• Biomolecules & Therapeutics
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• v.25 no.6
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• pp.593-598
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• 2017

The $Na^+/H^+$ exchanger-1 (NHE-1) is a ubiquitously expressed pH-regulatory membrane protein that functions in the brain, heart, and other organs. It is increased by intracellular acidosis through the interaction of intracellular $H^+$ with an allosteric modifier site in the transport domain. In the previous study, we reported that glutamate-induced NHE-1 phosphorylation mediated by activation of protein kinase C-${\beta}$ (PKC-${\beta}$) in cultured neuron cells via extracellular signal-regulated kinases (ERK)/p90 ribosomal s6 kinases (p90RSK) pathway results in NHE-1 activation. However, whether glutamate stimulates NHE-1 activity solely by the allosteric mechanism remains elusive. Cultured primary cortical neuronal cells were subjected to intracellular acidosis by exposure to $100{\mu}M$ glutamate or 20 mM $NH_4Cl$. After the desired duration of intracellular acidosis, the phosphorylation and activation of PKC-${\beta}$, ERK1/2 and p90RSK were determined by Western blotting. We investigated whether the duration of intracellular acidosis is controlled by glutamate exposure time. The NHE-1 activation increased while intracellular acidosis sustained for >3 min. To determine if sustained intracellular acidosis induced NHE-1 phosphorylation, we examined phosphorylation of NHE-1 induced by intracellular acidosis by transient exposure to $NH_4Cl$. Sustained intracellular acidosis led to activation and phosphorylation of NHE-1. In addition, sustained intracellular acidosis also activated the PKC-${\beta}$, ERK1/2, and p90RSK in neuronal cells. We conclude that glutamate stimulates NHE-1 activity through sustained intracellular acidosis, which mediates NHE-1 phosphorylation regulated by PKC-${\beta}$/ERK1/2/p90RSK pathway in neuronal cells.

• Journal of Trauma and Injury
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• v.32 no.4
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• pp.238-242
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• 2019

Extreme acidosis is a life-threatening physiological state that causes disturbances in the cardiovascular, pulmonary, immune, and hematological systems. Trauma patients commonly present to the operating room (OR) in hypovolemic shock, leading to tissue hypoperfusion and the development of acute metabolic acidosis with or without a respiratory component. It is often believed that trauma patients presenting to the OR in severe metabolic acidosis (pH <7.0) will have a nearly universal mortality rate despite aggressive resuscitation and damage control. The current literature does not include reports of successful resuscitations from a lower pH, which may lead providers to assume that a good outcome is not possible. However, here we describe a case of successful resuscitation from an initial pH of 6.5 with survival to discharge home 95 days after admission with almost full recovery. We describe the effects of acute acidosis on the respiratory and cardiovascular systems and hemostasis. Finally, we discuss the pillars of management in patients with extreme acute acidosis due to hemorrhage: transfusion, treatment of hyperkalemia, and consideration of buffering acidosis with bicarbonate and hyperventilation.

• The Korean Journal of Physiology
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• v.26 no.1
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• pp.89-97
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• 1992

In hypoxic tissue conditions, pyruvate can not enter the Krebs cycle and lactic acid, produced from pyruvate, accumulates to induce lactic acidosis. Pyruvate, However, can also be converted to alanine by glutamate pyruvate transaminase, that could be enhanced by glutamate. Therefore, it would be a fundamental measure to treat the lactic acidosis in tissue hypoxic conditions when one can convert the accumulated lactic acid, through pyruvate, to alanine. To test the above hypothesis, we induced a lactic acidosis in cats and the effect of glutamate on recovery of acid base state and removal of the lactic acid from blood were assessed and the results were compared with those of bicarbonate administration, which is one of the most frequently used conventional measure for correction of the acid base state during lactic acidosis. The results were that glutamate and combined glutamate bicarbonate solutions not only restored the acid base status completely from the lactic acidosis in an hour or two, but also restored the blood level of lactate partially. We concluded that administration of glutamate solution to convert pyruvate into alanine is effective in preventing lactic acid accumulation and treating lactic acidosis.

• Neonatal Medicine
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• v.17 no.2
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• pp.155-160
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• 2010

Metabolic acidosis is commonly encountered issues in the management of critically ill neonates and especially of preterm infants during early neonatal days. In extremely premature infants, low glomerular filtration rate and immaturity of renal tubules to produce new bicarbonate causes renal bicarbonate loss. Higher intake of amino acids, relatively greater contribution of protein to the energy metabolism and mineralization process in growing bones are also responsible for higher acid load in premature infant than in adult. Despite widespread use of sodium bicarbonate in the management of severe metabolic acidosis, use of sodium bicarbonate in premature infants should be restricted to a reasonable but unproven exception such as ongoing renal loss. Despite concern about the low pH value (<7.2) which can compromise cellular metabolic function, no treatment guideline has been established regarding the management of metabolic acidosis in premature infants. Appropriately powered randomized controlled trials of base therapy to treat metabolic acidosis in critically ill newborn infants are demanding.

• Childhood Kidney Diseases
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• v.14 no.2
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• pp.120-131
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• 2010

Renal tubular acidosis (RTA) is a metabolic acidosis due to impaired excretion of hydrogen ion, or reabsorption of bicarbonate, or both by the kidney. These renal tubular abnormalities can occur as an inherited disease or can result from other disorders or toxins that affect the renal tubules. Disorders of bicarbonate reclamation by the proximal tubule are classified as proximal RTA, whereas disorders resulting from a primary defect in distal tubular net hydrogen secretion or from a reduced buffer trapping in the tubular lumen are called distal RTA. Hyperkalemic RTA may occur as a result of aldosterone deficiency or tubular insensitivity to its effects. The clinical classification of renal tubular acidosis has been correlated with our current physiological model of how the nephron excretes acid, and this has facilitated genetic studies that have identified mutations in several genes encoding acid and base ion transporters. Growth retardation is a consistent feature of RTA in infants. Identification and correction of acidosis are important in preventing symptoms and guide approved genetic counseling and testing.

• Journal of Korean Neurosurgical Society
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• v.56 no.2
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• pp.135-140
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• 2014

Objective : Propofol and volatile anesthesia have been associated with metabolic acidosis induced by increased lactate. This study was designed to evaluate changes in pH, base excess (BE), and lactate in response to different anesthetic agents and to characterize propofol infusion-associated lactic acidosis. Methods : The medical records of patients undergoing neurosurgical anesthesia between January 2005 and September 2012 were examined. Patients were divided into 2 groups : those who received propofol (total intravenous anesthesia, TIVA) and those who received sevoflurane (balanced inhalation anesthesia, BIA) anesthesia. Propensity analysis was performed (1 : 1 match, n=47), and the characteristics of the patients who developed severe acidosis were recorded. Results : In the matched TIVA and BIA groups, the incidence of metabolic acidosis (11% vs. 13%, p=1) and base excess (p>0.05) were similar. All patients in the TIVA group who developed severe acidosis did so within 4 hours of the initiation of propofol infusion, and these patients improved when propofol was discontinued. Conclusions : The incidence of metabolic acidosis was similar during neurosurgical anesthesia with propofol or sevoflurane. In addition, severe acidosis associated with propofol infusion appears to be reversible when propofol is discontinued.

• Journal of Chest Surgery
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• v.12 no.4
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• pp.395-402
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• 1979

Intracellular pH was determined by distribution of 5.5-dimethyl-2,4-oxazolidlnedione [DMO]in the skeletal muscle of dogs before and after lactic acidosis induced by intravenous infusion of lactic acid solution. After infusion of lactic acid solution arterial pH decreased from 7.40 to around 7.12 [P<0.001]and metabolic acidosis was induced. However, dose-pH change response was not proportional as in the case of hydrochloric acid infusion. During lactic acidosis, intracellular pH changed very little except when venous blood $pCO_2$ increased significantly. The decrease of intracellular pH in lactic acidosis might be due primarily to the increase of intracellular $pCO_2$. And during lactic acidosis, change of extracellular pH was larger than that of intracellular pH, and this was also the case of change In hydrogen Ion concentration in extracellular and intracellular fluid. The fact was estimated that exogenous lactic acid transported into the cell does not contribute to pH change by the participation in the metabolism. Change in plasma potassium Ion concentration was not eminent as metabolic acid-base disturbances by other origin, and changing pattern of Hi/He ratio was not same as Ki/Ke ratio. In spite of no changes in extracellular potassium ion concentration after exogenous lactic acidosis total amount of potassium ion in extracellular fluid increased from 12.62mEg to 18.26mEg [P< 0.05].

• The Korean Journal of Pharmacology
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• v.31 no.1 s.57
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• pp.75-84
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• 1995

Acid secretion and NO synthase activity were determined in isolated gastric glands following hypoxia/reoxygenation and acidosis to investigate the involvement of NO in acid secretion. Isolated gastric glands were exposed to hypoxia (30 min)/reoxygenation (1 h) and/or to acidosis (pH 6.0 and 4.0). Acid secretion was measured by the ratio of $[^{14}C]-aminopyrine$ accumulation between intra- and extraglands. NO synthase activity was determined by percent conversion to $[^{14}C]-citrulline\;from\;[^{14}C]L-arginine$, a precursor of NO. The results indicate that dibutyryl cAMP stimulated acid secretion dose-dependently but had no effect on NO synthase activity in basal gastric glands. Hypoxia/reoxygenation significantly suppressed acid secretion both in unstimulated and stimulated gastric glands, which was exaggerated by acidosis. Constitutive NO synthase, activity, not responded to dibutyryl cAMP, was also inhibited by hypoxia/reoxygenation and acidosis. In conclusion, pathologic state of gastric mucosa such as hypoxia/reoxygenation and acidosis suppresses both acid secretion and NO release but the role of NO in acid secretion stimulated by dibutyryl cAMP in basal gastric glands is not significant.

• Journal of the Korean Applied Science and Technology
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• v.35 no.4
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• pp.1433-1441
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• 2018

The development of acidosis during intense exercise has traditionally been explained by the increased production of lactic acid which causes the release of a proton and the formation of the acid salt sodium lactate. Through this explanation, when the rate of lactate production is high enough to exceed cellular proton buffering capacity, cellular pH is decreased. This biochemical process has been termed lactic acidosis. This belief has been an interpretation that lactate production causes acidosis and fatigue during intense exercise. However, this review provides clear evidence that there is no biochemical support for lactate production causing acidosis and fatigue. Metabolic acidosis is caused by an increased reliance on nonmitochondrial ATP turnover. Lactate production is essential for muscle to produce cytosolic $NAD^+$ to support continued ATP regeneration from glycolysis. In addition, Lactate production consumes protons. Although lactate accumulation can be a good indirect indicator for decreased cellular and blood pH, that is not direct causing acidosis.

• Journal of The Korean Society of Clinical Toxicology
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• v.6 no.1
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• pp.42-44
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• 2008

Metformin which is an oral hypoglycemic agents, acts by enhancing insulin sensitivity, decreasing hepatic glucose production and increasing peripheral utilization of glucose. Deliberate self poisoning with oral hypoglycemic agents is rare. The lactic acidosis associated with metformin toxicity is well described in the medical literature. Metformin overdose even in otherwise healthy patients may produce a profound and life threatening lactic acidosis. We report a case of massive metformin ingestion(75g) in a patient presenting with lactic acidosis and hypotension. She died 24h after presenting to our emergency department despite bicarbonate treatment and hemofiltration therapy.