Metabolic acidosis

P Hantson

Department of Intensive Care, Cliniques St-Luc,

Université catholique de Louvain, Brussels, Belgium

Background

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)

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

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

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

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

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

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

Interactions between pHi and cellular functions

pHi

metabolicactivity changes in cytoskeleton

contractility

cell coupling

changes of intracellularmessengers

cell volume

intracellularmembranetransporters

activation, growth and cell proliferation

changes membraneconductance

Metabolism, activation, growth and cell proliferation

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

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

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

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

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

Consequences of increased Ca++ cytosolic concentration?– Metabolic responses?– Ca++dependent contractility?– => but may be blocked by acidosis

In contrast: acidosis could block the intracellular influx of Ca++ by voltage-dependent calcium channels

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

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

Regulation of cell volume

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

Metabolic acidosis => activation of Na+/H+ exchanger, cellular ballooning– activation of RVD

Competition between mechanisms of regulation of cell volume and of pHi

Other cellular properties

Membrane conductance of ion channels membrane potentials cytoskeleton cellular coupling

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 >< effects of extracellular and intracellular acidotic pH on a cell under hypoxic conditions

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

Effects of acidosis on cell function

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

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

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

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

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

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?