Transcript Metabolic acidosis

Metabolic acidosis
P Hantson
Department of Intensive Care, Cliniques St-Luc,
Université catholique de Louvain, Brussels, Belgium
Background
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How to discriminate the own effects of acidosis
from the effects of the underlying conditions =>
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
Where do H+ come from?
Where do H+ come from?
Where do H+ come from?
Regulation of intracellular pH (pHi)
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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
Intracellular buffering capacity
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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 => decrease of
intracellular HCO3-, changes in the electrical
load of the proteins
Ion exchange transporters
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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
Ions exchange transporters
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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- Na+dependent exchanger activated:
alcalinisation of the intracellular compartment
• HCO3- in, Cl- out
– electrogenic Na+ - HCO3- co-exchanger
• entry of HCO3- and Na+
Ion exchange transporters
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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
Metabolic acidosis
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Does acidemia itself cause clinical effects?
Or are these effects caused by the variables
producing acidosis?
– ischemia
– anoxia
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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
Interactions between pHi and cellular
functions
 metabolic
activity
changes in cytoskeleton
 cell volume
 intracellular
membrane
transporters
changes membrane
conductance
 activation,  growth and
 cell proliferation
pHi
 contractility
cell coupling
changes of intracellular
messengers
Metabolism, activation, growth and cell
proliferation
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A. Metabolism
– activation of cell metabolism => increased
production of organic acids => decrease in pHi
– decreased pHi => decreased cellular metabolic
activity
• changes in enzymes activity: phosphofructokinase,
phosphorylase
– also relationship between acidosis and energy
demand
Metabolism, activation, growth and cell
proliferation
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A. Metabolism
– hibernating mammals: decrease of pHi
induced by a rise of pCO2 => decreased
oxygen consumption
– decrease of pHi induced by extracellular
acidosis => 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+)
Metabolism, activation, growth and cell
proliferation
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A. Metabolism
– In conclusion,
• Biphasic effect of extracellular acidosis on
energy metabolism
– 1. Increase of energy demand <= activation of the
mechanisms of regulation of pHi
– 2. With prolonged and severe acidosis, decrease of
energy demand <= decrease of pHi
Metabolism, activation, growth and cell
proliferation
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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
Intracellular messengers: Ca++ & AMPc
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Intracellular acidosis => 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
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Consequences of increased Ca++ cytosolic
concentration?
– Metabolic responses?
– Ca++dependent contractility?
– => but may be blocked by acidosis
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In contrast: acidosis could block the
intracellular influx of Ca++ by voltagedependent calcium channels
Intracellular messengers: Ca++ & AMPc
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In summary
– acidosis could increase intracellular
Ca++ concentration
– acidosis may decrease cellular
responsiveness to Ca++ influx
– acidosis may decrease intracellular Ca++
influx
Intracellular messengers: Ca++ & AMPc
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Acidosis: variable effect on AMPc
according to the type of cells
– AMPc may be  or , but is usually
reduced following intracellular acidosis
Regulation of cell volume
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Changes in osmolarity => changes in cell volume
by membrane ion exchangers
Hypertonic shock => 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
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Metabolic acidosis => activation of Na+/H+
exchanger, cellular ballooning
– activation of RVD
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Competition between mechanisms of regulation
of cell volume and of pHi
Other cellular properties
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Membrane conductance of ion channels
membrane potentials
cytoskeleton
cellular coupling
Effects of acidosis on cell function
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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 >< effects of extracellular and intracellular
acidotic pH on a cell under hypoxic conditions
Effects of acidosis on cell function
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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
Effects of acidosis on cell function
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A. Response of a normal cell to an acidotic
extracellular pHe
– Changes of pCO2 => immediate effects on pHi ><
changes of HCO3- => 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++
Effects of acidosis on cell function
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B. Effects of acidosis on cells during hypoxia
– 1. Mechanisms leading to cell death
• 1.1 Energy failure
– Anoxia => 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++
Effects of acidosis on cell function
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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
Effects of acidosis on cell function
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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++
Effects of acidosis on cell function
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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 (< 6.5)
– …but protective effects only shown at cellular level
Conclusions
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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?