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PubMedDate not supplied

Acidosis regulates the stability, hydrophobicity, and activity of the BH3-only protein Bnip3.

Bnip3 is a prodeath member of the so-called BH3-only subfamily of Bcl-2 proteins. A major function of this class of proteins is to regulate the permeability state of the outer mitochondrial membrane by forming homoand hetero-oligomers inside the membrane. We reported previously that Bnip3 accumulates in cardiac myocytes during exposure to hypoxia, but coincident acidosis is required to activate the death program. Acidosis increased the rate of intracellular accumulation of Bnip3 and promoted a tighter association with mitochondria. Here we report that acidic pH mediates increased half-lives of Bnip3 dimers and monomers (>3-) as well as that of a faster-migrating fragment (>10-) and confers protection against degradation by protease. Hydrophobic partitioning experiments revealed that Bnip3 monomers and oligomers from hypoxia-acidic cell fractions associated significantly with the detergent layer, whereas protein from hypoxia-neutral myocytes did not. Acidosis promoted homodimerization of Bcl-xL but did not increase its association with detergent. Neutralization of the extracellular medium of cardiac myocyte cultures under hypoxia-acidosis resulted in rapid degradation of accumulated Bnip3 (half life, <2 h), coincident with cessation of the death program. Bnip3 monomers appear to be the active species because substitution of alanine for histidine at position 173 within the transmembrane (TM) domain prevented homodimerization but did not inhibit the death function. These results demonstrate a pH-sensitive shift in the stability and apparent hydrophobicity of Bnip3 monomers that correlates closely with membrane binding and function.

Acidosis↗
PubMed1983

Definition of clinically relevant lactic acidosis in patients with internal diseases.

In order to define clinically relevant lactic acidosis, 12 biochemical variables, eight clinical symptoms and signs, leading diagnoses, and mortality were evaluated prospectively in approximately 2,000 unselected patients with internal diseases, consecutively admitted to the hospital. Patients with incomplete data sets were not considered. Of those patients who repeatedly were admitted to the hospital during the time of the study, only the first admission was included for statistical analysis. In addition to 11 definitions of lactic acidosis given in the literature, sequential cluster analyses of the biochemical variables were used to estimate the incidence of lactic acidosis in 1,467 patients. Depending upon which definition was used, 0.5-3.8% of all patients were classified as suffering from lactic acidosis, with a mortality rate ranging from 30-88%. From this study it is concluded that a limit of less than or equal to 7.35 for pH and of greater than 5-6 mmol/L for the concentration of lactate in whole blood will minimize false-negative or false-positive classifications.

Acidosis↗
PubMed2002

Aggressive undifferentiated carcinoma of unknown primary site complicated by lactic acidosis after bleeding: a case report.

Undifferentiated carcinoma of unknown primary site complicated by lactic acidosis has not been documented. We describe a young female with undifferentiated carcinoma of unknown primary site manifested by widespread lymph node and hepatic infiltration, hyperuricemia and very high levels of lactate dehydrogenase. She developed lactic acidosis suddenly after an episode of bleeding following nasal biopsy. The bleeding episode is likely to have caused subclinical hepatic hypoperfusion and hypoxemia, thereby aggravating lactate overproduction by tumor cells and clearance impairment due to diffuse hepatic infiltration to result in rapidly fatal acidosis before cytotoxic agents could be instituted. Although uncommon, when a critical event occurs in aggressive malignancies with massive hepatic involvement, the clinician should be alert for the development of lactic acidosis because the life-threatening metabolic complication is best avoided by prompt and effective cytoreduction therapy.

Acidosis, Lactic↗
PubMed1998

The effect of uraemia, acidosis, and dialysis treatment on protein metabolism: a longitudinal leucine kinetic study.

BACKGROUND: Uraemia and dialysis are viewed as catabolic processes resulting in malnutrition in chronic renal failure (CRF) patients. To sort out the effects of uraemia, acidosis, and dialysis on protein metabolism, we measured leucine flux in CRF patients before and after initiation of maintenance dialysis. SUBJECTS AND METHODS: Whole-body leucine flux was measured by primed-constant infusion of L[1-(13)C] leucine in nine CRF patients longitudinally; twice before and once after initiation of maintenance dialysis (D). Before dialysis, one leucine flux was measured when the patients were acidotic (A), and the other, when acidosis was corrected with NaHCO, (NA). Five normal subjects underwent one single leucine flux measurement to serve as control (N). Both patients and normal subjects consumed a constant diet for 6 days and leucine flux was measured on the 7th day 12 h post-absorption. Diet for the CRF patients was identical during the three periods. Plasma L[1-(13)C] leucine and L[1-(13)C]KIC were measured by gas chromatography/mass spectrometry and expired 13CO2 by isotope ratio spectrometry. Leucine kinetics were calculated using standard equations. RESULTS: Plasma CO2 levels were 19, 26 and 31 mmol/l in A, NA and D periods respectively. All kinetic results (micromol/kg/h) are presented as means +/- SD in the order of A, NA, D, and N, and CRF values that are statistically different from N are identified (*). The amounts of leucine release from endogenous protein breakdown (Ra or Q) were 101 +/- 12* 95 +/- 9* 113 +/- 22 and 117 +/- 6. Leucine oxidation (C), quantities of leucine irreversibly oxidized to CO2, were 16.5 +/- 5.4, 9.7 +/- 3.7*, 12.3 +/- 3.0*, and 23.2 +/- 3.1. Leucine protein incorporation levels (S) were 85 +/- 10, 85 +/- 8, 101 +/- 19 and 94 +/- 6. The S of 101 in CRF patients at period D was statistically higher than those during A and NA periods. CONCLUSIONS: These data indicate that when acidosis was corrected, CRF patients adapted to lower protein intake by reducing amino-acid oxidation and protein degradation, and maintained protein synthesis at normal levels. Metabolic acidosis impaired the downregulation of amino-acid oxidation. Maintenance dialysis treatment longitudinally restored protein flux to normal and increased protein synthesis. The general notion that uraemia and dialysis are protein catabolic is not supported by this work.

Acidosis↗
PubMed1993

Ischemia: from acidosis to oxidation.

Organ damage can occur quickly when blood flow is compromised. Lactic acidosis has long been associated with such ischemia, and many physicians assume that organ damage is caused by this acidosis. However, reviewing the literature related to hypoxia and ischemia reveals little data to support the concept of acidosis as damaging to tissue. In contrast, recent studies indicate that the acidosis is actually protective, even during reperfusion when cellular damage may occur. Reperfusion is accompanied by generation of free radicals and other reactive species that can damage proteins, membranes, and nucleic acids, supporting an emerging view that implicates these reactive species in the actual tissue damage. The critical targets of the damaging species are not known, but reaction with key enzymes and structural proteins could certainly disrupt organ function. Cellular proteins are oxidatively modified during reperfusion, in part by metal-catalyzed oxidation in which cellular iron plays a key role. Metal-catalyzed oxidation of proteins may be important in the pathogenesis of other disorders, including the potentially blinding disease, retinopathy of the premature.

Acidosis↗
PubMed2004

Intracellular acidosis-activated p38 MAPK signaling and its essential role in cardiomyocyte hypoxic injury.

Activation of p38 mitogen-activated protein kinase (MAPK) plays a central role in cellular responses to a multitude of stress signals. In the heart, enhanced p38 MAPK signaling has been implicated in cardiac hypoxic and ischemic injury. However, the mechanism underlying hypoxia-induced p38 MAPK activation remains elusive. We investigated p38 MAPK activation during hypoxia in adult rat cardiomyocytes. Here, we reported that hypoxia leads to concurrent intracellular acidosis and activation of p38 MAPK and that the hypoxia-induced p38 MAPK signaling can be fully abolished by neutralizing intracellular pH, whereas intracellular acidosis (intracellular pH<7.0) per se overtly augments activation of p38 MAPK but not ERK1/2 and JNK. Furthermore, inhibition of p38 MAPK protects myocytes against hypoxic cell death, suggesting that acidosis-evoked p38 MAPK signaling plays an important role in hypoxic cell injury and cell death. These results demonstrate, for the first time, that intracellular acidosis constitutes a necessary and sufficient link responsible for hypoxia-activated p38 MAPK signaling and the subsequent hypoxic cardiomyocyte injury and death.

Acidosis↗
PubMed1987

The athlete, cocaine, and lactic acidosis: a hypothesis.

The muscular makeup of the sprint-trained athlete may make him especially susceptible to severe lactic acidosis from cocaine-induced seizures. Because of a high percentage of glycolytic muscle fibers (compared to the muscle fiber type of the endurance-trained athlete), the lactic acidosis and heat generated from muscular activity is much greater in the sprint-trained athlete than in the endurance-trained athlete. The role of cocaine in producing seizures and increasing glycolysis, both of which produce lactic acidosis, is discussed. The hypothesis is presented that the elite athlete may be at greater risk of death than the general population from lactic acidosis produced as a result of cocaine-induced seizures.

Acidosis, Lactic↗
PubMed2002

Early postoperative respiratory acidosis after large intravascular volume infusion of lactated ringer's solution during major spine surgery.

UNLABELLED: In this study, we compared the effects of large intravascular volume infusion of 0.9% saline (NS) or lactated Ringer's (LR) solution on electrolytes and acid base balance during major spine surgery and evaluated the postoperative effects. Thirty patients aged 18-70 yr were included in the study. General anesthesia was induced with 5 mg/kg thiopental and 0.1 mg/kg vecuronium IV. Anesthesia was maintained with oxygen in 70% nitrous oxide and 1.5%-2% sevoflurane. In Group I, the NS solution, and in Group II, the LR solution were infused 20 mL. kg(-1). h(-1) during the operation and 2.5 mL. kg(-1). h(-1), postoperatively. Electrolytes (Na+, K+, Cl-) and arterial blood gases were measured preoperatively, every hour intraoperatively and at the 1st, 2nd, 4th, 6th, and 12th hours postoperatively. In the NS group, pHa, HCO3 and base excess decreased, and Cl- values increased significantly at the 2nd hour and Na+ values increased at the 4th hour intraoperatively (P < 0.001). The values returned to normal ranges at the 12th hour postoperatively. In the LR group, blood gas analysis and electrolyte values did not show any significant difference intraoperatively, but the increase in PaCO2 and the decrease in pHa and serum Na+ was significant at the 1st hour postoperatively. Although intraoperative 20 mL. kg(-1). h(-1) LR infusion does not cause hyperchloremic metabolic acidosis as does NS infusion, it leads to postoperative respiratory acidosis and mild hyponatremia. IMPLICATIONS: The infusion of large-volume lactated Ringer's solution does not cause hyperchloremic metabolic acidosis as does 0.9% saline during major surgery, but leads to postoperative mild hyponatremia and respiratory acidosis.

Acid-Base Equilibrium↗
PubMed1990

Enhancement of hypoxic pulmonary vasoconstriction by metabolic acidosis in dogs.

The effects of HCl infusion on multipoint mean pulmonary arterial pressure (PAP)/cardiac index (CI) plots in pentobarbital-anesthetized dogs whose lungs were ventilated alternately in hyperoxia (fraction of inspired O2 [FIO2], 0.4) and hypoxia (FIO2, 0.1) were investigated. Over the range of CI studied (1 to 5 l.min-1.m-2), hypoxia increased PAP in 22 dogs (responders) and did not affect PAP in 16 other dogs (nonresponders). In eight nonresponders, two repetitions of alternated 0.4 and 0.1 FIO2 exposures did not restore hypoxic pulmonary vasoconstriction (HPV), defined as a hypoxia-induced increase in PAP at a given flow. Intravenous infusion of 2 M HCl (2 mmol.kg-1.h-1) decreased arterial pH from normal to around 7.20 in eight responders and eight nonresponders. This metabolic acidosis increased PAP at all levels of CI in hyperoxia and in hypoxia in all the dogs, enhanced HPV in the responders, and restored HPV in the nonresponders. In eight responders, 2 M HCl infusion (2 mmol.kg-1.h-1) together with a 7% sodium bicarbonate infusion (adjusted to maintain arterial pH unchanged) did not affect hyperoxic or hypoxic PAP/CI plots. Pretreatment with 1 g acetylsalicylic acid iv (6 dogs) did not affect the pulmonary vasoreactivity to HCl-induced (2 M HCl, 2 mmol.kg-1.h-1) metabolic acidosis. It was concluded that in intact dogs: 1) metabolic acidosis enhances HPV; 2) at the given dose, HCl does not produce pulmonary vascular effects unrelated to the circulating blood pH; and 3) it is unlikely that the pulmonary vasoreactivity to metabolic acidosis is mediated by products of the cyclooxygenase pathway.

Acidosis↗
PubMed1998

Acidosis reduces neuronal apoptosis.

Acidosis is a well established concomitant of tissue ischemia. Acidosis in the pH range 6.0-7.0 is seen in cerebral ischemia and within solid tumors. Extracellular acidosis of pH 6.0 and 6.4 provided essentially complete protection from 48 h serum deprivation induced apoptotic death of cultured primary murine neurons. We tested the effect of p53 using transformed mouse embryo fibroblasts of either p53+/+ or p53-/- genotype. Both were markedly protected from serum deprivation by acidity. Hypoxia induced fibroblast injury was also reduced at pH 6.8. Lower pH resulted in a shift from apoptotic to necrotic morphology after 42 h hypoxia. Acidosis reduces apoptosis of both normal and transformed cells, irrespective of p53 status.

Acidosis↗
PubMedDate not supplied

Influence of rapid correction of metabolic acidosis on serum osteocalcin level in chronic renal failure.

Metabolic acidosis induces a combination of inhibited osteoblastic and stimulated osteoclastic activity. To determine the role of alkali therapy in osteoblast function in chronic renal failure, serum bone isoenzyme of alkaline phosphatase (BAP) and osteocalcin were assessed before and after bicarbonate infusion. Eighteen patients with mild to moderate metabolic acidosis, none of whom had received dialysis therapy, were enrolled in this study. Metabolic acidosis was corrected by continuous bicarbonate infusion while plasma ionized calcium was monitored at 5 min intervals and held at the preinfusion level by calcium solution infusion during the entire procedure. The end-point of the study was reached when the plasma bicarbonate was approximately 24 mmol/l or pH was approximately 7.4 and plasma ionized calcium was clamped at the preinfusion level with only a 0.01 mmol/l fluctuation. The plasma pH (7.31 +/- 0.04 vs. 7.40 +/- 0.03, P < 0.001), bicarbonate (18.46 +/- 2.49 vs. 23.66 +/- 2.72 mmol/l, P < 0.001), serum total calcium, and osteocalcin (15.61 +/- 6.45 vs. 18.79 +/- 6.71 mg/l, P < 0.05) levels were significantly increased, whereas serum concentrations of alkaline phosphatase and albumin levels were significantly decreased after bicarbonate infusion. The serum BAP (1.85 +/- 1.29 vs. 1.79 +/- 1.18 mukat/l, P = 0.252), and inorganic phosphorus levels showed no significant differences before and after bicarbonate infusion. These results demonstrate that rapid correction of metabolic acidosis improves osteoblast function and may underline the importance of maintaining normal acid-base homeostasis in chronic renal failure.

Acid-Base Equilibrium↗
PubMedDate not supplied

Impact of dialysis modality and acidosis on nutritional status.

Experimental evidence suggests that acidosis may have a deleterious effect on protein metabolism. We evaluated 124 chronic dialysis patients (59 +/- 17 years) and defined acidosis as an anion gap >18 meq/L. A direct correlation (p < 0.0001 was found between anion gap and serum albumin (R = 0.402), BUN (R = 0.488), and serum creatinine (R = 0.473) concentrations. Acidotic patients (43%), when compared with nonacidotic patients, had greater serum albumin concentrations (3.95 +/- 0.50 vs. 3.60 +/- 0.48 g/dl, p = 0.0001, respectively), higher normalized protein catabolic rates (1.12 +/- 0.27 vs. 0.96 +/- 0.26 g/kg/d, respectively; p = 0.0004), and higher BUN (70 +/- 19 vs. 55 +/- 17 mg/dl, p = 0.0001) and serum creatinine (11.1 +/- 3.4 vs. 8.3 +/- 3.2, p = 0.0001 mg/dl) concentrations. However, no differences in midarm muscle circumference, fat free mass, or body cell mass were noted between groups when assessed by dialysis modality or acidosis status. In conclusion, mild chronic metabolic acidosis, likely caused by increased dietary protein intake, does not independently and adversely impact nutritional status in chronic dialysis patients.

Acid-Base Equilibrium↗
PubMed1997

Extracellular acidosis delays cell death against glucose-oxygen deprivation in neuroblastoma x glioma hybrid cells.

OBJECTIVE: To determine whether extracellular acidosis delays cell death against glucose-oxygen deprivation and, if so, whether this result is due to inhibition of calcium (Ca2+) influx or preservation of cellular energy state. DESIGN: Randomized, controlled, prospective study. SETTING: University research laboratory. SUBJECTS: Differentiated neuroblastoma x glioma NG108-15 cells. INTERVENTIONS: Experiment 1: cells were incubated for 8 hrs in N-(2-hydroxyethyl)piperazine-N'-2-ethanesulfonic acid-buffered medium under glucose-oxygen deprivation at pH 7.4, 6.8, 6.5, 6.2, 5.6, or 5.0. Experiment 2: cells were incubated for 8 hrs under glucose-oxygen deprivation after excluding extracellular calcium from culture medium at pH 7.4 or 6.2. Experiment 3: cells were incubated for 2, 4, 6, or 8 hrs in N-(2-hydroxyethyl)piperazine-N'-2-ethanesulfonic acid-buffered medium under glucose-oxygen deprivation at pH 7.4 or 6.2 and assayed for high-energy phosphates. MEASUREMENTS AND MAIN RESULTS: Cell viability was measured with flow cytometry after the cells were stained with fluorescein diacetate and propidium iodide. Cellular adenosine triphosphate, adenosine diphosphate, and adenosine monophosphate were analyzed with high-performance liquid chromatography. Cell viability was significantly greater at pH 6.2 than at pH 7.4 in experiment 1. By excluding extracellular calcium, a significant difference in viability between pH 7.4 and 6.2 persisted in experiment 2. Energy charge and the concentration of adenosine triphosphate were significantly greater at pH 6.2 than at pH 7.4 in the intervals preceding manifestation of a differential effect of acidosis on cell viability in experiment 3. CONCLUSIONS: Extracellular acidosis at pH 6.2 delayed cell death against glucose-oxygen deprivation. This protective effect by extracellular acidosis may be due to preservation of the cellular energy state in NG108-15 cells, although this study does not exclude the possibility that in other cell types, inhibition of calcium influx may have an effect.

Acidosis↗
PubMed1998

Gastric intramucosal acidosis in mechanically ventilated patients: role of mucosal blood flow.

OBJECTIVE: To investigate whether gastric intramucosal acidosis is associated with a decreased gastric mucosal blood flow in mechanically ventilated patients. DESIGN: Prospective, clinical investigation. SETTING: University hospital intensive care unit. PATIENTS: Seventeen mechanically ventilated patients with stable hemodynamic status. INTERVENTIONS: Gastric tonometry and endoscopic assessment of mucosal blood flow. MEASUREMENTS AND MAIN RESULTS: Six patients had gastric intramucosal acidosis (intramucosal pH [pHi] of 7.24 +/- 0.06), whereas the remaining 11 patients had pHi values within the normal range (7.44 +/- 0.01). No differences were found between intramucosal acidotic and nonacidotic patients with respect to their general and hemodynamic characteristics. Patients with intramucosal acidosis had a lower gastric mucosal blood flow, as assessed by laser-Doppler flowmetry, than nonacidotic patients (1.4 +/- 0.1 vs. 2.1 +/- 0.2 volts, respectively; p < .05). Reflectance spectrophotometry disclosed that patients with low gastric pHi had also a significantly (p < .05) lower hemoglobin content index (61 +/- 4 arbitrary units) than patients with normal pHi (81 +/- 3 arbitrary units), whereas oxygen saturation index was similar for both groups. CONCLUSION: Our results support the hypothesis that gastric mucosal hypoperfusion underlies the development of intramucosal acidosis in mechanically ventilated patients.

APACHE↗
PubMed2000

Pyroglutamic acidemia: a cause of high anion gap metabolic acidosis.

OBJECTIVE: To report four cases of pyroglutamic acidemia in adults causing clinically significant acidosis. DATA SOURCES: Patients admitted to the intensive care units of the Alfred Hospital (a quaternary referral center) and Geelong Hospital (a major regional center) with an unexplained high anion gap acidosis. CONCLUSIONS: Pyroglutamic acidemia (5-oxoprolinemia) is a rare cause of high anion gap metabolic acidosis that should be suspected in patients presenting with sepsis, hepatic, and/or renal dysfunction who are receiving drugs such as acetaminophen, flucloxacillin, and vigabatrin after the more common causes of a high anion gap acidosis have been excluded. Should pyroglutamic aciduria be present, known precipitants should be ceased, infection should be managed aggressively, and supportive management should be instituted.

Acidosis↗
PubMed1997

Modified cow's milk formula with reduced renal acid load preventing incipient late metabolic acidosis in premature infants.

BACKGROUND: Premature infants receiving alimentation with cow's milk formulas are at a considerably high risk of developing incipient late metabolic acidosis, an early stage in the development of manifest late metabolic acidosis. Is it possible to reduce this risk by modification of the composition of a standard formula? METHODS: The mineral composition of a cow's milk preterm formula A was modified (formula B) with the aim of reducing the alimentary load to that of human milk. 160 premature infants were fed either mother's milk (n = 50) or the modified formula B (enriched with sodium and potassium) (n = 110), and their urine pH was tested twice a week. Randomly collected subgroups of infants were studied in detail for nutrient balances. The results were compared with earlier observations of 282 premature infants fed either mother's milk (n = 28) or the standard formula A (n = 254). RESULTS: Incipient late metabolic acidosis was observed in nine of 78 premature infants receiving mother's milk, 53 of 254 premature infants receiving the standard formula A, and only one of 110 premature infants fed the modified formula B. Net acid excretion was 0.58 mmol/kg/day in 11 premature infants receiving alimentation with the modified formula B compared with 1.73 mmol/kg/day in 23 premature infants fed formula A. This reduction was mainly due to an increased alkali excess (sodium + potassium-chloride) in intake and urine. CONCLUSIONS: Reduction of renal acid load with the modified formula B had a preventive effect on the rate of development of incipient late metabolic acidosis in premature infants.

Acidosis, Renal Tubular↗
PubMed2000

Lactobacilli and acidosis in children with short small bowel.

BACKGROUND: In patients with a short small bowel, D-lactic acidemia and D-lactic aciduria are caused by intestinal lactobacilli. The purpose of this study was to obtain a detailed picture of the metabolic acidosis in young children with short small bowel. METHODS: Feces, blood, and urine of children with short small bowel and acidosis were studied microbiologically and/or biochemically. RESULTS: Previous findings were confirmed that more than 60% of the fecal flora of patients with small short bowel, who are not receiving antibiotics, consists of lactic acid-producing lactobacilli. In blood, D-lactic acid was the most prominent metabolite: the highest serum D-lactate (15.5 mmol/l) was observed in a sample taken immediately after the onset of hyperventilation. The highest D-lactate excretion was in urine collected some hours after the onset of hyperventilation, and amounted to 59 mol/mol creatinine. Acidosis in the patients with short small bowel was related to strongly increased serum D-lactate and anion gap and to strongly decreased serum bicarbonate and pH. CONCLUSION: In children with small short bowel and acidosis, the common intestinal flora of mainly lactobacilli abundantly produces D-lactic acid from easily fermentable carbohydrates. Thus, these bacteria directly cause shifts of bicarbonate, pH, and base excess and indirectly cause shifts of the anion gap, as well as hyperventilation. These kinetic parameters are strongly associated.

Acidosis↗
PubMed1988

Malignancy-induced lactic acidosis.

Lactic acidosis, a rare and usually fatal complication of malignancy, is defined as a clinical condition in which the pH is less than or equal to 7.35 and the serum lactate level greater than or equal to 5 mEq/L. We have described the clinical aspects of four cases of lactic acidosis associated with malignancy, and have reviewed all reported cases of lactic acidosis in malignancy meeting the criteria. Rapid recognition of the condition and prompt institution of chemotherapy led to reversal of lactic acidosis in three of our four patients, but long-term survival is related to the responsiveness of the underlying tumor.

Acidosis, Lactic↗