Physiology 30: Acid-Base Regulation
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All enzyme systems in body are influenced by H+ concentration
o Normally kept at low level (.00004 mEg/L) and precisely regulated (within 3-5 nEq/L)
Acids release H+ in solutions (ex. HCl, H2CO3)
Base accepts H+ (ex. HCO3, HPO4, proteins [i.e. Hgb])
o Alkali = molecule formed by combo of 1+ alkaline metals (Na, K, Li, etc) with highly basic
ion like OHStrong acid = rapidly dissociates and releases H+ (HCl); weak acid = less likely to dissociate
(H2CO3)
Strong base = reacts rapidly and strongly with H+ (OH-); weak base = binds H+ weakly (HCO3)
o Most acids and bases in ECF are weak
In extreme conditions [H+] can vary from 10 nEq/L to 160 nEq/L without causing death
pH = log(1/[H+]) = -log [H+]
o normal pH of arterial blood = 7.4 and venous blood = 7.35 (extra CO2)
 acidosis <7.4 and alkalosis >7.4 (limits of survival 6.8-8)
o intracellular pH slightly lower than plasma (metabolism produces acid) -> 6-7.4
o pH of urine 4.5-8 and in stomach 0.8
Chemical acid-base buffer systems of body fluids, respiratory center, and kidneys regulate [H+]
(in order of speed of reaction)
Buffer = reversibly bind H+ (Buffer + H+ ↔ H Buffer)
o With high H+ pushed to right as long as buffer available
Bicarbonate buffer system: weak acid (H2CO3) and bicarbonate salt (NaHCO3)
o CO2 + H2O ↔ H2CO3 (via carbonic anhydrase)
 CA abundant in lung alveoli and renal tubules
o
-- → H
H2CO3 ←

o
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+ HCO3-
Weak ionization
NaHCO3 ←
--→ Na
+
+ HCO3-
 NaHCO3 in ECF; ionizes almost completely
o ↑H + HCO3 → H2CO3 → CO2 + H2O (strong acid stimulates respiration)
o NaOH + H2CO3 → NaHCO3 + H2O (CO2 in blood decrease, inhibits respiration, renal
HCO3 excretion)
Dissociation constant K’ = H+ x HCO3/H2CO3
o Cannot be directly measured but CO2 dissolved in blood directly proportional to H2CO3
so… H+ = K x CO2/HCO3
 K is only 1/400 of K’
 CO2 = 0.03 x Pco2 ← measured in labs
Henderson-Hasselbalch equation = -log H+ = -log pK – log (0.03 x Pco2)/HCO3o pH = pK – log (0.03 x Pco2)/HCO3- OR pH = 6.1 + log HCO3-/ (0.03 x Pco2)
 HCO3 concentration is regulated by kidneys, Pco2 controlled by rate of respiration
 Disturbance in ECF [HCO3] = metabolic; Disturbance in Pco2 = respiratory
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When HCO3 and CO2 are equal, pH = pK (6.1). When acid added, HCO3 buffers. When base
added, CO2 converts to HCO3
Bicarbonate buffer system is most effective in central part of titration curve (around pK)
o Between 5.1-7.1 units still effective but beyond this ineffective
o Most powerful extracellular buffer system
Phosphate buffer system: role in buffering renal tubular fluid and intracellular fluids
o Main elements: H2PO4 and HPO4
 HCl + Na2HPO4 → NaH2PO4 + NaCl (strong acid replaced by weak acid)
 NaOH + NaH2PO4 → Na2HPO4 + H2O (strong base replaced by weak base)
o pK of 6.8 allows system to operate near max buffering power
o important in tubular fluids of kidney because phosphate becomes greatly concentrated
in tubules, tubular fluid has lower pH than ECF
o important in buffering ICF because phosphate greater in ICF
Proteins as buffers:
o Diffusion of elements of bicarbonate buffer system causes pH in ICF to change with ECF
o H+ + Hgb ↔ HHgb
 60-70% of chemical buffering of body fluids is inside cells (ICF proteins) but takes
longer to kick in
All buffer systems work together because H+ common in all = isohydric principle
o H+ = K1 x (HA1/A1) = K2 x (HA2/A2) = K3 x (HA3/A3)
Respiratory regulation of acid-base balance = second line of defense
o CO2 formed by intracellular metabolism and diffuses into blood to lungs (1.3 mol/L
normally in ECF = Pco2 of 40 mmHg)
 Change in pulmonary ventilation or rate of CO2 formation changes ECF Pco2
o High alveolar ventilation lowers PCO2
 H+ concentration affects rate of alveolar ventilation (compensation for high pH
not as effective as response to reduced pH)
o Respiratory system acts as negative feedback controller of [H+]
 Cannot return [H+] to normal when disturbance outside respiratory system
(Effective between 50-75% feedback gain of 1-3)
o Respiratory regulation of acid-base balance is a physiologic type of buffer system (acts
rapidly until kidneys take over)
o Abnormalities of respiration (emphysema) -> respiratory acidosis and inability to
respond to metabolic acidosis
Renal control of acid-base balance:
o HCO3 filtered continuously into tubules and H+ secreted
o Body produces 80mEq of nonvolatile acids (can’t be excreted by lungs) and removed by
kidney
 most HCO3 reabsorbed conserving primary buffer system but must react with
H+ to form H2CO3 first
o Kidneys regulate ECF [H+] via secretion of H+, reabsorption of filtered HCO3 and
production of new HCO3
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H+ secretion and HCO3 reabsorption occur in all tubules except descending and ascending thin
limbs of loop of Henle
o Bicarb reabsorption: 85% in proximal tubule, 10% in TAL, and 5% in early distal tubule
 All secrete H+ by Na/H counter-transport (sodium-hydrogen exchanger protein)
 Gradient established by Na/K ATPase on basolateral membrane
 CO2 (from diffusion or metabolism) combines with H2O -> H2CO3 (via
carbonic anhydrase) -> dissociates into HCO3 and H+
o H+ secreted in tubules counter to Na and HCO3 moves with Na
out into blood
H+ secretion and HCO3 filtration combine -> H2CO3 -> CO2 + H2O. CO2 diffuses into tubular cell
and recombines with H2O -> H2CO3 -> HCO3 + H+
o HCO3 diffuses into blood via Na-HCO3 co-transport in proximal tubule and Cl-HCO3
exchange in late proximal tubule, TAL, and collecting tubules
 Each time H+ formed in tubular epithelial cells, HCO3 also formed and released
back into blood
HCO3 and H+ “titrate” each other in tubules (slight excess of H+ to rid nonvolatile acids)
o Excess H+ complete reabsorption of HCO3, excess HCO3 exceeds H+ available
In late distal tubule -> H+ secreted by primary active transport (via hydrogen-transporting
ATPase) -> occurs in intercalated cells
o CO2 in cell combines with H2O -> H2CO3 -> HCO3 (reabsorbed) + H+ (secreted)
o Only 5% of total H+ secreted (important for max acidic urine pH 4.5)
Only small H+ excreted in ionic form. Most excretion via combo with phosphate and ammonia
buffers (urate and citrate too)
o In excess H+ in ECF, kidneys reabsorb all filtered HCO3 and generate new HCO3
Phosphate buffer carries excess H+ into urine, generates new HCO3
o HPO4 and H2PO4 concentrated in tubular fluid and pK of system 6.8
o When all HCO3 reabsorbed, excess H+ + HPO4 -> H2PO4 (excreted as NaH2PO4)
 Net effect is addition of new HCO3 to blood
o Only 30-40 mEq/day of phosphate available to buffer
Ammonia buffer (NH3 and NH4+): synthesized from glutamine (AA metabolism in liver) ->
metabolized in tubules to form 2 NH4 and 2 HCO3 (new bicarbonate)
o HCO3 transported with Na across basolateral membrane and NH4 secreted (countertransport with Na)
o In collecting tubules H+ secreted combining with NH3 (diffuses into lumen) -> NH4+
(impermeant so excreted)
 For each NH4+ excreted, a new HCO3 is generated and added to blood
o Ammonia buffer subject to physiologic control
 Increased ECF [H+] stimulates glutamine metabolism and vice versa
o H+ eliminated via ammonia buffer = 50% of acid excreted and 50% of new HCO3
 In chronic acidosis, dominant mechanism by which acid is eliminated is excretion
of NH4+
Bicarbonate excretion = V x U[HCO3]
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New HCO3 = H+ secretion
o Calculated by measuring NH4 excretion = V x U[NH4+]
NonHCO3, nonNH4 buffer in urine measured by determining titratable acid
o titrate strong base NaOH to pH of 7.4. mEq required = mEq of H+ added to tubule fluid
Net acid excretion = NH4+ excretion + urinary titratable acid – HCO3 excretion
o Must equal nonvolatile acid production in body
o In acidosis, net addition of HCO3 back to blood; in alkalosis, negative net acid secretion
Most important stimuli for increasing H+ secretion by tubules in avidosis = increase in Pco2 of ECF
(respiratory acidosis) and increase in [H+] of ECF (respiratory or metabolic acidosis)
o ↑Pco2 -> ↑ H+ formation in tubular cells -> secretion
o Excessive aldosterone may increase H+ secretion by intercalated cells (Conn’s
syndrome) -> alkalosis
o Because of Na/H exchanger, Na reabsorption may 2ndarily increase H+ secretion
 Via angiotensin II (directly stimulate exchanger) and aldosterone
o Hypokalemia stimulates H+ secretion and hyperkalemia inhibits (in proximal tubule)
Acidosis -> decreased HCO3:H+ ratio in tubular fluid (excess H+)
o Metabolic acidosis -> excess H+ from decreased HCO3 filtration
 Compensatory response = ↑ ventilation and generation of HCO3 in kidney
o Respiratory acidosis -> excess H+ from high ECF Pco2
 Compensatory response = ↑ plasma HCO3 from generation in kidney
o Chronic acidosis -> increased NH4+ production (raises ECF HCO3 to correct)
Alkalosis -> increased HCO3:H+ ratio in tubular fluid (not enough H+)
o Respiratory alkalosis caused by ↓ plasma Pco2 (hyperventilation)
 Compensatory response = increased renal excretion of HCO3
o Metabolic alkalosis caused by rise in ECF [HCO3]
 Compensatory response = ↓ ventilation and renal HCO3 excretion
Respiratory acidosis can occur from damage to respiratory centers (medulla oblongata) or
decreased lung CO2 elimination (obstruction, pneumonia, emphysema, ↓ pulmonary memb SA)
o Compensate with buffers of body fluids and kidneys
Respiratory alkalosis from excess ventilation (psychoneurosis) or high altitude
o Compensate with body fluid buffers and kidneys
Metabolic acidosis from kidney failure to excrete acids, excess acid formation, ingestion or
infusion of acids, or loss of base
o Renal tubular acidosis = defect in renal secretion of H+ and/or reabsorption of HCO3
 Inadequate amounts of titratable acid and NH4 excreted
 Causes: chronic renal failure, Addison’s disease, hereditary/acquired disorders
(Fanconi’s syndrome)
o Diarrhea (most frequent cause of metabolic acidosis) -> loss of large amounts of
NaHCO3
o Vomiting of intestinal contents -> loss of HCO3 -> metabolic acidosis
o Diabetes mellitus -> fats split into acetoacetic acid -> metabolic acidosis
o Ingestion of acids -> acetylsalicylics (aspirin) and methyl alcohol (forms formic acid)
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Chronic renal failure -> buildup of anions of weak acids not excreted, ↓GFR reduces
phosphate and NH4 excretion (metabolic acidosis)
Metabolic alkalosis
o Diuretics (except carbonic anhydrase inhibitors) -> increase flow rate increase Na
reabsorption/H+ secretion
o Excess aldosterone -> milk metabolic alkalosis (Na reabsorbed, H+ secreted)
o Vomiting of gastric contents -> loss of HCl (pyloric stenosis)
o Ingestion of alkaline drugs -> NaHCO3 (gastritis or peptic ulcer treatment)
To neutralize excess acid -> oral sodium bicarbonate, or IV sodium lactate/gluconate
To treat alkalosis -> oral ammonium chloride (liberates HCl) or lysine monohydrochloride
Diagnosis of acid-base disorders =
o Examine pH (<7.4 acidosis, >7.4 alkalosis)
o Examine plasma Pco2 and [HCO3] (normal 40 mmHg, and 24 mEq/L respectively)
 Expected value for respiratory acidosis: ↓ pH, ↑ Pco2, ↑ plasma HCO3 after
renal compensation
 Expected value for metabolic acidosis: ↓ pH, ↓ plasma [HCO3] and ↓ Pco2 after
respiratory compensation
 Respiratory alkalosis: ↑ pH, ↓ Pco2, ↓ [HCO3}
 Metabolic alkalosis: ↑ pH, ↑ [HCO3] and ↑ Pco2
Mixed acid-base disorder = 2+ underlying causes for disturbance
o Ex. acute HCO3 loss from GI tract diarrhea (acidosis) + emphysema (acidosis)
o Diagnosis -> avid-base nomogram (pH, [HCO3}, Pco2 intersect with normal range in
middle)
 Assume sufficient time for compensatory response; within shaded area = simple
acid-base disturbance. Outside shaded area = mixed
Cation normally measured = Na+ and anions = Cl and HCO3
o Plasma anion gap = [Na] – [HCO3] –[Cl] = 144 – 24 – 108 = 12 mEq/L
 Used in diagnosing different causes of metabolic acidosis
 HCO3 changed so Cl must increase to compensate -> hyperchloremic
metabolic acidosis
 HCO3 changed w/o Cl increase, unmeasured anions increased
(increased anion gap) -> lactic acidosis or ketoacidosis
o Important unmeasured cations = Ca, Mg, K and anions = albumin, PO4, SO4