Antidiuretic hormone | Anatomy2Medicine
Antidiuretic hormone

Antidiuretic hormone

Antidiuretic hormone

    • ADH has three actions on the renal tubule
      • It increases the water permeability of the principal cells of the late distal tubule and collecting ducts. (most important function ) (MCQ)
      • It increases the activity of the Na+-K+-2Cl cotransporter of the thick ascending limb (MCQ)
        • thereby it enhances countercurrent multiplication and the size of the corticopapillary osmotic gradient(MCQ)
      • It increases urea permeability in the inner medullary collecting ducts (but not in the cortical or outer medullary collecting ducts)

 

  • thereby it enhances urea recycling and the size of the corticopapillary osmotic gradient. (MCQ)

 

    • In the absence of ADH, the principal cells are impermeable to water. (MCQ)
    • In the presence of ADH, water channels, or aquaporins, are inserted in the luminal membrane of the principal cells, making them permeable to water. (MCQ)
    • The following steps are involved in the action of ADH on the principal cells
      • When circulating levels of ADH are high, ADH is delivered to the principal cells via the peritubular capillary blood
      • V2 receptors for ADH, present in the basolateral membrane, are coupled to adenylyl cyclase via a stimulatory G protein (Gs). (MCQ)
      • When ADH binds to the receptors, adenylyl cyclase is activated and catalyzes the conversion of ATP to cAMP. (MCQ)
      • cAMP activates protein kinase A.
      • Activated protein kinase A then causes phosphorylation of intracellular structures.
      • phosphorylation  causes vesicles containing water channels are shuttled to and inserted into the luminal membrane of the principal cell, thus increasing its water permeability.
      • The specific water channel that is controlled by ADH is aquaporin 2 (AQP2).

 

  • Regulation of Antidiuretic Hormone Secretion

 

      • Increased plasma osmolarity is the most important physiologic stimulus for increasing ADH secretion(MCQ)
        • For example, when a person is deprived of water, serum osmolarity increases.
        • The increase is sensed by osmoreceptors in the anterior hypothalamus.
        • Action potentials are initiated in cell bodies of the nearby ADH neurons and propagated down the axons, causing the secretion of ADH from nerve terminals in the posterior pituitary.
      • Hypovolemia, or volume contraction (e.g., due to hemorrhage),
        • a potent stimulus for ADH secretion.
        • Decreases in extracellular fluid (ECF) volume of 10% or more cause a decrease in arterial blood pressure (MCQ)
        • Low BP  is sensed by baroreceptors in the left atrium, carotid artery, and aortic arch. (MCQ)
        • This information about blood pressure is transmitted via the vagus nerve to the hypothalamus, which directs an increase in ADH secretion. (MCQ)
        • ADH then stimulates water reabsorption in the collecting ducts, attempting to restore ECF volume.

 

  • Importantly, hypovolemia stimulates ADH secretion, even when plasma osmolarity is lower than normal (MCQ)
  • Conversely, hypervolemia (volume expansion) inhibits ADH secretion, even when plasma osmolarity is higher than normal. (MCQ)

 

 

  • ADH (vasopressin) has two actions
  • Increase in water permeability.
  • Contraction of vascular smooth muscle.
    • The receptor for ADH on vascular smooth muscle is a V1 receptor, which is coupled to phospholipase C via a Gq protein. (MCQ)
    • The second messenger for this action is IP3/Ca2+,

produces (MCQ)

    • contraction of vascular smooth muscle
    • constriction of arterioles
    • increased total peripheral resistance.

 

    • Hyperosmotic urine is produced when the circulating levels of ADH are high, as occurs in (MCQ)

 

  • water deprivation
  • SIADH

 

    • SIADH
      • circulating levels of the hormone ADH are abnormally high owing to either

 

  • Causes (MCQ)

 

        • head injury

 

  • lung tumors

 

      • ADH is secreted autonomously, without an osmotic stimulus
      • high levels of ADH increase water reabsorption by the late distal tubule and collecting ducts, making the urine hyperosmotic and diluting the plasma osmolarity. (MCQ)
      • Normally, a low plasma osmolarity would inhibit secretion of ADH; however, in SIADH, this feed- back inhibition does not occur because ADH is secreted autonomously (MCQ)
      • Treatment
        • demeclocycline, which inhibits the ADH action on the renal principal cells. (MCQ)
    • Central Diabetes Insipidus
      • follow head injury,
      • Because circulating levels of ADH are low or zero, the entire distal tubule and collecting ducts are impermeable to water. (MCQ)
      • large volumes (as much as 15 L/day) of very dilute urine are excreted.
      • Plasma osmolarity increases to abnormally high values as excessive amounts of water are excreted in the urine which is the water that would have been reabsorbed if ADH were present
      • The high plasma osmolarity would normally stimulate ADH secretion, but in central diabetes insipidus, there is no ADH to be secreted from the posterior pituitary gland. (MCQ)
      • Treatment of central diabetes insipidus consists of administration of an ADH analogue, such as 1-deamino-8-D-arginine vasopressin (dDAVP). (MCQ)
    • Nephrogenic Diabetes Insipidus
      • a defect in the response of the kidneys to ADH

 

  • Although ADH secretion from the posterior pituitary gland is normal, a defect in the receptor, the Gs protein, or adenylyl cyclase makes the principal cells unresponsive to ADH. (MCQ)

 

      • As a result, ADH fails to increase water permeability in the late distal tubule and collecting ducts(MCQ)
      • As in central diabetes insipidus, water cannot be reabsorbed by these segments, and large volumes of dilute urine are excreted.
      • The plasma osmolarity increases, which stimulates the posterior pituitary to secrete even more ADH. (MCQ)

 

  • Circulating ADH levels are higher than normal in nephrogenic diabetes insipidus, but these high levels of ADH still are ineffective on principal cells.
  • Nephrogenic diabetes insipidus is treated with thiazide diuretics

 

    • Rationale for using thiazide diuretics (MCQ)
      • first consider the fundamental problem in nephrogenic diabetes insipidus: Because the principal cells are unresponsive to ADH, there is excretion of large volumes of dilute urine.
      • Thiazide diuretics are helpful as follows (MCQ)
        • They inhibit Na+ Cl-  cotransport in the early distal tubule, thereby preventing dilution of the urine in this segment.
          • As more NaCl is excreted, the urine is less dilute than it would be without treatment.
        • Thiazide diuretics produce a decrease in GFR and, secondary to decreased Na+ reabsorption, a decrease in ECF volume
          • The decrease in ECF volume causes an increase in proximal tubule reabsorption via effects on Starling forces.
          • The combination of less water filtered and more water reabsorbed in the proximal tubule means that the total volume of water excreted is decreased.

 

  • FREE-WATER CLEARANCE
    • Free water is defined as distilled water that is free of solutes (or solute-free water).
    • In the nephron, free water is generated in the diluting segments, where solute is reabsorbed without water.
    • The diluting segments of the nephron are the water-impermeable segments: (MCQ)
      • the thick ascending limb
      • the early distal tubule.
    • Measurement of free-water clearance (CH2O) provides a method for assessing the ability of the kidneys to dilute or concentrate the urine.
    • When ADH levels are low(MCQ)
      • all of the free water generated in the thick ascending limb and early distal tubule is excreted (since it cannot be reabsorbed by the collecting ducts).
      • The urine is hyposmotic, and free-water clearance is positive.
    • When ADH levels are high(MCQ)
      • all of the free water generated in the thick ascending limb and the early distal tubule is reabsorbed by the late distal tubule and collecting duct.
      • The urine is hyperosmotic, and free-water clearance is negative.

Measurement of CH2O

Free-water clearance (CH2O) is calculated by the follow- ing equation:

 

    • Significance of CH2O
    • CH2O is zero.
      • CH2O is zero when no solute-free water is excreted.
      • Under these conditions, urine is isosmotic with plasma (called isosthenuric

 

  • it can occur during treatment with a loop diuretic – Mechanism

 

        • NaCl reabsorption is inhibited in the thick ascending limb.
        • When solute reabsorption is inhibited in the thick ascending limb, no free water is generated at this site:
        • If free water is not generated, it cannot be excreted.
        • Therefore, the ability to dilute the urine during water drinking is impaired in a per- son who is treated with a loop diuretic.
      • With Loop diuretics , the ability to concentrate the urine during water deprivation is impaired because loop diuretics also interfere with generation of the corticopapillary osmotic gradient (by inhibiting Na+-K+-2Cl- cotransport and countercurrent multiplication).
    • CH2O is positive. (MCQ)
      • CH2O is positive when
        • ADH levels are low
        • ADH is ineffective and the urine is hyposmotic.
      • The solute-free water, which is generated in the thick ascending limb and early distal tubule, is excreted in the urine because the late distal tubules and collecting ducts are impermeable to water under these conditions
    • CH2O is negative. (MCQ)
      • CH2O is negative when ADH levels are high and the urine is hyperosmotic.
      • All of the solute-free water generated in the thick ascending limb and early distal tubule (and more) is reabsorbed by the late distal tubules and collecting ducts. negative CH2O is called free-water reabsorption

 

  • Example

 

    • A man has a urine flow rate of 15 mL/min, a urine osmolarity of 150 mOsm/L, and a plasma osmolarity of 300 mOsm/L. What is his free-water clearance, and what is its significance?
    • SOLUTION.
      • The man’s free-water clearance is calculated as follows:
      • CH2 O =  V – Cosm

=  V- (U) osm  x V

 Posm

=  15 mL/min – 150 mOsm/Lx 15 mL/min

300 mOsm/L

=  15 mL/min – 7.5 mL/min

=  + 7.5 mL/ min

  • CH2O is a positive value, which means that free water is being excreted.
  • The solute-free water generated in the thick ascending limb and early distal tubule is not reabsorbed by the collecting ducts, but it is excreted.
  • This situation occurs when circulating ADH levels are low, as in water drinking or central diabetes insipidus (or if ADH is ineffective, as in nephrogenic diabetes insipidus).