Effects Of Acute Metabolic Acidosis Research Articles

Acute but not chronic metabolic acidosis potentiates the acetylcholine-induced reduction in blood pressure: an endothelium-dependent effect

Metabolic acidosis has profound effects on vascular tone. This study investigated the in vivo effects of acute metabolic acidosis (AMA) and chronic metabolic acidosis (CMA) on hemodynamic parameters and endothelial function. CMA was induced by ad libitum intake of 1% NH4Cl for 7 days, and AMA was induced by a 3-h infusion of 6 M NH4Cl (1 mL/kg, diluted 1:10). Phenylephrine (Phe) and acetylcholine (Ach) dose-response curves were performed by venous infusion with simultaneous venous and arterial blood pressure monitoring. Plasma nitrite/nitrate (NOx) was measured by chemiluminescence. The CMA group had a blood pH of 7.15±0.03, which was associated with reduced bicarbonate (13.8±0.98 mmol/L) and no change in the partial pressure of arterial carbon dioxide (PaCO2). The AMA group had a pH of 7.20±0.01, which was associated with decreases in bicarbonate (10.8±0.54 mmol/L) and PaCO2 (47.8±2.54 to 23.2±0.74 mmHg) and accompanied by hyperventilation. Phe or ACh infusion did not affect arterial or venous blood pressure in the CMA group. However, the ACh infusion decreased the arterial blood pressure (ΔBP: -28.0±2.35 mm Hg [AMA] to -4.5±2.89 mmHg [control]) in the AMA group. Plasma NOx was normal after CMA but increased after AMA (25.3±0.88 to 31.3±0.54 μM). These results indicate that AMA, but not CMA, potentiated the Ach-induced decrease in blood pressure and led to an increase in plasma NOx, reinforcing the effect of pH imbalance on vascular tone and blood pressure control.

Treatment of acute metabolic acidosis: a pathophysiologic approach

Acute metabolic acidosis is associated with increased morbidity and mortality because of its depressive effects on cardiovascular function, facilitation of cardiac arrhythmias, stimulation of inflammation, suppression of the immune response, and other adverse effects. Appropriate evaluation of acute metabolic acidosis includes assessment of acid-base parameters, including pH, partial pressure of CO(2) and HCO(3)(-) concentration in arterial blood in stable patients, and also in central venous blood in patients with impaired tissue perfusion. Calculation of the serum anion gap and the change from baseline enables the physician to detect organic acidoses, a common cause of severe metabolic acidosis, and aids therapeutic decisions. A fall in extracellular and intracellular pH can affect cellular function via different mechanisms and treatment should be directed at improving both parameters. In addition to supportive measures, treatment has included administration of base, primarily in the form of sodium bicarbonate. However, in clinical studies of lactic acidosis and ketoacidosis, bicarbonate administration has not reduced morbidity or mortality, or improved cellular function. Potential explanations for this failure include exacerbation of intracellular acidosis, reduction in ionized Ca(2+), and production of hyperosmolality. Administration of tris(hydroxymethyl)aminomethane (THAM) improves acidosis without producing intracellular acidosis and its value as a form of base is worth further investigation. Selective sodium-hydrogen exchanger 1 (NHE1) inhibitors have been shown to improve haemodynamics and reduce mortality in animal studies of acute lactic acidosis and should also be examined further. Given the important effects of acute metabolic acidosis on clinical outcomes, more intensive study of the pathogenesis of the associated cellular dysfunction and novel methods of treatment is indicated.

Metabolic acidosis: pathophysiology, diagnosis and management

Metabolic acidosis is characterized by a primary reduction in serum bicarbonate (HCO(3)(-)) concentration, a secondary decrease in the arterial partial pressure of carbon dioxide (PaCO(2)) of approximately 1 mmHg for every 1 mmol/l fall in serum HCO(3)(-) concentration, and a reduction in blood pH. Acute forms (lasting minutes to several days) and chronic forms (lasting weeks to years) of the disorder can occur, for which the underlying cause/s and resulting adverse effects may differ. Acute forms of metabolic acidosis most frequently result from the overproduction of organic acids such as ketoacids or lactic acid; by contrast, chronic metabolic acidosis often reflects bicarbonate wasting and/or impaired renal acidification. The calculation of the serum anion gap, calculated as [Na(+)] - ([HCO(3)(-)] + [Cl(-)]), aids diagnosis by classifying the disorders into categories of normal (hyperchloremic) anion gap or elevated anion gap. These categories can overlap, however. Adverse effects of acute metabolic acidosis primarily include decreased cardiac output, arterial dilatation with hypotension, altered oxygen delivery, decreased ATP production, predisposition to arrhythmias, and impairment of the immune response. The main adverse effects of chronic metabolic acidosis are increased muscle degradation and abnormal bone metabolism. Using base to treat acute metabolic acidosis is controversial because of a lack of definitive benefit and because of potential complications. By contrast, the administration of base for the treatment of chronic metabolic acidosis is associated with improved cellular function and few complications.

Acute metabolic acidosis decreases muscle protein synthesis but not albumin synthesis in humans

Chronic metabolic acidosis induces negative nitrogen balance by either increased protein breakdown or decreased protein synthesis. Few data exist regarding effects of acute metabolic acidosis on protein synthesis. We investigated fractional synthesis rates (FSRs) of muscle protein and albumin, plasma concentrations of insulin-like growth factor-I (IGF-I), thyroid-stimulating hormone (TSH), and thyroid hormones (free thyroxin [fT4] and triiodothyronine [fT3]) in seven healthy human volunteers after a stable controlled metabolic period of 5 days and again 48 hours later after inducing metabolic acidosis by oral ammonium chloride intake (4.2 mmol/kg/d divided in six daily doses). Muscle and albumin FSRs were obtained by the [2H5ring]phenylalanine flooding technique. Ammonium chloride induced a significant decrease in pH (7.43 ± 0.02 versus 7.32 ± 0.04; P < 0.0001) and bicarbonate concentration (24.6 ± 1.6 versus 16.0 ± 2.7 mmol/L; P < 0.0001) within 48 hours. Nitrogen balance decreased significantly on the second day of acidosis. The FSR of muscle protein decreased (1.94 ± 0.25 versus 1.30 ± 0.39; P < 0.02), whereas the FSR of albumin remained constant. TSH levels increased significantly (1.1 ± 0.5 versus 1.9 ± 1.1 mU/L; P = 0.03), whereas IGF-I, fT4, and fT3 levels showed no significant change. We conclude that acute metabolic acidosis for 48 hours in humans induces a decrease in muscle protein synthesis, which contributes substantially to a negative nitrogen balance. In contrast to prolonged metabolic acidosis of 7 days, a short period of acidosis in the present study did not downregulate albumin synthesis. © 2001 by the National Foundation, Inc.

O.46 Whole body protein turnover assessed with leucine and glutamine kinetics in vivo at an early stage of human immunodeficiency virus infection

0.45 Acute metabolic acidosis decreases muscle protein synthesis and induces negative nitrogen balance in humans G.-R. Kleger 1 , M. A. McNurlan 2, R. Imoberdorf 3, M. Turgay 1, P. J. Garlick 2 and P. E. Ballmer ~ ~Department of Internal Medicine, University of Berne, Beme, Switzerland; 2Department of Surgery, State University of New York at Stony Brook, USA; Department of Medicine, Kantonsspital, St. Gallen, Switzerland, Acute and chronic metabolic acidosis are associated with negative nitrogen balance in cell culture systems and in experimental animals. Recently, we have demonstrated that chronic metabolic acidosis induced negative nitrogen balance and a decrease in albumin synthesis in human subjects [1]. However, the effects of acute metabolic acidosis (AMA) on protein metabolism, in particular on muscle protein synthesis, in humans are so far not well understood. In the present study we have, therefore, measured both muscle protein synthesis and urinary nitrogen excretion in 7 healthy subjects before and during AMA. They were on a constant metabolic diet before (control period) and throughout the whole experiment. AMA was induced by oral ammonium chloride (4.2 mmol/kg body weight per day in 6 divided doses over 48 h). Fractional synthesis rates (FSR) of muscle protein were measured by i.v. injection of L-[2H5ring]phenylalanine (43 mg/kg bw were 7.5 and 15 atom%, respectively). Muscle protein and plasma free phenylalanine enrichments were measured by gas chromatography-mass spectrometry. Nitrogen excretion was determined from 24-h urine collections photometrically after wet incineration, by formation of indophenol with salicylate and hypochlorite. Plasma pH decreased from 7.43 + 0.02 (mean _+ SD), in the control period, to 7.35 _+ 0.04 (P < 0.01 ; paired t-test) in acidosis, and bicarbonate from 24.4 _+ 1.4 mmol/L to 18.0 _+ 3.0 (P < 0.01). FSR of muscle protein decreased in all subjects from an average 1.94 _+ 0.25 %/d to 1.30 _+ 0.39 (P = 0.027), whereas urinary nitrogen excretion increased from 13.9 _+ 2.8 mmol/kg bw to 18.5 _+ 4.0 (P < 0.01). In conclusion, experimental AMA effectively decreased muscle protein synthesis while increasing urinary nitrogen excretion. Whether these effects are directly caused by acidosis or mediated by other factors such as a decrease in IGF-1 [1] remains to be shown. Early correction of AMA in acutely ill patients might restrict protein wasting and preserve muscle mass. Reference: [1] Ballmer PE et al. J Clin Invest 1995; 95: 39-45.

Regulation of the insulin-like growth factor system by acute acidosis.

Many catabolic conditions are characterized by disturbances in acid-base balance and concomitant alterations in the insulin-like growth factor (IGF) system. However, the influence of acidosis per se on the various components of the IGF system has not been extensively examined. The purpose of the present study was to determine the effect of acute metabolic acidosis on the plasma and tissue concentrations of IGF-I and the various IGF-binding proteins (IGFBPs). Conscious unrestrained fasted rats were infused iv with either 0.2 N HCl or an equal volume of saline for 4 h. The arterial blood pH decreased within 60 min after starting the HCl infusion and remained lower than time-matched control values for the entire experimental protocol. Although the plasma IGF-I concentration fell gradually and was reduced by 30%, compared to time-matched control values, GH levels were unaltered. The IGF-I content of tissues collected at the conclusion of the experiment was increased in liver (35%) and kidney (63%), and unchanged in skeletal muscle. However, whereas acidosis moderately increased IGF-I messenger RNA abundance in liver, no significant alteration in IGF-I expression was detected in kidney. Acidosis also increased the plasma levels of IGFBP-1 and -2 as well as the IGFBP-1 content of liver and kidney. In contrast, the concentration of intact IGFBP-3 was decreased in acid-infused rats, and this reduction was associated with an increased rate of IGFBP-3 protease activity. Acidotic rats demonstrated unremarkable changes in the plasma concentrations of glucose and insulin, but corticosterone levels were elevated throughout the experiment. The results of the present study demonstrate that in the absence of underlying pathology, acute metabolic acidosis decreases circulating levels of IGF-I, probably by increasing renal clearance of the peptide, not by decreasing hepatic IGF-I synthesis.

Ammonium chloride metabolic acidosis and the activity of renin-angiotensin-aldosterone system in children

The present study was undertaken to assess the effects of acute metabolic acidosis on the activity of the renin-angiotensin-aldosterone system in 12 children with a mean age of 8.9 years who underwent NH4Cl loading test. Ammonium chloride was given in a dose of 0.15 g/kg per day for 3 consecutive days to evaluate renal acidification. Prior to and following NH4Cl administration blood acid-base parameters, plasma and urine electrolytes, creatinine and aldosterone concentrations as well as plasma renin activity (PRA), urine flow rate and net H+ excretion were measured. Ammonium chloride administration significantly depressed blood pH (P less than 0.05), bicarbonate (P less than 0.01) and base excess (P less than 0.01) and resulted in a slight, but significant elevation of plasma potassium concentration (P less than 0.05). Furthermore, NH4Cl ingestion induced a marked increase in urine flow rate (P less than 0.01) and urinary sodium, potassium and chloride excretion (P less than 0.01). In response to NH4Cl metabolic acidosis, PRA doubled (4.72 +/- 1.18 vs 8.13 +/- 1.02 ng/ml per hour, P less than or equal to 0.05) and there was a nearly four-fold increase in plasma aldosterone level (0.49 +/- 0.12 vs 1.52 +/- 0.24 ng/ml, P less than 0.01) and in urinary aldosterone excretion (19.2 +/- 4.3 vs 71.8 +/- 13.8 micrograms/day, P less than 0.01). The elevated aldosterone production observed in this study is assumed to be mediated by the combined effect of sodium and water diuresis-related increased PRA, hyperkalaemia and the direct stimulation of adrenal steroidogenesis by metabolic acidosis.

Comparative effects of plasma from acutely acidotic rats on the activity of phosphate-dependent glutaminases from several animal tissues

The effects of acute metabolic acidosis, induced by the administration of NH 4 C1, and also plasma from acutely acidotic rats on the kinetics of phosphate-dependent glutaminase (PDG) from several animal tissues have been studied. During acute metabolic acidosis only the enzyme activity from kidney cortex was altered. On the other hand, PDG activity from the kidney cortex, small intestine and brain significantly increased in the direct presence of plasma from acutely acidotic rats at subsaturating concentration of glutamine. No such effect was observed with liver tissue. This kinetic behaviour leads to a significant depression in the Km values for the three affected enzymes but no variation in the Vmax. These results go to support the idea that PDG from the kidney cortex, brain and small intestine are kinetically and immunologically identical and also confirm that during acute metabolic acidosis a factor is released into the plasma, probably produced and concentrated by the kidneys, which induces a conformational change in the enzyme from the kidney, brain and intestine and brings about a significant decrease in the Km for glutamine but no change in the Vmax.

Effects of Acute Metabolic Acidosis and Alkalosis on Leucine Metabolism in Conscious Dogs

To determine the effects of acute metabolic acidosis and alkalosis on leucine metabolism in vivo, mongrel dogs were infused with [1-14C]leucine for 8 h, along with NaCl, HCI, or NaHCO3 over the last 4 h. Arterial pH did not change from the basal value during NaCl infusion but decreased (P less than .01) and increased (P less than .01) during HCl and NaHCO3 infusions, respectively. Total leucine carbon entry did not change from the basal value during saline infusion but increased (P less than .01) with acidosis and decreased (P less than .05) with alkalosis. Compared with saline controls, acidosis increased (P less than .01) leucine oxidation. During alkalosis decreased (P less than .01) leucine oxidation. During acidosis, total plasma essential and nonessential amino acid concentrations increased (P less than .05), whereas during alkalosis, total plasma essential and nonessential amino acid concentrations decreased (P less than .05). These studies suggest that acute alterations in arterial pH may affect the regulation of protein metabolism in vivo and must be considered in the interpretation of results from experiments in which alterations of acid-base homeostasis may have occurred.

Effects of acute metabolic acidosis and alkalosis on leucine metabolism in conscious dogs

Effects of acute metabolic acidosis and alkalosis on leucine metabolism in conscious dogs

Effect of acute metabolic acidosis on ammonia metabolism in kidney.

To understand the mechanisms that initiate the increase in ammonia formation during acute acidosis in kidney [amino-15N]- and [amino-15N]glutamine were used as substrates in isolated perfused rat kidney experiments. Perfused kidneys from methionine sulfoximine-treated rats take up glutamine nitrogen at the rate of 1.50 +/- 0.08 mumol.g kidney-1.min-1 while forming ammonia at a rate of 0.65 +/- 0.09 mumol.g.kidney-1.min-1. Mass spectrometer analysis of the perfusate and urine reveals that ammonia is formed from the amide nitrogen of glutamine at the rate of 0.32 +/- 0.06 mumol.g kidney-1.min-1 and ammonia is formed from glutamate derived from glutamine at the rate of 0.21 +/- 0.04 mumol.g kidney-1.min-1. The balance of the ammonia formed is from unidentified endogenous sources. Addition of HCl to the perfusate to lower perfusate pH increases ammonia formation to 1.09 +/- 0.10 mumol.g kidney-1.min-1. The results exclude a role for the purine nucleotide cycle during acute acidosis and confirm that ammonia formation from glutamate derived from glutamine is via glutamate dehydrogenase. Lowering perfusate pH increases the rate of glutamine deamidation significantly by 0.33 +/- 0.06 mumol.g kidney-1.min-1 and increases the rate of ammonia formation via glutamate dehydrogenase insignificantly by only 0.08 +/- 0.04 mumol.g kidney-1.min-1, whereas ammonia formation from endogenous sources remains unchanged. The results demonstrate that regulation of glutamine deamidation is an important controlling step in ammonia formation during acute metabolic acidosis in kidney.

Effect of acute metabolic acidosis on transmembrane electrolyte gradients in individual renal tubule cells.

We studied the effect of acute metabolic acidosis on potassium, sodium and chloride gradients across the apical membrane of proximal and distal tubule cells by determining electrolyte concentrations in individual cells and in tubule fluid employing electron microprobe analysis. Cellular measurements were performed on freeze-dried cryosections of the renal cortex, analysis of tubule fluid electrolyte concentrations on freeze-dried microdroplets of micropuncture samples obtained from proximal and from early and late distal collection sites. Acidosis (NH4Cl i.v. and i.g.) induced a substantial rise in plasma potassium concentration without significant effects on cell potassium concentrations. Potassium concentrations along the surface distal tubule were also unaltered; thus the chemical driving force for potassium exit from cell to lumen was not affected by acidosis. In all but intercalated cells acidosis markedly increased cell phosphorus concentration and cell dry weight indicating cell shrinkage and thus diminution of cell potassium content. Because the increase in intracellular chloride concentration exceeded the increase in plasma chloride concentration, the chemical chloride gradient across the contraluminal membrane was markedly depressed by acidosis.

Respiration of chemodenervated goats in acute metabolic acidosis

In awake goats before and after ablation of carotid bodies (CBx) we studied the effect of acute metabolic acidosis (AMA) produced by intravenous infusion of HCl on composition of arterial blood and CSF, and on ventilatory responsiveness to hyperoxic CO 2 rebreathing. AMA caused decrease in Pa CO 2 (breathing air at rest) indicating that alveolar ventilation was increased relative to CO 2 production; position of CO 2 response curves was shifted toward lower values of P CO 2. These changes were similar before and after CBx, though the levels of P CO 2 in arterial blood during air breathing at rest, and in expired gas at a given level of ventilation during CO 2 rebreathing, were higher after CBx. We conclude that a respiratory adaptation to AMA does occur in goats deprived of peripheral chemoreceptors, and is probably mediated by the central chemoreceptors.

Effects of acute metabolic acidosis on renal, gut, liver, and muscle metabolism of glutamine and ammonia in the dog

Previous studies have shown a rise in arterial glutamine in acute acidosis in the dog. In these experiments glutamine and ammonia metabolism was studied in anesthetized dogs during normal acid-base status and following acute hydrochloric acidosis to determine the mechanism for the rise in arterial glutamine in acidosis. Splanchnic, liver, renal, and hind-half extraction/production were measured by arteriovenous (A-V) sampling and simultaneous blood flow measurements using electromagnetic flow probes. In the normal dog, muscle produced glutamine, and the kidneys, gut, hepatosplanchnic bed, and liver extracted it. Whole blood arterial glutamine rose in acidosis. Renal and muscle glutamine and ammonia extraction/production were unchanged. Gut ammonia release and hepatic ammonia uptake increased by similar amounts in acidosis, but no change in gut glutamine uptake occurred. Hepatic and total hepatosplanchnic glutamine uptake was markedly reduced thereby contributing to the raised arterial glutamine. These results demonstrate that acute metabolic acidosis in the dog-influences marked changes in glutamine extraction and ammonia metabolism across the hepatosplanchnic bed without significant changes in kidney or muscle metabolism.

Effect of acute metabolic acidosis on plasma phosphorus concentration.

The effects of acid-base disturbances on plasma phosphorus concentration remain poorly defined. In a previous study, we infused anesthetized mongrel dogs with several mineral and non-mineral acids for one to three hours. HCl and NH4Cl infusions were not associated with changes in plasma phosphorus in contrast to the findings with the organic acids lactic (LA) and beta-hydroxybutyric which increased, and methylmalonic which decreased phosphorus levels. To evaluate these observations further and to gain insight into the mechanism(s) involved we measured plasma phosphorus concentration and renal phosphorus handling in dogs infused with 0.45% NaCl (control), HCl and LA for six hours. In the control group there was no significant change in phosphorus levels whereas the increase in phosphorus concentration for LA was significant after hour four. Although with HCl, phosphorus concentration decreased in the first hour, there was a tendency for an elevation by five hours. Cumulative six hour UpV was significantly lower with HCl than with either LA or NaCl and the data suggest that the infusion of both acids may have blunted the augmentation of phosphorus excretion associated with mild volume expansion. Plasma glucose and insulin measured for three hours showed no significant differences between the groups.

Effect of hypocapnia on intracellular pH during metabolic acidosis

Separate and combined effects of acute metabolic acidosis and hypocapnia were determined in skeletal and cardiac muscles of intact rats. Normocapnic metabolic acidosis, imposed by intraperitoneal injection of hydrochloric acid (6 mEq/kg), did not change skeletal muscle intracellular acid-base parameters. Hypocapnia, induced by mechanical hyperventilation, resulted in intracellular alkalosis within skeletal muscle during both respiratory alkalosis and compensated metabolic acidosis; changes of skeletal muscle intracellular bicarbonate concentration per unit change in carbon dioxide tension were identical during these procedures. These data suggest that processes other than physiochemical buffering neutralize protons taken into skeletal muscle cells during acute metabolic acidosis. The acid-base state of the heart was quite stable during these experimental manipulations; thus, it appears that cardiac muscle has an extraordinary buffering ability. Moreover, our date suggest that processes other than physicochemical buffering maintain cardiac intracellular pH normal during hypocapnia.

The effect of acute metabolic acidosis on plasma cortisol, renin activity and aldosterone.

The effect of metabolic acidosis on the renin-aldosterone system remains unclear. In the present study anesthetized mongrel dogs (n = 19) were infused at similar rates with 0.45% NaCl (controls), HCl or NH4Cl (2.5mEq/kg) for 1--3 h. The induced metabolic acidosis in the two experimental groups was not associated with increases in plasma renin activity. Plasma cortisol (as a marker for ACTH secretion) and serum potassium concentration increased in both HCl- and NH4Cl-treated animals. Plasma aldosterone increased after 30 min in the HCl group and 60 min in the NH4Cl group and did not change in controls. These findings demonstrate that metabolic acidosis induced by HCl or NH4Cl is associated with increased aldosterone production without concomitant changes in plasma renin activity.

Effect of Acute Metabolic Acidosis on the Levels of some Metabolic Intermediates in the Rat Kidney

Rats were sacrificed 30 min, 1 and 2 h after a single dose of ammonium chloride and metabolite levels were measured in quick frozen kidneys. The most striking finding was the early depression of glutamate, 2-oxoglutarate, malate, phosphoenolpyruvate and glycerol-3-phosphate. At the end of 2 h, 2-oxoglutarate and malate still remained depressed but glutamate, phosphoenolpyruvate and glycerol-3-phosphate had returned to normal levels. The results cannot be explained on the basis of acceleration or inhibition of a single enzyme but possibly represent a general effect of pH and/or bicarbonate.

Effect of Acute Metabolic Acidosis on Vasopressin-Dependent Cyclic AMP in Rat Kidney

Acidic media have been reported to inhibit the hydro-osmotic effect of vasopressin in toad bladders, probably through inhibition of the cyclic AMP system. However, the mechanism of inhibition of the cyclic AMP system is controversial. Therefore, that inhibitory mechanism was further investigated in rat kidneys. The antidiuretic response to vasopression was significantly inhibited in animals with metabolic acidosis. The inhibition of the antidiuretic response was associated with a smaller than normal increase of urinary excretion of cyclic AMP after the iv injection of vasopressin. In in vitro experiments, both the increase of cyclic AMP concentration in renal medullary slices and the activation of adenylate cyclase in medulla by vasopressin were significantly less in acidic than in control media. These findings suggest that medabolic acidosis inhibits the antidiuretic effect of vasopressin by inhibiting the vasopressin-dependent cyclic AMP system in the kidney. Acidic media also inhibited cyclic AMP-phosphodiesterase. These dual effects of acidosis on adenylate cyclase and cyclic AMP-phosphodiesterase may explain the conflicting findings observed in the experiments on toad bladders.