2. Amount of NaCl body determines the volume of ECF Change in the amount of NaCl always leads to change in ECF volume! Change in ECF volume causes change in urine excretion via: 1. Directly- pressure diuresis 2. Sympethetic nervous system (volume and pressure receptors) 3. Hormonones (renin) ↑ ECF osmolality ↑ ADH ↑ thirst & H 2 O intake ↓ urine excretion (concentrated urine) ↑ ECF volume ↑ NaCl intake

3. Changes in mean arterial pressure  changes in urine excretion Mechanism ( ↑ Pa): 1. ↑ MGF 2. ↑ Pk  ↑ backleak of Na+ in tubules 3. ↓ angiotensin II Pressure diuresis/ natriuresis

4. Main mechanism of control of ECF volume. Intrinsic to isolated kidney! But But, hormonones (renin-ang- aldo) increase its efficacy!

5. Sensors of ECF volume Low- and high-pressure sensors react to changes in blood circulating volume and mean arterial pressure.

6. Factors that affect (increase efficacy) pressure diuresis

7. Axis renin – angiotensin – aldosterone ACE inhibitors

8. Integrated response to decreased ECF volume

9. Integrated response to increased ECF volume

11. Regulation of internal potassium distribution Normal ECF concentration: 4.2 ± 0.3 mEq/l Narrow range of ECF concentration - great influence of resting E m and excitability! After meal, distribution of K + into the cells.

12. Factors influencing extracellular concentration of K + ↑ Na + /K + ATP-ase activity

13. Main regulator for K + - kidney Late distal tubule and collecting duct – regulate final amount of excreted K +. Increased K + intake Increased secretion in DT and CD. Minimal excretion in urine ≈ 1 % of filtered K + load.

14. Principal cells – K + secretion

15. Factors regulating K + excretion 1. K + concentration in ECF 2. Aldosterone 3. Tubular flow Increased flow – increased secretion 4. Acid-base status Acute acidosis ( ↓ ) Chronic acidosis ( ↑ ) Addison disease

16. Influence of acute and chronic acidosis on tubular K + excretion

19. pH H + concentration is very low (3x10 6 lower than Na + )  expressed as –log [H + ] ili pH. Normal pH = 7.4 (between 6.8 i 7.8 compatible with life). All biochemical reactions are sensitive to pH. Production/intake of acid and base = elimination of acid/base  constant pH

20. Production of acid and base volatile acid In physiological conditions, large amounts of volatile acid (CO 2 ) are produced (15-20 mol/day) eliminated completely in the lungs. CO 2 + H 2 O  H 2 CO 3  H + + HCO 3 - nonvolatile acid Metabolism of normal diet results in more acid than alkali (50-100 mmol/day)  nonvolatile acid (eliminated in kidneys). Nonvolatile acid: aminoacid metabolism(H 2 SO 4, HCl), anaerobic metabolism (lactic acid)…

21. Control of acid-base balance buffer systems 1. Buffering of H + by body fluids (buffer systems). 2. Respiratory regulation (CO 2 ) 3. Renal control (regulation of amount of nonvolatile acid/base) Buffer systems in body fluids (ECF and ICF) prevent changes in pH until lungs and kidneys (especially!) excrete the surplus of acid or base.

22. Buffer systems First line of defence – prevent local changes of pH Do not remove H + from the body or add them (just prevent local changes in free H + ). Pairs of weaks acids and bases (can reversibly release or bind H + ): buffer + H + ↔ Hbuffer

23. 1. Bicarbonate buffer system (H 2 CO 3/ HCO 3 - ) 1. CO 2 + H 2 O ↔ H 2 CO 3 ↔ H + + HCO 3 - extracellular buffer. The most important extracellular buffer. Addition of acid  decrease in HCO 3 -, increase in CO 2 (expired). Addition of base  increase in HCO 3 -, decrese in CO 2 All HCO 3 - would be spent in 5 days (if there was no HCO 3 - restoration by the kidneys).

24. 2. Phosphate buffer system (H 2 PO 4 - /HPO 4 2- ) Buffers intracellular and renal tubular fluid. H 2 PO 4 - ↔ H + + HPO 4 2-

25. Protein buffer systems H + + Hb ↔ HHb (RBC) H + + Protein ↔ HProtein Intracellular buffers. 60-70 % of total buffering by body fluids, but they are slow (hours). Important for buffering of respiratory acid-base disorders! In resp. acidosis CO 2 enters the cells and CO 2 + H 2 O ↔ H 2 CO 3 ↔ H + + HCO 3 -

26. Respiracijska regulacija acidobazne ravnoteže  Plućna ventilacija – regulacija količine hlapljive kiseline (CO 2 ) CO 2 + H 2 O ↔ H 2 CO 3 ↔ H + + HCO 3 - ↑[H + ] → ↑ alveolarna ventilacija ↓ ↓P CO2 -  brži od bubrega (minute).

27. Renal control of acid base balance Kidney control the amount of H + i HCO 3 - iona which they excrete. Excretion of either acid or basic urine. Normally Reabsorption of all filtered HCO 3 - ( 180 l/day x 23 mmol/l = 4320 mmol/day) And, excrete the excess H + (replenish HCO 3 - used for buffering) In all processes : tubular secretion of secretion of H +. pH of urine cannot be lower than 4!

28. Reabsorption of HCO 3 - Except in alkalosis, all filtered HCO 3 - is reabsorbed.

29. Reabsorption of HCO 3 - i secretion of H + Proximal tubule Collecting duct Reabsorption of HCO 3 - is always coupled to tubular secretion of H +. Reabsorption of HCO 3 - is not coupled with net excretion of H +, since H + binds to the filtered HCO 3 - (in tubular fluid).

30. “Titration” of H + and HCO 3 - Usually slight excess of H + secreted compared to amount of filtered HCO 3 - (= nonvolatile acid). This excess H + of cannot be titrated with HCO 3 -. H + cannot be excreted as free ion ( ↓↓ pH). H + is combined with urinary buffers (phosphate and ammonia).

31. Phosphate urinary buffer H 2 PO 4 - /HPO 4 2- Combining of H + with urinary buffers - net addition of new HCO 3 - in ECF. Phosphate buffer binds ≈ 15-20 mmol/day (total excretion 80 mmol/day)

32. Ammonia urinary buffers  NH 3 / NH 4 +  Acid-base conditions regulate production and excretion of NH 4 +.

33. Amount of excreted acid Net-acid excretion = NH 4 + excretion + Urinary titrable acid – HCO 3 - excretion

34. Regulation of renal tubular H + secretion Acidosis: H + secretion >>HCO 3 - filtration Alkalosis: H + secretion < HCO 3 - filtration

35. Acid-base disorders CO 2 + H 2 O ↔ H 2 CO 3 ↔ H + + HCO 3 -

36. Metabolic acidosis ↓ pH, ↓ [HCO 3 - ] Compensation: Intra- and extra-cellular buffering hyperventilation i ↓ pCO 2 ↑ renal H + excretion Causes: loss of alkali (diarrhea) addition of acid (ketoacidosis, lactacidosis, renal failure). Acidosis can be solved only when primary cause is removed (compensation cannot bring pH to normal!)

37. Metabolic alkalosis ↑ pH, ↑ [HCO 3 - ] Compensation: Intra- and extra-cellular buffering hypoventilation i ↑ pCO 2 (limited due to hypoxia) ↑ renal HCO 3 - excretion (decreased in hypovolemia) Causes: loss of acid (vomiting), addition of alkali (anticaids).

38. Respiratory acidosis ↓ pH, ↑ pCO 2 ↑ [HCO 3 - ] Compensation: Intracellular buffering ↑ renal H + excretion Requires few days Before renal compensation (acute acidosis) increase in [HCO 3 - ] is smaller per unit of pCO 2 than in chronic phase. Causes: hypoventilation (pulmonary edema, supression of respiratory center) CO 2 + H 2 O  H 2 CO 3  H + + HCO 3 -

39. Respiratory alkalosis ↑ pH, ↓ pCO 2 Causes: hyperventilatio Compensation: Intracellular buffering ↑ renal HCO 3 - excretion (in chronic phase) Fall in [HCO 3 - ] is smaller in acute than in chronic phase. Requires few days Before renal compensation (acute acidosis) increase in [HCO 3 - ] is smaller per unit of pCO 2 than in chronic phase. CO 2 + H 2 O  H 2 CO 3  H + + HCO 3 -

40. Analysis of acid-base disorders 5.3 kPa