Essentials of Clinical Medicine

1. Essentials of Clinical Medicine Session 17 Lecture 2 Homeostasis Peter Stanfield

2. The concept of homeostasis and the internal environment Comparator Set point Often the nervous system Often the nervous or endocrine systems Sensor Effector Controlled quantity

3. Water and salt loads are distributed differently and dealt with by different mechanisms changes osmolality changes volume of ECF and Na+ balance From: G Pocock & CD Richards Human Physiology – The Basis of Medicine 3rd Edition 2006 Fig 28.1

4. Water and salt loads are distributed differently Saline will expand the ECF volume Extracellular fluid (ECF) 14 Plasma Interstitial fluid Secretions Intracellular fluid (ICF) 1 3 28 10 Water is distributed through these compartments Total body water 42

5. Two classes of mechanism are required for homeostasis of body fluids 1. To deal with a water load – which will lower the osmolality of all compartments – need to sense and to regulate this quantity (osmolality). • To deal with a saline load – which will expand ECF volume – need to sense and to regulate: • ECF volume – plasma volume that is sensed • Na+ load of the body In both cases, nervous and endocrine systems are involved in regulation. Renal excretion is regulated to restore the internal environment. Thirst and sodium appetite are also regulated.

6. The response to a water load

7. A water load will lead to cellular swelling. Since water will distribute among all fluid compartments, all will be increased in volume. The cellular compartment will thus swell slightly owing to movement of water into cells. This swelling is sensed - particularly in the brain – and in osmoreceptors of the hypothalamus.

8. Osmoreceptors in the hypothalamus Hypothalamus is part of the forebrain – part of the diencephalon - linking nervous and endocrine function – through its connections to the pituitary From: G Pocock & CD Richards Human Physiology – The Basis of Medicine 3rd Edition 2006 Fig 6.3

9. Osmoreceptors in the hypothalamus Neurones acting as osmoreceptors controlling secretion of vasopressin from posterior pituitary ↓osmolality /Anti-diuretic hormone (ADH) ↓secretion of ADH From: G Pocock & CD Richards Human Physiology – The Basis of Medicine 3rd Edition 2006 Fig 12.6

10. Vasopressin - alias anti-diuretic hormone - has two principal physiological effects Vasopressin – has effects on the circulation, constricting blood vessels. It also has effects on the kidney, regulating the volume and the dilution/concentration of urine

11. Vasopressin/ADH targets kidney The kidney excretes urine, the composition of which is varied according to physiological need. Vasopressin increases water reabsorption in the renal tubule – altering the osmolality of urine In response to a water load, vasopressin secretion is reduced and copious dilute urine of low osmolality is excreted. (Though note that electrolyte – especially NaCl will also be also be lost.)

12. The renal tubule filters blood and then works on the filtrate The glomerulus forms a filtrate Vasopressin acts here – increasing water permeability – to concentrate the urine that is finally produced. From: G Pocock & CD Richards Human Physiology – The Basis of Medicine 3rd Edition 2006 Fig 17.10 Details will be given in the urinary tract module (semester 3)

13. The renal tubule filters blood and then works on the filtrate An increase in water load gives ↓Vasopressin secretion, reducing water permeability →copious dilute urine From: G Pocock & CD Richards Human Physiology – The Basis of Medicine 3rd Edition 2006 Fig 17.10 Details will be given in the urinary tract module (semester 3)

14. The concept of homeostasis and the internal environment Comparator Set point Paraventricular and supraoptic nuclei Often the nervous system Altered secretion of vasopressin (ADH), acting to alter water excretion Osmoreceptors in anterior hypothalamus Often the nervous or endocrine systems Sensor Effector Osmolality of body fluids Controlled quantity

15. The response to dehydration Dehydration will lead to an increase in osmolality – the sensing of this increase will lead to an increase in vasopressin secretion. Vasopressin will increase the reabsorption of water in the renal tubule. Leading to production of a low volume of hypertonic urine. Since water is still lost – need to increase water intake to restore water balance. Thirst is also stimulated as a result of sensing the increased osmolality in the hypothalamus.

16. Dehydration Dehydration Is usually associated with loss of both salt and water. Changes in excitability – muscle cramps Collapse of the circulation Lack of vasopressin Leads to diabetes insipidus – damage to pituitary or loss of receptors for vasopressin in the kidney. Inappropriately copious dilute urine, so that fluid must be replaced by copious drinking.

17. Water intoxication Hypersecretion of vasopressin For example from a pituitary tumour – leads to a reduced tonicity of body fluids, yet a hypertonic urine. Water intoxication • Uncommon and usually associated with disease • Cellular swelling in brain leads to: • Headache • Fits • Coma

18. The response to an increase in extracellular fluid volume

19. Water and salt loads are distributed differently and dealt with by different mechanisms changes volume of ECF and Na+ balance From: G Pocock & CD Richards Human Physiology – The Basis of Medicine 3rd Edition 2006 Fig 28.1

20. Isotonic saline increases both ECF volume and the Na+ load of the body An increase in ECF volume will be distributed between the plasma and interstitial fluid. If plasma – and therefore blood – volume increases, pressures in the vasculature will increase, and the heart will have to do more work*. Correction will involve sensing of: 1. the volume of the ECF sensed as blood volume 2. the sodium load of the body sensed in the kidney Two interrelated processes * This will be explained in the CVS module; it is why there are health recommendations about salt intake

21. Atrial natriuretic peptide is released in response to an increase in plasma volume

22. The plasma (blood) volume is sensed in volume receptors in the great veins & atria An increase in volume stretches the atria. In response to stretch, atrial myocytes enhance the secretion of a hormone: atrial natriuretic peptide (ANP) Left Right The heart is an endocrine organ as well as a pump

23. Atrial natriuretic peptide increases the excretion of NaCl and water. Increased stretch of atrial myocytes Increased secretion of ANP Increased loss of Na+ (and water) in urine Correction of the increased ECF volume

24. ANP increases filtering of blood, by increasing filtration into the renal tubule ANP acts to increase filtration Increased filtration leads to natriuresis and diuresis. From: G Pocock & CD Richards Human Physiology – The Basis of Medicine 3rd Edition 2006 Fig 17.10 Details will be given in the urinary tract module (semester 3)

25. The kidney responds to an increased Na+ load. The roles of renin, angiotensin, and aldosterone

26. The amount of Na+ handled by the kidney is sensed in the renal tubule Na+ load in distal part of the renal tubule is sensed In juxtaglomerular apparatus, where distal tubule contacts glomerulus From: G Pocock & CD Richards Human Physiology – The Basis of Medicine 3rd Edition 2006 Fig 17.10 Details will be given in the urinary tract module (semester 3)

27. The amount of Na+ sensed regulates the secretion of a hormone, renin Renin is a proteolytic enzyme, released into blood stream angiotensinogen renin catalyses angiotensin I angiotensin converting enzyme* catalyses angiotensin II An increased Na+ load reduces the secretion of renin, and hence inhibits this cascade occurring in the blood stream. A fall in Na+ stimulates secretion. * on inner lining of blood vessels

28. Angiotensin II has important physiological actions Vasoconstriction throughout the vasculature angiotensin II Acts on hypothalamus to stimulate thirst stimulate vasopressin release Stimulates the secretion of the hormone aldosterone from adrenal cortex Aldosterone increases reabsorption of Na+ in the kidney, reducing its output in urine

29. Aldosterone is a steroid hormone from the adrenal cortex (zona glomerulosa) adrenal cortex – steroid hormones r. adrenal r. kidney adrenal medulla – adrenaline and noradrenaline From: Abrahams et al (2005) Illustrated Clinical Anatomy Fig 8.9 Outermost part of adrenal cortex is the zona glomerulosa

30. The action of aldosterone and the reversal of its action take time. • Aldosterone is a steroid hormone – with a cytoplasmic receptor • It affects transcription of genes involved in Na+ transport in the renal tubule, including: • Na+-K+ ATPase • Epithelial Na+ channel (ENaC) • These responses take time – and the response to a reduction in aldosterone also takes time • Response to a Na+ load is relatively slow

31. A result of long term action of aldosterone – a saline load takes time to clear: high intake of salt will override homeostatic control. Excessive salt intake becomes difficult to counteract: high salt diet is a risk factor for hypertension . changes volume of ECF and Na+ balance From: G Pocock & CD Richards Human Physiology – The Basis of Medicine 3rd Edition 2006 Fig 28.1

32. The amount of Na+ sensed regulates the secretion of a hormone, renin Isotonic saline, added to the body fluids Reduced secretion of renin Reduced levels of angiotensin II correcting Reduced reabsorption of Na+; ie increased Na+ loss in urine Reduced levels of aldosterone

33. The amount of Na+ sensed regulates the secretion of a hormone, renin increased secretion of renin Deficit of Na+ Defending body Na+ and ECF volume increased levels of angiotensin II Increased reabsorption of Na+; ie increased Na+ loss in urine Increased levels of aldosterone

34. Renin release is also stimulated by: 1. A reduction in blood pressure, sensed within the kidney Na+ load will increase and a Na+ deficit will reduce blood volume and hence blood pressure; Renin secretion is reduced or increased, respectively. 2. Nervous - sympathetic (autonomic nervous system) - stimulation of kidney If the atrial volume receptors sense a reduction in volume, reflex stimulation of renin release occurs through sympathetic innervation of the kidney.

35. Addison’s disease Addison’s disease is associated with the loss of adrenal cortical hormones, including aldosterone. Result in a loss of Na+ and retention of K+ - resulting in progressive weakness owing to effects on excitability of nerve and muscle. Excessive dehydration, owing to loss of Na and water from kidney, is associated with reduced blood pressure Patients have a high salt appetite

36. Aldosteronism Conn’s syndrome associated with increased secretion of aldosterone. Increased renin also increases aldosterone secretion. Result in a retention of Na+ and loss of K+. Expansion of the extracellular fluid volume (and the vascular effects of angiotensin II) is associated with hypertension.

37. Two hormonal pathways act in antagonism to each other Altered secretion of ANP ANP → loss of Na+ A change in Na+ load Altered secretion of aldosterone aldosterone → retention of Na+ Such hormonal mechanisms, working in opposition to each other, are a common feature of homeostasis

38. In summary • Threats to body fluid balance are dealt with by hormonal responses regulating the excretion of water and Na+, the principal cation of the extracellular fluid. • Vasopressin – increases osmolality of the urine • Atrial natriuretic peptide – accelerates the loss of Na+. • Aldosterone – causes retention of Na+. • Regulation of aldosterone release is complex – through the renin-angiotensin-aldosterone system.