Oxidative Stress

Factor VII deficiency

pH 7.4 PCO2

A. Oxidative Stress

Development of Alkalosis

The pH of blood depends on the ratio of HCO3– to CO2concentration:

pH = pK + lg [HCO3–]/[CO2]

pK contains the dissociation constant of H2CO3

and the reaction constant of CO2to H2CO3. Al-kalosis (pH > 7.44) thus occurs either when the CO2concentration in blood is too low (hypo-capnia, respiratory alkalosis), or that of HCO₃^– is too high (metabolic alkalosis).

Respiratory alkalosis occurs in hyperventila-tion (→A 3 and p. 86). Causes include emotion-al excitement (fear, pain), pregnancy (proges-terone), fever, heat, salicylate poisoning, or damage to the respiratory neurons (e.g., by in-flammation, injury, or liver failure). Occasion-ally hypoxia (ventilation to perfusion distribu-tion abnormality, severe anemia, low O2 pres-sure in the inspiratory air [e.g., at high alti-tude]) causes increased ventilation resulting in an increased amount of CO2 being expired.

Numerous disorders can lead to metabolic (i.e., non-respiratory) alkalosis:

◆In hypokalemia (causes→p. 134) the chemi-cal gradient for K⁺across all cell membranes is increased. In some cells this leads to hyperpo-larization, which drives more negatively charged HCO3–from the cell. Hyperpolarization, for example, increases HCO3–efflux from the proximal (renal) tubule cell via Na⁺(HCO3–)3 co-transport (→A 4). The resulting intracellular acidosis stimulates the luminal Na⁺/H⁺ ex-change and thus promotes H⁺secretion as well as HCO3–production in the proximal tubule cell.

Ultimately both processes lead to (extracellular) alkalosis.

◆In vomiting of stomach contents the body loses H⁺(→A 6). What is left behind is the HCO3–produced when HCl is secreted in the parietal cells. Normally the HCO3–formed in the stomach is reused in the duodenum to neu-tralize the acidic stomach contents and only transiently leads to (weak) alkalosis (alkali tide).

◆Vomiting also reduces the blood volume.

Edemas as well as extrarenal and renal loss of fluid can similarly result in volume depletion (→A 4; see also p. 132). Reduced blood volume stimulates Na⁺/H⁺exchange in the proximal

tubules and forces increased HCO3– reabsorp-tion by the kidneys even in alkalosis. In addi-tion, aldosterone is released in hypovolemia, stimulating H⁺secretion in the distal nephron (→A 5). Thus, the kidneys ability to eliminate HCO3–is compromised and the result is volume depletion alkalosis. Hyperaldosteronism can lead to alkalosis without volume depletion.

◆Parathyroid hormone (PTH) normally inhib-its proximal renal tubular HCO₃^–absorption (→A 4). Hypoparathyroidism can thus lead to alkalosis.

◆The liver forms either glutamine or urea from the NH4+generated by amino acid ca-tabolism. The formation of urea requires, in ad-dition to two NH4+, the input of two HCO3–that are lost when urea is excreted. (However, NH4+ is split off from glutamine in the kidney and then excreted as such). In liver failure hepatic production of urea is decreased (→A 7), the liv-er uses up less HCO3–, and alkalosis develops.

However, in liver failure respiratory alkalosis often predominates as a result of inadequate stimulation of the respiratory neurons (see above).

◆An increased supply of alkaline salts or mo-bilization of alkaline salts from bone (→A 2), for example, during immobilization, can cause alkalosis.

◆Metabolic activity may cause the accumu-lation of organic acids, such as lactic acid and fatty acids. These acids are practically completely dissociated at blood pH, i.e., one H⁺ is produced per acid. If these acids are metabo-lized, H⁺disappears again (→A 1). Consump-tion of the acids can thus cause alkalosis.

◆The breakdown of cysteine and methionine usually produces SO42–+ 2 H⁺, the breakdown of arginine and lysine produces H⁺. Reduced protein breakdown (e.g., as a result of a pro-tein-deficient diet; →A 8), reduces the metabolic formation of H⁺and thus favors the development of an alkalosis.

The extent to which the bloodʼs pH is changed depends, among other factors, on the buffering capacity of blood (e.g., release of H⁺ from plasma proteins), which is reduced when the plasma protein concentration is lowered.

94

4Respiration,Acid–BaseBalance

Plate4.13DevelopmentofAlkalosis

95 CO32–

HCO3–

PO43–

HCl

NH4+

[HCO3–] [CO2] Met

SO42– H⁺ Cys

[H⁺]

pH = pK + lg [HCO3–] [CO2]

H2O CO2

H⁺

K⁺ HCO3–

2 1

5

3

6

7

8

HCO3–

H⁺ 4

K⁺

HCO3–

H⁺ Na⁺

3HCO3–

Na⁺ K⁺

H2PO4–

H⁺

Demineralization Hyperventilation

Vomiting

Liver failure

Urea

HCO3– consumption

Protein deficiency

CO2 output with expiration

H⁺ excretion Hypo-volemia

Hypo-kalemia

Hypopara-thyroidism Aldosterone Proximal tubules

Distal nephron

Lactate, dissociated fatty acids, etc.

Consumption of organic anions Metabolism

H⁺ consumption

Lys Arg

PrH Pr HCO3– production

>7.45 Alkalosis A. Causes of Alkalosis

Development of Acidosis

The pH of blood is a function of the concentra-tions of HCO3–and CO2(→p. 86). An acidosis (pH < 7.36) is caused by too high a concentra-tion of CO2(hypercapnia, respiratory acidosis) or too low a concentration of HCO3–(metabolic acidosis) in blood.

Many primary or secondary diseases of the respiratory system (→p. 70–84) as well as ab-normal regulation of breathing (→p. 86) can lead to respiratory acidosis (→A 3). This can also be caused by inhibition of erythrocytic car-bonic anhydrase, because it slows the forma-tion of CO2from HCO3–in the lung and thus im-pairs the expiratory elimination of CO2from the lungs.

There are several causes of metabolic aci-dosis:

◆In hyperkalemia (→A 4, causes p. 134) the chemical gradient across the cell membrane is reduced. The resulting depolarization dimin-ishes the electrical driving force for the electro-genic HCO3–transport out of the cell. It slows down the efflux of HCO₃^–in the proximal tu-bules via Na⁺(HCO3–)3cotransport. The result-ing intracellular alkalosis inhibits the luminal Na⁺/H⁺exchange and thus impairs H⁺secretion as well as HCO3–production in the proximal tu-bule cells. Ultimately these processes lead to (extracellular) acidosis.

◆Other causes of reduced renal excretion of H⁺ and HCO3– production are renal failure (→p. 120 ff.), transport defects in the renal tubules (→p. 104 ff.), and hypoaldosteronism (→A 5). (Normally aldosterone stimulates H⁺ secretion in the distal tubules;→p. 292).

◆PTH inhibits HCO3–absorption in the proxi-mal tubules; thus in hyperparathyroidism renal excretion of HCO3–is raised. As PTH simulta-neously promotes the mobilization of alkaline minerals from bone (→p. 142), an acidosis only rarely results. Massive renal loss of HCO3– occurs if carbonic anhydrase is inhibited (→p. 104 ff.), because its activity is required for HCO3–absorption in the proximal tubules.

◆Loss of bicarbonate from the gut (→A 6) oc-curs in vomiting of intestinal contents, diar-rhea, or fistulas (open connections from the gut or from excretory ducts of glands). Large amounts of alkaline pancreatic juice, for exam-ple, can be lost from a pancreatic duct fistula.

◆As the liver needs two HCO3–ions when in-corporating two molecules of NH4+; in the for-mation of urea (→p. 94), increased urea pro-duction can lead to acidosis. In this way the supply of NH4Cl can cause acidosis (→A 7).

In certain circumstances the infusion of large amounts of NaCl solution can lead to an acidosis, because extracellular HCO3–is “dilut-ed” in this way. In addition, expansion of the extracellular space inhibits Na⁺/H⁺exchange in the proximal tubules as a result of which not only Na⁺absorption in the proximal tu-bules but also H⁺secretion and HCO3– absorp-tion is impaired.

◆Infusion of CaCl2results in the deposition of Ca²⁺in bone (→A 2) in the form of alkaline salts (calcium phosphate, calcium carbonate). H⁺ ions, formed when bicarbonate and phosphate dissociate, can cause acidosis.

◆Mineralization of bone, even without CaCl2, favors the development of acidosis (→A 2).

◆Acidosis can also develop when there is in-creased formation or dein-creased breakdown of organic acids (→A 1). These acids are practical-ly fulpractical-ly dissociated at the blood pH, i.e., one H⁺ is formed per molecule of acid. Lactic acid is produced whenever the energy supply is pro-vided from anaerobic glycolysis, for example, in O2deficiency (→p. 90), circulatory failure (→p. 248), severe physical exercise, fever (→p. 26 ff.), or tumors (→p. 18 ff.). The elimi-nation of lactic acid by gluconeogenesis or deg-radation is impaired in liver failure and some enzyme defects. Fatty acids,β-hydroxybutyric acid and acetoacetic acid accumulate in certain enzyme defects but especially in increased fat mobilization, for example, in starvation, diabe-tes mellitus (→p. 310 ff), alcohol withdrawal, and hyperthyroidism.

◆A protein-rich diet promotes the develop-ment of metabolic acidosis, because when ami-no acids containing sulfur are broken down (methionine, cystine, cysteine), SO42–+ 2 H⁺ are generated; when lysine and arginine are broken down H⁺is produced (→A 8).

The extent of acidosis depends, among other factors, on the bloodʼs buffering capacity (e.g., binding of H⁺to plasma proteins).

96

4Respiration,Acid–BaseBalance

Plate4.14DevelopmentofAcidosis

97 HCO3–

NH4+

[HCO3–] [CO2]

H2O [H⁺]

pH = pK + log[HCO3–] [CO2] Met

SO42– H⁺ Cys

4 K⁺

HCO3–

HCO3–

H⁺ H⁺

Na⁺ 3HCO3–

Na⁺ K⁺

CO32–

HCO3–

PO43–

H2PO4–

H⁺

2 1

5

3

8

6

7

Mineralization Hypoventilation

Renal failure

Protein excess

Diarrhea

HCO3– absorption and formation

NH4+ uptake

HCO3– excretion

HCO3– consumption

CO2 output with expiration

Hypoaldo-steronism Hyperkalemia

H⁺ excretion

Proximal tubule

Distal nephron Formation of organic acids Lactate,

dissociated fatty acids, acetic acids, etc.

Metabolism

H⁺ formation

Lys Arg

< 7.35 Acidosis Urea

PrH Pr A. Causes of Acidosis

Effects of Acidosis and Alkalosis

It is through changes in breathing and renal functions that the body tries to compensate for abnormalities of acid–base metabolism, thus to keep blood pH constant. Changes in pH as well as HCO3–and CO2concentrations in blood, when acid–base balance is abnormal, and how they are compensated can be demon-strated in graphs (e.g., [HCO3–] may be plotted as a function of PCO2[→A, left] or the logarithm of P_CO2, plotted as a function of pH [→A, right];

Siggaard-Andersen nomogram: gray lines = CO2equilibration lines).

◆Respiratory alkalosis (→A 1) is compensated by decreased reabsorption of HCO3–in the kid-neys.

◆Metabolic alkalosis (→A 2) can theoretically be compensated by hypoventilation. But the need to take up sufficient O2sets narrow limits to this form of compensation.

◆Respiratory acidosis (→A 4) is compensated by increased renal excretion of acids (or through forming HCO3–). The increased plasma HCO3– results in more HCO₃^–being filtered at the glo-meruli. The kidney must therefore continually reabsorb an increased amount of filtered HCO3–if renal loss of HCO3–is to be avoided.

◆Metabolic acidosis (→A 3) can be compen-sated by respiratory reduction in plasma CO2

concentration. However, the lower the plasma CO2concentration the less CO2is given off with each breath. Thus, in order to exhale the particular amount of CO₂, hyperventilation must be maintained until the plasma HCO3– concentration is again normal, either through raised renal excretion of acid or through the breakdown of organic anions (→p. 94).

Effects of alkalosis include hypokalemia, be-cause the cells release less HCO3–, depolarize less, and thus lose less K⁺. If H⁺is removed from the cell by Na⁺/H⁺exchange, Na⁺gains ac-cess to the cell, but is again pumped out of the cell in exchange for K⁺(→B). Partially through the hypokalemia alkalosis may trigger cardiac arrhythmia.

In addition, more Ca²⁺is bound to plasma proteins in alkalosis (→B, right). As a result, there is a fall in the concentration of ionized Ca²⁺ in plasma. As part of Ca²⁺in plasma is also bound to HCO3–, the concentration of free Ca²⁺falls more in metabolic than in respiratory alkalosis.

Effects, especially of respiratory alkalosis (hypo-capnia), include among others raised neuromus-cular excitability with cramps, in large part the result of constriction of the cerebral vessels and thus hypoperfusion of the brain. Intracellular al-kalosis can inhibit neuromuscular excitability by activating the K⁺channels. Hypocapnia also stimulates contraction of the bronchial muscula-ture and thus increases airway resistance. Alka-losis inhibits gluconeogenesis and promotes glycolysis so that hypoglycemia and lactacide-mia may occur. Intracellular alkalosis further favors cell division. Inhibition of the respiratory drive in alkalosis could result in hypoxemia.

The effects of respiratory and metabolic aci-dosis (→B, red arrows) are largely similar. They are in part due to activation of H⁺sensing recep-tors. In extracellular acidosis the cells lose HCO3−; through depolarization they also lose K⁺. In addition, acidosis inhibits the Na⁺/K⁺ -ATPase. Hyperkalemia develops (→p. 134). On the other hand, acidosis stimulates Na⁺/H⁺ ex-change. The result is not only Na⁺uptake but also cell swelling.

Furthermore, intracellular acidosis inhibits K⁺channels and has a negative inotropic effect as well as (by blocking the intercellular connec-tions) a negative dromotropic effect on the car-diac muscle (→B, right). Acidosis and hypercap-nia may induce relaxation of the bronchial mus-cles and constriction of the pulmonary arteri-oles. The latter may increase pulmonary vascu-lar pressure and predispose to the development of pulmonary edema. Hyperkapnia may further lead to peripheral vasodilation (fall in blood pressure, rise in intracerebral pressure, head-ache, lethargy, and coma). Intracellular acidosis inhibits the pacemaker enzymes of glycolysis and hyperglycemia occurs. Prolonged acidosis promotes demineralization of bone (→B, right), because of dissolution of alkaline bone salts as well as inhibition of osteoclast apoptosis, of re-nal Ca²⁺reabsorption, and of calcitriol forma-tion (→p. 142). In intracellular acidosis H⁺is taken up by the mitochondria in exchange for Ca⁺. H⁺also inhibits adenylylcyclase and thus impairs hormonal effects. Finally, cellular acido-sis inhibits cell division and favors apoptotic cell death. Stimulation of respiration during acido-sis may result in Kussmaul breathing (→p. 86).

98

4Respiration,Acid–BaseBalance

Plate4.15EffectsofAcidosisandAlkalosis

99 H⁺

100 10 50

20

10 5 40

30

20

10

0

40 30 20 10

0 50 60 70

2 4 6 8

3 2

1 4 4

2 3

2

7.6 7.8 7.4

7.2

7.0 pH

[Ca²⁺]i Na⁺

HCO3– (mmol/L)

K⁺

H⁺Ca²⁺

Cl^–

G6P ATP cAMP

K⁺ Na⁺

H⁺ H⁺

HPO42–

PO43–

H⁺

PCO2 (kPa) 1

K⁺ HCO3–

mmHg kPa

Protein Ca²⁺

Protein H⁺ H⁺

Ca²⁺

Abnormality Compensation Alkalosis

Acidosis

Alkalosis

Acidosis

Siggaard-Andersen nomogram

Plasma potassium level

Excitability, transport

Intercellular connections

Cell division, apoptosis

Glycolysis

Hormonal effects Acidosis

Alkalosis

Lactate Respiratory abnormality Metabolic abnormality Normal

Respiratory compensation Renal compensation

Cell volume

PCO2 (mmHg) blood

Contraction Vasodilation Respiratory

drive

Bronchoconstriction Vasodilation Hypocalcemia in alkalosis PCO2 blood

Demineralization Acidosis B. Effects of Acidosis and Alkalosis