1. From Finch to Fish to Man: Role of Body Fluid Volume Regulation Robert W. Schrier, MD Professor of Medicine University of Colorado School of Medicine

2. Darwin’s Origin of the Species

4. “The constancy of the Milieu Intérieur is the condition of free and independent existence” Claude Bernard 19 th Century French Physiologist

5. “The kidney presents in the highest degree the phenomenon of ‘sensibility’; the power of reacting to various stimuli in a direction which is appropriate for the survival of the organism; a power of adaptation which gives one the idea that its component parts must be endowed with intelligence.” E.H. Starling The Fluids of the Body The Harter Lectures, 1909

8. BODY FLUID DISTRIBUTION COMPARTMENT AMOUNT VOLUME IN 70 KG MAN Total Body Fluid 60% of Body Weight 42.0 liters Intracellular Fluid 40% of Body Weight 28.0 liters Extracellular Fluid (ECF) 20% of Body Weight 14.0 liters Interstitial Fluid Two-thirds of ECF 9.4 liters Plasma Fluid One-third of ECF 4.6 liters Venous Fluid 85% of Plasma Fluid 3.9 liters Arterial Fluid 15% of Plasma Fluid 0.7 liters

9. Sodium and Water Retention with Plasma Volume Expansion in Edematous Disorders

10. Body Fluid Volume Regulation Hypothesis

11. Volume Regulatory Hypothesis

12. NEW YORK HEART ASSOCIATION CLASSES OF CARDIAC FAILURE: ASSOCIATED HEMODYNAMIC AND HORMONAL CHANGES Cardiac Index Plasma Hormones (AVP, Renin, Aldosterone, NE) Plasma Volume CLASS IICLASS IIICLASS IV Normal

14. Plasma Renin Activity (ng/ml/hr) r=0.68 p<0.001 log e y=0l7x+24.32 n=96 SEE=0.94 Pretreatment Serum Na Concentration (mEq/L) PRETREATMENT SERUM SODIUM CONCENTRATION CORRELATES WITH PLASMA RENIN ACTIVITY IN PATIENTS WITH SEVERE HEART FAILURE

15. Pretreatment Hyponatremia Predicts an Unfavorable Prognosis in Patients with Heart Failure

16. Evidence for Non-Osmotic Release of Vasopressin in Hyponatremic Patients with Congestive Heart Failure

17. Frank-Starling Curve in Normal Subjects and Patients with Heart Failure

18. Cardiac Index in Cardiac Failure Patients Before and During After-Load Reduction

19. Water Excretion in Cardiac Failure Patients Before and During After-Load Reduction

20. Plasma Effective Osmolality and Minimum Urinary Osmolality in Cardiac Failure Patients Before and During After-Load Reduction

21. Arginine Vasopressin in Cardiac Failure Patients Before and During After-Load Reduction

22. AVP-mRNA in the Hypothalamus of Sham and Chronic Cardiac Failure (CCF) Rats

23. V2 Receptor Blockade Prevents the Impaired Water Excretion in Rats with Heart Failure

24. Selective V2 Receptor Antagonism Decreases Urinary Osmolality in Patients with Chronic Heart Failure

25. Selective V2 Receptor Antagonism Increases Serum Sodium in Patients with Chronic Heart Failure

26. The Intracellular Action of the Antidiuretic Hormone, Arginine- Vasopressin

27. Effects of V2 Antagonist on AQP2 Protein in CHF Rats

28. The Relationships between Plasma AVP Levels and Urinary Excretion of AQP2 in Normal Subjects

29. Selective V2 Receptor Antagonism Decreases 24- Hour Urinary AQP2 Excretion in Human Heart Failure

30. Edematous Disorders

31. Role of Distal Sodium Delivery in States of Arterial Underfilling

32. Reversal of Sodium Retention with Aldosterone Antagonism in Heart Failure Patients

33. Infused ANP Causes Natriuresis in Normal Subjects but not in CHF Patients

34. Plasma Atrial Natriuretic Peptide Correlates with Urinary cGMP in Heart Failure Patients

35. Effect of Renal Denervation to Reverse Atrial Natriuretic Peptide Resistance in Experimental Congestive Heart Failure in Rats

36. Peripheral Arterial Vasodilation

37. Baseline Hemodynamic Data in Control Rats and Rats with High Output Cardiac Failure Secondary to Aorto-Caval Fistula

38. Hormonal Results in Control rats and Rats with High Output Cardiac Failure Secondary to Aorto-Caval Fistula

39. Body Fluid Volume Regulation Hypothesis

40. The Pathophysiology of Heart Failure