species.

Perfil acido-base de pacientes con cirrosis descompensada por hemorragia digestiva alta en el departamento de emergencias: serie de casos

Introducción: La hemorragia digestiva (HVDA) es la principal causa de descompensación en pacientes con cirrosis. Caracterizar el estado ácido-base de estos pacientes sería útil para reflejar la severidad del sangrado e identificar pacientes con alto riesgo de complicación. Objetivo: Describir el estado ácido-base de los pacientes que consultaron a urgencias con cirrosis descompensada por HVDA y posteriormente fueron manejados en la unidad de cuidado intensivo (UCI) o fallecieron. Métodos: Se realizó el análisis del estado ácido-base a 10 pacientes con estas características, utilizando tres métodos distintos. Resultados: El perfil ácido-base encontrado fue: acidosis metabólica por iones no medidos, acidosis láctica, alcalosis por hipoalbuminemia y anión gap elevado en la mayoría de pacientes. Conclusiones: La teoría de Henderson-Hasselbach no fue suficiente para identificar pacientes con alto riesgo, debería implementarse concomitantemente el análisis anión gap, base déficit y el método físico–químico, para entender los fenómenos acido base de estos pacientes.

DESCRIPCIÓN DEL ESTADO ÁCIDO BASE POR MODELO DE STEWART EN PACIENTES POSTOPERATORIO DE TRASPLANTE HEPÁTICO

Introducción: Los pacientes en postoperatorio de trasplante hepático presentan múltiples cambios hemodinámicos y alteraciones hidroelectrolíticas que generan cambios en el estado ácido base. El presente trabajo, busca describir el comportamiento ácido base en pacientes pos trasplante hepático, a través del análisis del modelo de Stewart, enfocado en la búsqueda etiológica de cada trastorno y planteando posibles formas de optimizar el manejo en Cuidado Intensivo (CI). Metodología: Estudio observacional, descriptivo histórico de los gases arteriales de los pacientes en post operatorio de trasplante hepático por cualquier causa, interpretados por método de Stewart. Se realizó con el universo de pacientes ingresados en el año 2014 en la Fundación Santa Fe de Bogotá. Resultados: Ingresaron en total 24 pacientes al estudio, entre el 1 de enero al 31 de septiembre de 2014. La mediana de pH fue de 7.36 con un valor mínimo de 7.05 y el máximo de 7.49. El 41% de los pacientes al ingreso a cuidado intensivo tenían lactato normal (menor a 2), y el 88% tenían niveles de albumina bajos. El trastorno electrolítico más común fue hipercloremia (58%), seguido de hipomagnesemia (25%). Conclusiones. El análisis de gases arteriales por el modelo de Stewart permite realizar un diagnóstico de un trastorno específico y adicionalmente, permite buscar la etiología del trastorno. Esta serie de casos mostró que el 95% de los pacientes tenían algún trastorno metabólico al ingreso, siendo el más frecuente la acidosis metabólica (66%).

pH-Sensitive Binding of Cytochrome c to the Inner Mitochondrial Membrane. Implications for the Participation of the Protein in Cell Respiration and Apoptosis

Cytochrome c exhibits two positively charged sites: site A containing lysine residues with high pK(a) values and site L containing ionizable groups with pK(aobs),values around 7.0. This protein feature implies that cytochrome c can participate in the fusion of mitochondria and have its detachment from the inner membrane regulated by cell acidosis and alkalosis. In this study, We demonstrated that both horse and tuna cytochrome c exhibited two types of binding to inner mitochondrial membranes that contributed to respiration: a high-affinity and low-efficiency pi-I-independent binding (microscopic dissociation constant K(sapp2), similar to 10 nM) and a low-affinity and high-efficiency pH-dependent binding that for horse cytochrome c had a pK(a) of similar to 6.7. For tuna cytochrome c (Lys22 and His33 replaced with Asn and Trp, respectively), the effect of pH on K(sapp1), was less striking than for the horse heme protein, and both tuna and horse cytochrome c had closed K(sapp1) values at pH 7.2 and 6.2, respectively. Recombinant mutated cytochrome c H26N and H33N also restored the respiration of the cytochrome c-depleted mitoplast in a pH-dependent manner. Consistently, the detachment of cytochrome c from nondepleted mitoplasts was favored by alkalinization, suggesting that site Lionization influences the participation of cytochrome c in the respiratory chain and apoptosis.

Effect of sodium bicarbonate on muscle metabolism during intense endurance cycling

Introduction: Sodium bicarbonate (NaHCO₃) ingestion has been shown to increase both muscle glycogenolysis and glycolysis during brief submaximal exercise. These changes may be detrimental to performance during more prolonged, exhaustive exercise. This study examined the effect of NaHCO₃ ingestion on muscle metabolism and performance during intense endurance exercise of ~60 min in seven endurance-trained men. Methods: Subjects ingested 0.3 g·kg^-1 body mass of either NaHCO₃ or CaCO₃ (CON) 2 h before performing 30 min of cycling exercise at 77 ± 1% [latin capital V with dot above]O_2peak followed by completion of 469 ± 21 kJ as quickly as possible (~30 min, ~80% [latin capital V with dot above]O_2peak). Results: Immediately before, and throughout exercise, arterialized-venous plasma HCO₃- concentrations were higher (P < 0.05) whereas plasma and muscle H⁺ concentrations were lower (P < 0.05) in NaHCO₃ compared with CON. Blood lactate concentrations were higher (P < 0.05) during exercise in NaHCO₃, but there was no difference between trials in muscle glycogen utilization or muscle lactate content during exercise. Reductions in PCr and ATP and increases in muscle Cr during exercise were also unaffected by NaHCO₃ ingestion. Accordingly, exercise performance time was not different between treatments. Conclusion: NaHCO₃ ingestion resulted in a small muscle alkalosis but had no effect on muscle metabolism or intense endurance exercise performance in well-trained men.