In which order do the events of antidiuretic hormone secretion stimulated by plasma osmolarity occur

2.2 AVPR2 mutations and nephrogenic diabetes insipidus

Vasopressin, a peptide hormone synthesized in the hypothalamus and released in response of increased blood osmolarity or decreased cardiac volume, plays an important role in renal water reabsorption to maintain water homeostasis. This antidiuretic effect is achieved by activation of its receptor, V2R, via the Gs–adenylyl cyclase–cAMP-dependent signaling, leading to translocation of water channel aquaporin-2 to the apical membrane. Mutations in the AVPR2 (arginine vasopressin receptor 2) gene (encoding V2R) are the major cause for X-linked nephrogenic diabetes insipidus (NDI), a rare inherited disease characterized by failure to respond to vasopressin and to concentrate urine.9 The clinical symptoms include polyuria, polydipsia, and hyposthenuria. To date, more than 200 AVPR2 mutations have been reported in X-linked NDI patients, with intracellular retention being the most common defect.10

Other Consequences of Sustained Inhibition of Magnocellular Oxytocin Neurons in Pregnancy

Oxytocin has peripheral actions that promote natriuresis, and thus impact the control of extracellular fluid and volume regulation. Reduced oxytocin secretion in response to changes in blood volume and osmolarity (which without pregnancy stimulate oxytocin secretion) contribute to the changes in body fluid regulation in pregnancy (see the section Osmoregulation in Pregnancy). Furthermore, oxytocin released within the brain by magnocellular neuron dendrites may contribute to anorectic actions of oxytocin (see the section Food Intake and Metabolism in Pregnancy). Hence reduced oxytocin release in the brain in pregnancy may be an important factor in increased food intake (see the section Food Intake and Metabolism in Pregnancy).

21 How does mannitol decrease ICP?

Brain tissue has slightly higher osmolarity than blood, with a gradient of approximately 3 mOsm/L maintained by the blood–brain barrier. Mannitol is an osmotically active agent that reverses this osmotic gradient and shifts water from the brain to the blood. An increase in blood osmolarity by 10 mOsm/L removes 100–150 mL of water from the brain.

Hyperosmolar treatment of elevated ICP increases the normal serum osmolarity of 290 to 300–315 mOsm/L. An osmolarity < 300 mOsm/L is not so effective; > 315 mOsm/L results in renal and neurologic dysfunction.

Over the past several years, the use of hypertonic saline has become used increasingly for osmolar treatment of increased ICP. Hypertonic saline appears to have at least equal efficacy in lowering ICP, and the effect appears to be more prolonged than that of mannitol.

Qureshi AI, Suarez JI: Use of hypertonic solutions in treatment of cerebral edema and intracranial hypertension. Crit Care Med 28:3301–3313, 2000.

Abstract

Diabetes insipidus refers to a condition of impaired regulation of water economy reflected by excessive urination with compensatory water consumption. The condition is usually caused by impaired production of vasopressin in the hypothalamus or impaired production of vasopressin receptors in the kidney. Vasopressin neurons in the supraoptic nucleus of the hypothalamus sense blood osmolarity. When osmolarity increases (e.g., after a meal, especially a salty one) vasopressin is secreted, stimulating the kidney to reabsorb more water, reducing urinary volume. Conversely, in the absence of vasopressin (usually because of damage to the hypothalamus, often associated with surgery to remove a tumor, though sometimes rarely because of a mutation in the vasopressin gene), the kidney reabsorbs relatively little water, increasing urinary volume and blood osmolarity, leading to increased thirst to compensate.

Vasopressin Analogs (Desmopressin)

As depicted in Figure 12-7, vasopressin (also known as antidiuretic hormone) controls fluid balance in response to osmoreceptor stimulation. Desmopressin is a long-acting synthetic analog of vasopressin. Oral and nasal spray formulations are available and are used to treat both centrally mediated diabetes insipidus and enuresis. In both situations, it is desirable to form less urine. Desmopressin accomplishes this by enhancing water reabsorption from renal tubules. The adverse effect is hyponatremia, or “water intoxication.” Patients should be cautioned to ingest only enough fluid to satisfy their thirst.

Vasopressin antagonists, such as conivaptan, are reviewed in Chapter 9 as agents to treat hypernatremia.

Filtration Effects on Blood Pressure, Regional Blood Flow, and Solute Removal

Blood pressure falls as fluid is removed in part because the normal response of vasoconstriction to fluid removal is impaired in dialysis patients. Use of bioincompatible membranes and acetate as sources of bicarbonate during hemodialysis can cause vasodilation and further predispose the patient to hypotension. To aggravate the situation further, solute removal decreases blood osmolarity, causing slight fluid shifts from the intravascular compartment into the intracellular compartment. In patients at high risk for hypotension during dialysis, separating filtration (isolated ultrafiltration) from dialysis may improve their hemodynamic stability.

Although theoretically filtration may account for a significant fraction of solute removal during hemodialysis, in practice it can also interfere with solute removal by diffusion. In addition, the development of intravascular volume depletion during dialysis causes vasoconstriction in the skin and skeletal muscle and shunts blood through more central vascular circuits (such as the AV shunt), enhancing flow-related solute disequilibrium.

Intrinsic Hypothalamic Connections

The pathways that interconnect the many nuclei of the hypothalamus are numerous and complex. Only two especially important ones are considered here: the supraopticohypophysial tract and the tuberoinfundibular tract. Both of these tracts link the hypothalamus to the pituitary (Fig. 30.5).

OSMOLARITY

Excessive alterations of extracellular osmolarity are only encountered in kidney medulla, where extracellular osmolarity may approach 1400 mosmol/L in humans (see Chapter 40). Renal medullary cells are exposed to this excessive extracellular osmolarity during antidiuresis, and have to cope with rapid changes of extracellular osmolarity during transition from antidiuresis to diuresis. Blood cells passing the kidney medulla experience high medullary osmolarity and subsequent return to isoosmolarity within seconds (see Chapter 40).

During intestinal absorption, intestinal cells are exposed to anisosmotic luminal fluid and liver cells to minor alterations of portal blood osmolarity. Other tissues are exposed to anisotonic extracellular fluid during deranged regulation of extracellular osmolarity (see Chapters 41 and 42). As Na+ salts (mainly NaCl) contribute normally more than 90% to extracellular osmolarity, hypernatremia is necessarily paralleled by increase of extracellular osmolarity (see Chapter 42). During hypernatremia, extracellular osmolarity is always enhanced, and cells avoid cell shrinkage by triggering regulatory cell volume increase involving cellular accumulation of osmolytes. Owing to cell volume regulation, cell volume may become normal despite enhanced extracellular osmolarity. Rapid correction of chronically enhanced osmolarity may then lead to deleterious cell swelling since the organic osmolytes accumulated during hyperosmolarity cannot be rapidly released. The most serious consequence is cerebral edema.

Hyponatremia cannot be equated with hypoosmolarity but may occur in isoosmolar or even hyperosmolar states, as in hyperglycemia of uncontrolled diabetes mellitus and ethanol poisoning (see Chapter 41). When hyponatremia reflects a decreased extracellular osmolarity the cells must undergo regulatory cell volume decrease to escape cell swelling. Among other mechanisms cells release organic osmolytes. Upon rapid correction of hyponatremia, cells are unable to rapidly accumulate the osmolytes, and the iatrogenic cell shrinkage may prove more harmful than the untreated hypoosmolarity.

Hypoosmolar hyponatremia is observed following burns, pancreatitis, and crush syndrome, which are generally paralleled by cell shrinkage (93). In those conditions, the primary event may be cell shrinkage leading to ADH release with subsequent renal water retention and to cellular catabolism with enhanced release of organic solutes to the extracellular fluid.

Increased Plasma Osmolarity and Decreased Blood Volume Stimulate ADH Release

Increasing plasma osmolarity and decreasing blood volume independently increase ADH release (see Figure 9.2.5). Osmoreceptors in the anterior hypothalamus tonically stimulate magnocellular neurons to secrete ADH. Lowering the osmolarity reduces ADH secretion and increasing plasma osmolarity increases it. This forms a negative feedback loop, as ADH retains water by action on the kidneys, as described in Chapter 7.6. Briefly, ADH engages a Gs mechanism through V2 receptors that increase the water and urea permeability of principal cells of the collecting duct, by recruiting latent aquaporin-2 water channels to the apical membrane. High ADH increases reabsorption of water and produces a low volume of highly concentrated urine; low ADH is associated with a high volume of highly dilute urine. Lowered osmolarity decreases ADH secretion, causing loss of water over salt in the kidney and the blood osmolarity returns toward normal. Increased osmolarity increases ADH secretion, leading to reabsorption of water. Salt can be excreted in excess of water, leading to a return toward normal plasma osmolarity.

Reduction in blood volume and pressure also stimulates ADH release, but not as strongly as increased osmolarity. High-pressure receptors in the carotid sinus and aortic arch, and low-pressure receptors in the atria and pulmonary veins, inform the central nervous system of the state of the circulation. The afferents travel over cranial nerves IX (glossopharyngeal nerve) and X (vagus nerve) to the medulla. These inputs tonically inhibit ADH release. Reduction in blood volume reduces the firing rate of the stretch receptors, thereby reducing the tonic inhibition and increasing ADH release, causing water retention by the kidney. This cannot raise blood volume by itself, but it helps conserve water that is consumed. ADH also binds to V1 receptors on the blood vessels, causing vasoconstriction through a Gq mechanism and raising the pressure toward normal.

Although the adjustment of water and salt excretion can adjust plasma osmolarity and correct for excess plasma volume, conservation of water alone cannot correct reduced plasma volume. This requires drinking fluids and absorbing the fluid into the blood. Thirst is stimulated by the same sensory afferents that control ADH release: high-pressure and low-pressure receptors, and osmoreceptors in the anterior hypothalamus.

Summary

The renal system regulates the volume and osmolarity of the plasma and, by extension, of the ISF and ICF, by excreting either a concentrated urine or a dilute urine. This is controlled principally by ADH, but other factors are involved including the RAA system, stretch receptors in the left atria and intrathoracic veins, and the thirst mechanism. Increased osmolarity increases ADH release, which results in excretion of a highly concentrated urine. This eliminates salt in excess of water, so that the blood osmolarity returns toward normal. Stretch of the left atria inhibits ADH release, and less stretch during plasma depletion relieves the inhibition, causing increased ADH release. This in itself cannot restore plasma volume, but it helps retain water when it is ingested.

ADH exerts its effects on the kidney through V2 receptors linked to a Gs mechanism. Binding of ADH to V2 receptors increases cytosolic [cAMP] that activates PKA to phosphorylate aquaporin channels (AQP2) that in turn signal the cell to transport the channels to the apical membrane. This increases the water permeability of the late distal tubule and the collecting duct. In the absence of ADH, protein phosphatases gradually dephosphorylate the AQP2 channels and they are removed from the apical membrane and stored in endocytotic vesicles.

The RAA system is activated by: (1) decreased afferent arteriolar pressure; (2) increased renal sympathetic nervous stimulation; and (3) decreased distal tubule [NaCl]. These all signal the granule cells in the afferent arteriole to release renin, an enzyme that breaks down plasma angiotensinogen to angiotensin I, which is further converted to the active angiotensin II by ACE. Angiotensin II has multiple effects, including: (1) vasoconstriction; (2) release of aldosterone from the adrenal cortex; (3) release of ADH; (4) increased thirst; and (5) increased absorption of Na+ and HCO3− from the proximal tubule. All of these actions defend against reduced blood pressure and blood volume. The vasoconstriction helps return blood pressure to normal; aldosterone retains Na+ by preventing renal loss; ADH minimizes renal water loss; increased thirst motivates replacement of lost fluids; increasing Na+ reabsorption in the proximal tubule complements actions of aldosterone in the distal nephron.