Metabolic acidosis

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Metabolic acidosis

• P Hantson
• Department of Intensive Care, Cliniques St-Luc,
• Université catholique de Louvain, Brussels,
  Belgium

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Background

• How to discriminate the own effects of acidosis
  from the effects of the underlying conditions gt
  acidosis?
• Is the cell the cause or the victim of acidosis?
  Is acidosis deleterious or protective?
• Different mechanisms leading to acidosis
• mineral acidosis normal cells in an acidotic
  extracellular pH
• acidosis is the cause of cellular dysfunction
• organic acidosis cellular failure with organic
  acids overproduction
• acidosis is the consequence of cellular
  dysfunction

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Where do H come from?
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Where do H come from?
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Where do H come from?
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Metabolic acidosis

• Cardiovascular
• Impairment of cardiac contractility
• Arteriolar dilatation, venoconstriction, and
  centralization of blood volume
• Increased pulmonary vascular resistance
• Reduction in cardiac output, arterial blood
  pressure, and hepatic and renal blood flow
• Sensitization to reentrant arrhythmias and
  reduction in threshold of ventricular
  fibrillation
• Attenuation of cardiovascular responsiveness to
  catecholamines
• Respiratory
• Hyperventilation
• Decreased strength of respiratory muscles and
  promotion of muscle fatigue
• Metabolic
• Increased metabolic demands
• Insulin resistance
• Inhibition of anaerobic glycolysis
• Reduction in ATP synthesis
• Hyperkalemia
• Increased protein degradation
• Cerebral
• Inhibition of metabolism and cell-volume
  regulation

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Metabolic versus respiratory acidosis
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Regulation of intracellular pH (pHi)

• Values of pHi experimental conditions, types of
  cells, level of metabolic activation
• Usually 6,8-7,2
• Strict regulation of pHi
• at least two systems
• intracellular buffering capacity
• several systems of ion exchange transporter

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Intracellular buffering capacity

• Intrinsic buffering capacity (proteins and
  phosphates buffers) buffering capacity of
  HCO3-/CO2 system
• intracellular pCO2 extracellular pCO2
  interstitial pCO2 ? venous pCO2
• intracellular concentration of HCO3- ? 12 mmol/l
• intracellular acid load 99.99 of the protons
  kept by the buffering systems gt decrease of
  intracellular HCO3-, changes in the electrical
  load of the proteins

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Ion exchange transporters

• A. Na/H exchanger
• energy gradient Na e - i, ejection of H
• activation
• alcalanisation of the intracellular compartment
• entry of Na, and of water
• selectively inhibited by amiloride
• activated by a decrease of pHi, hypertonic shock,
  some anabolic hormones (insulin, cortisol, growth
  hormone)
• sensitivity of Na/H exchanger different from
  cell to cell

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Ions exchange transporters

• B. Transport of HCO3-
• also activated by changes in pHi
• Cl-/HCO3- exchanger activated acidification of
  the intracellular compartment
• HCO3- out, Cl- in
• Cl-/HCO3- Nadependent exchanger activated
  alcalinisation of the intracellular compartment
• HCO3- in, Cl- out
• electrogenic Na - HCO3- co-exchanger
• entry of HCO3- and Na

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Ion exchange transporters

• C. Other systems
• production of organic acids
• cetogenesis and glycolysis are stimulated in
  presence of alcalosis
• normalisation of pHi
• regulation of pHi level of
  cellular
• 
  activation

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Metabolic acidosis

• Does acidemia itself cause clinical effects?
• Or are these effects caused by the variables
  producing acidosis?
• ischemia
• anoxia
• Are the clinical consequences associated with
  acidosis related to the intra-cellular acid-base
  status or that of the extracellular fluid?
• Comparison of the effects associated with
  respiratory vs metabolic acidosis
• diffusibility of CO2 compared to strong ions

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Interactions between pHi and cellular functions
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Metabolism, activation, growth and cell
proliferation

• A. Metabolism
• activation of cell metabolism gt increased
  production of organic acids gt decrease in pHi
• decreased pHi gt decreased cellular metabolic
  activity
• changes in enzymes activity phosphofructokinase,
  phosphorylase
• also relationship between acidosis and energy
  demand

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Metabolism, activation, growth and cell
proliferation

• A. Metabolism
• hibernating mammals decrease of pHi induced by a
  rise of pCO2 gt decreased oxygen consumption
• decrease of pHi induced by extracellular acidosis
  gt inhibition of neoglucogenesis, decrease of
  hepatic urea, increase of the cytoplasmic ATP/ADP
  ratio
• but the activation of Na/H exchanger could in a
  first step increase E demand (activation of
  Na/K ATPase pump secondary the cytoplasmic load
  of Na)

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Metabolism, activation, growth and cell
proliferation

• A. Metabolism
• In conclusion,
• Biphasic effect of extracellular acidosis on
  energy metabolism
• 1. Increase of energy demand lt activation of the
  mechanisms of regulation of pHi
• 2. With prolonged and severe acidosis, decrease
  of energy demand lt decrease of pHi

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Metabolism, activation, growth and cell
proliferation

• B. Activation, growth and proliferation
• increase of pHi by the activation of the Na/H
  exchanger after exposure to anabolic hormones
• role of pHi on cell proliferation in humans
  controversial
• on the whole
• alcalosis anabolic responsiveness, metabolic
  activation, cell growth, proliferation
• acidosis reduced metabolic activity

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Intracellular messengers Ca AMPc

• Intracellular acidosis gt increase of cytosolic
  Ca
• 1. Removal of Ca from protein binding sites
• 2. Activation of a Na/Ca exchanger secondary
  to increase of Na intracellular influx due to
  the decrease of pHi
• Consequences of increased Ca cytosolic
  concentration?
• Metabolic responses?
• Cadependent contractility?
• gt but may be blocked by acidosis
• In contrast acidosis could block the
  intracellular influx of Ca by voltage-dependent
  calcium channels

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Intracellular messengers Ca AMPc

• In summary
• acidosis could increase intracellular Ca
  concentration
• acidosis may decrease cellular responsiveness to
  Ca influx
• acidosis may decrease intracellular Ca influx

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Intracellular messengers Ca AMPc

• Acidosis variable effect on AMPc according to
  the type of cells
• AMPc may be ? or ?, but is usually reduced
  following intracellular acidosis

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Regulation of cell volume

• Changes in osmolarity gt changes in cell volume
  by membrane ion exchangers
• Hypertonic shock gt passive decrease of cell
  volume
• restoration of initial volume by RVI
• activation of Na/H exchanger with
  alcalinisation of intracellular compartment,
  entry of Na and water
• Metabolic acidosis gt activation of Na/H
  exchanger, cellular ballooning
• activation of RVD
• Competition between mechanisms of regulation of
  cell volume and of pHi

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Other cellular properties

• Membrane conductance of ion channels
• membrane potentials
• cytoskeleton
• cellular coupling

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Effects of acidosis on cell function

• Cellular response to metabolic acidosis ? effect
  of lowering extracellular pH on cell function
• Decrease of plasma pH during metabolic acidosis
• impaired elimination of an extracellular acid
  load
• overproduction of intracellular acid due to
  energy failure
• Effects of extracellular acidotic pH on a normal
  cell gtlt effects of extracellular and
  intracellular acidotic pH on a cell under hypoxic
  conditions

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Effects of acidosis on cell function

• A. Response of a normal cell to an acidotic
  extracellular pHe
• 1. Cell in normoxia exposed to acid pHe with
  constant pCO2 level progressive ? of pHi //
  degree of extracellular acidosis
• 2. Cell exposed to a decrease of pHe with
  decreased pCO2 level first sudden ? of pHi, then
  progressive ? of pHi // degree of extracellular
  acidosis
• 3. Cell exposed to a decrease of pHe with
  increased pCO2 level, first sudden ? of pHi, then
  progressive ? of pHi

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Effects of acidosis on cell function

• A. Response of a normal cell to an acidotic
  extracellular pHe
• Changes of pCO2 gt immediate effects on pHi gtlt
  changes of HCO3- gt progressive effects
• Value of pHi at equilibrium inhibition of the
  intracellular transfer mechanisms of HCO3- /
  activation of the Na/H exchanger
• With decreased pHi swelling, catabolism, ?
  sensitivity to Ca

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Effects of acidosis on cell function

• B. Effects of acidosis on cells during hypoxia
• 1. Mechanisms leading to cell death
• 1.1 Energy failure
• Anoxia gt reduction of mitochondrial ATP
  production
• Inhibition of the Na/K ATPase pump
• 1.2. Activation of cytolytic enzymes
• Reduction of membrane phospholipides,
  phospholipase A2 activated by intracellular
  influx of Ca
• 1.3. Ischemia - reperfusion
• Hypoxic-ischemic stress production of free
  radicals
• Changes of mitochondrial membrane permeability
• Activation of Na/H exchanger influx of Na,
  activation of Na/Ca , with influx of Ca

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Effects of acidosis on cell function

• B. Effects of acidosis on cells during hypoxia
• 2. Is acidosis deleterious or protective during
  hypoxia?
• Classically said detrimental acidosis inhibits
  phosphofructokinase, activates Na/H exchanger,
  stimulates free radical production
• Protective? Several experimental models
• hepatocytes intoxicated by cyanide
• anoxic cells and acidotic environment

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Effects of acidosis on cell function

• Effects of acidosis on cells during hypoxia
• 2. Is acidosis deleterious or protective during
  hypoxia?
• Decrease of pHi is responsible for the protective
  effect of external acidosis
•  Sparing  effect of intracellular acidosis on
  metabolism
• Prevention of the activation of phospholipase A2
  in the presence of an influx of Ca

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Effects of acidosis on cell function

• B. Effects of acidosis on cells during hypoxia
• 2. Is acidosis deleterious or protective during
  hypoxia?
• Also with ischemia-reperfusion models
• the  pH paradox  re-oxygenation or
  re-perfusion in an acidotic environment give
  better results
• but deleterious effects when pH too low (lt 6.5)
• but protective effects only shown at cellular
  level

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Conclusions

• Results on cell function may vary according to
  the origin of acidosis
• Hypoxic cell adaptative energetic metabolism,
  protective effect of acidosis
•  Normal  cell exposed to external acidosis
  increased energy demand to maintain homeostasis
• What is important for the cell?
• Energy vs pH homeostasis?

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Particularities of poisoning

• Impaired oxygen utilisation cyanide, carbon
  monoxide increased lactate production
• Exogenous source of acids methanol, salicylates