Urine Concentration and Dilution; Regulation of ECF Osmolarity and Sodium Concentration

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_____ Controls the URINE CONCENTRATION

-ADH

1) When osmolarity of the body fluids increases above normal (i.e., the solutes in the body fluids become too concentrated), the posterior pituitary gland secretes more ADH, which increases the permeability of the distal tubules and collecting ducts to water - does not markedly alter the rate of renal excretion of the solutes

2) When there is excess water in the body and extracellular fluid osmolarity is reduced, the secretion of ADH by the posterior pituitary decreases, thereby reducing the permeability of the distal tubule and collecting ducts to water, which causes large amounts of dilute urine to be excreted
-total amount of solute excreted remains CONSTANT

Tubular fluid remains ____ in the PROXIMAL TUBULE

-Isoosmotic
-As fluid flows through the proximal tubule, solutes and water are reabsorbed in equal proportions, so little change in osmolarity occurs;

As fluid passes down the DESCENDING LOOP OF HENLE _____

-water is reabsorbed by osmosis and the tubular fluid reaches equilibrium with the surrounding interstitial fluid of the renal medulla, which is very hypertonic-about two to four times the osmolarity of the original glomerular filtrate. Therefore, the tubular fluid becomes more concentrated as it flows into the inner medulla.

Tubular fluid is _____ in the Ascending Loop of Henle

-DILUTED
- sodium, potassium, and chloride are avidly reabsorbed. However, this portion of the tubular segment is impermeable to water, even in the presence of large amounts of ADH

Tubular Fluid in Distal and Collecting Tubules is _______ in the absence of ADH

-further diluted

Obligatory urine volume

-.5 L/day

Urine specific gravity

-often used in clinical settings to provide a rapid estimate of urine solute concentration.
-The more concentrated the urine, the higher the urine specific gravity

2 requirements for excreting concentrated urine

1) a high level of ADH, which increases the PERMEABILITY of the distal tubules and collecting ducts to water, thereby allowing these tubular segments to avidly reabsorb water

(2) a high osmolarity of the renal medullary interstitial fluid, which provides the OSMOTIC GRADIENT necessary for water reabsorption to occur in the presence of high levels of ADH.

What is the process by which the renal medullary interstitial fluid becomes HYPEROSMOTIC?

*Countercurrent mechanism

The major factors that contribute to the buildup of solute concentration into the renal medulla are as follows:

1) Active transport of sodium ions and co-transport of potassium, chloride, and other ions out of the thick portion of the ascending limb of the loop of Henle into the medullary interstitium

2) Active transport of ions from the collecting ducts into the medullary interstitium

3) Facilitated diffusion of urea from the inner medullary collecting ducts into the medullary interstitium

4) Diffusion of only small amounts of water from the medullary tubules into the medullary interstitium, far less than the reabsorption of solutes into the medullary interstitium

Countercurrent multiplier

-the repetitive reabsorption of sodium chloride by the thick ascending loop of Henle and continued inflow of new sodium chloride from the proximal tubule into the loop of Henle is called the countercurrent multiplier. The sodium chloride reabsorbed from the ascending loop of Henle keeps adding to the newly arrived sodium chloride, thus "multiplying" its concentration in the medullary interstitium.

Role of distal tubule and CORTICAL COLLECTING DUCTS in excreting concentrated urine

**When there is a high concentration of ADH, the cortical collecting tubule becomes highly permeable to water, so large amounts of water are now reabsorbed from the tubule into the cortex interstitium, where it is swept away by the rapidly flowing peritubular capillaries. The fact that these large amounts of water are reabsorbed into the cortex, rather than into the renal medulla, helps to preserve the high medullary interstitial fluid osmolarity.

**As the tubular fluid flows along the medullary collecting ducts, there is further water reabsorption from the tubular fluid into the interstitium, but the total amount of water is relatively small compared with that added to the cortex interstitium

Urea contributes _____ % of the osmolarity of the renal medullary interstitium

-40-50% when the kidney is forming a maximally concentrated urine

-Urea remains in the tubules, building up in [ ] until the concentration becomes so high in the INNER MEDULLARY COLLECTING DUCT that it diffuses out of the tubule into the renal interstitial fluid

**This diffusion is greatly facilitated by specific urea transporters, UT-A1 and UT-A3. One of these urea transporters, UT-A3, is activated by ADH, increasing transport of urea out of the inner medullary collecting duct even more when ADH levels are elevated. The simultaneous movement of water and urea out of the inner medullary collecting ducts maintains a high concentration of urea in the tubular fluid and, eventually, in the urine, even though urea is being reabsorbed

A healthy person usually excretes about _______ percent of the filtered load of urea.

In general, the rate of urea excretion is determined mainly by two factors:

-20-50%

-(1) the concentration of urea in the plasma and

-(2) the glomerular filtration rate (GFR)

RECIRCULATION of Urea from Collecting duct to loop of Henle Contributes to hyperosmotic renal medulla

-In the proximal tubule, 40 to 50 percent of the filtered urea is reabsorbed, but even so, the tubular fluid urea concentration increases because urea is not nearly as permeant as water.

-The concentration of urea continues to rise as the tubular fluid flows into the thin segments of the loop of Henle, partly because of water reabsorption out of the descending loop of Henle but also **because of some secretion of urea into the thin loop of Henle from the medullary interstitium**

-The passive secretion of urea into the thin loops of Henle is facilitated by the urea transporter UT-A2.

Countercurrent exchange in the vasa recta ____

-preserves HYPEROSMOLARITY of the renal medulla
*Blood enters and leaves the medulla by way of the vasa recta at the boundary of the cortex and renal medulla. The vasa recta, like other capillaries, are highly permeable to solutes in the blood, except for the plasma proteins.

1) As blood descends into the medulla toward the papillae, it becomes progressively more concentrated, partly by solute entry from the interstitium and partly by loss of water into the interstitium. By the time the blood reaches the tips of the vasa recta, it has a concentration of about 1200 mOsm/L, the same as that of the medullary interstitium.

2) As blood ascends back toward the cortex, it becomes progressively less concentrated as solutes diffuse back out into the medullary interstitium and as water moves into the vasa recta.

$$ The U-shaped structure of the vessels minimizes loss of solute from the interstitium but does not prevent the bulk flow of fluid and solutes into the blood through the usual colloid osmotic and hydrostatic pressures that favor reabsorption in these capillaries


*Medullary blood flow is also LOW -SLUGGISH BLOOD FLOW = helps to minimize solute loss from the medullary interstitium

Increased medullary blood flow ____ Urine concentrating ability

-REDUCES
-via WASHOUT
-certain vasodilator drugs AND increases in arterial pressure

**the kidney can, when needed, excrete a highly concentrated urine that contains little sodium chloride. The hyperosmolarity of the urine in these circumstances is due to high concentrations of other solutes, especially of waste products such as urea. One condition in which this occurs is dehydration accompanied by low sodium intake.
--> low sodium intake stimulates formation of the hormones angiotensin II and aldosterone, which together cause avid sodium reabsorption from the tubules while leaving the urea and other solutes to maintain the highly concentrated urine.

free water clearance

- represents the rate at which solute-free water is excreted by the kidneys. When free-water clearance is positive, excess water is being excreted by the kidneys; when free-water clearance is negative, excess solutes are being removed from the blood by the kidneys and water is being conserved.

**whenever urine osmolarity is greater than plasma osmolarity, free-water clearance is negative, indicating water conservation.

Disorders of Urinary concentrating ability

1) Inappropriate secretion of ADH. Either too much or too little ADH secretion results in abnormal fluid handling by the kidneys.

2) Impairment of the countercurrent mechanism. A hyperosmotic medullary interstitium is required for maximal urine concentrating ability. No matter how much ADH is present, maximal urine concentration is limited by the degree of hyperosmolarity of the medullary interstitium.

3) Inability of the distal tubule, collecting tubule, and collecting ducts to respond to ADH.

Distinguishing Nephrogenic Diabetes and Central Diabetes Insipidus

***Nephrogenic diabetes insipidus can be distinguished from central diabetes insipidus by administration of DESMOPRESSIN, the synthetic analog of ADH. Lack of a prompt decrease in urine volume and an increase in urine osmolarity within 2 hours after injection of desmopressin is strongly suggestive of nephrogenic diabetes insipidus. The treatment for nephrogenic diabetes insipidus is to correct, if possible, the underlying renal disorder. The hypernatremia can also be attenuated by a low-sodium diet and administration of a diuretic that enhances renal sodium excretion, such as a thiazide diuretic.

Rough estimate of PLASMA OSMOLARITY

Posm = 2.1 x Plasma Sodium Concentration

2 primary systems especially involved in regulating the [ ] of sodium and osmolarity of ECF

1) the osmoreceptor-ADH system

2) the THIRST MECHANISM

Osmoreceptor-ADH system steps:

1) An increase in extracellular fluid osmolarity (which in practical terms means an increase in plasma sodium concentration) causes the special nerve cells called OSMORECEPTOR CELLS, located in the ANTERIOR HYPOTHALAMUS near the SUPRAOPTIC NUCLEI, to shrink.

2) *Shrinkage of the osmoreceptor cells causes them to fire*, sending nerve signals to additional nerve cells in the supraoptic nuclei, which then relay these signals down the stalk of the pituitary gland to the posterior pituitary.

3) These action potentials conducted to the posterior pituitary stimulate the release of ADH, which is stored in secretory granules (or vesicles) in the nerve endings.

4) ADH enters the blood stream and is transported to the kidneys, where it increases the water permeability of the late distal tubules, cortical collecting tubules, and medullary collecting ducts.

5) The increased water permeability in the distal nephron segments causes increased water reabsorption and excretion of a small volume of concentrated urine.

**Brings osmolarity back to normal (less concentrated/ more dilute) - cells regain water and deshrink)

A SECOND neuronal area of importance in CONTROLLING OSMOLARITY and ADH SECRETION

***located along the anteroventral region of the third ventricle, called the AV3V region. At the upper part of this region is a structure called the SUBFORNICAL ORGAN, and at the inferior part is another structure called the ORGANUM VASCULOSUM of the lamina terminalis. Between these two organs is the MEDIAN PREOPTIC NUCLEUS, which has multiple nerve connections with the two organs, as well as with the SUPRAOPTIC NUCLEI and the blood pressure control centers in the medulla of the brain.

**Lesions of the AV3V region cause multiple deficits in the control of ADH secretion, thirst, sodium appetite, and blood pressure. Electrical stimulation of this region or stimulation by angiotensin II can increase ADH secretion, thirst, and sodium appetite.

In the vicinity of the AV3V region and the supraoptic nuclei are neuronal cells that are excited by small increases in extracellular fluid osmolarity; hence, the term OSMORECEPTORS has been used to describe these neurons. These cells send nerve signals to the supraoptic nuclei to control their firing and secretion of ADH. It is also likely that they induce thirst in response to increased extracellular fluid osmolarity.

Both the subfornical organ and the organum vasculosum of the lamina terminalis have vascular supplies that LACK the typical blood-brain barrier that impedes the diffusion of most ions from the blood into the brain tissue. This makes it possible for ions and other solutes to cross between the blood and the local interstitial fluid in this region

ADH cardiovascular reflex controls (2)

1) the arterial baroreceptor reflexes

(2) the cardiopulmonary reflexes.

**These reflex pathways originate in high-pressure regions of the circulation, such as the aortic arch and carotid sinus, and in the low-pressure regions, especially in the cardiac atria.
--> Afferent stimuli are carried by the VAGUS and GLOSSOPHARYNGEAL nerves with synapses in the nuclei of the TRACTUS SOLITARIUS. Projections from these nuclei relay signals to the hypothalamic nuclei that control ADH synthesis and secretion.

$$ADH is considerable MORE SENSITIVE to small changes in osmolarity than to similar changes in blood VOLUME

OTHER stimuli for ADH secretion

-NAUSEA is a potent stimulus for ADH release, which may increase to as much as 100 times normal after vomiting.

-Also, drugs such as NICOTINE and MORPHINE stimulate ADH release, whereas some drugs, such as ALCOHOL, inhibit ADH release. The marked diuresis that occurs after ingestion of alcohol is due in part to inhibition of ADH release.

Thirst Center

-the same area along the anteroventral wall of the third ventricle (AV3V region) that promotes ADH release also stimulates thirst.

-Located anterolaterally in the preoptic nucleus is another small area that, when stimulated electrically, causes immediate drinking that continues as long as the stimulation lasts. All these areas together are called the THIRST CENTER

-Increased osmolarity of the cerebrospinal fluid in the third ventricle has essentially the same effect to promote drinking. It is likely that the ORGANUM VASCULOSUM of the lamina terminalis, which lies immediately beneath the ventricular surface at the inferior end of the AV3V region, is intimately involved in mediating this response.

important stimuli for thirst

1) increased extracellular fluid osmolarity --> intracellular dehydration in the thirst centers

2) Decreases in ECF volume and ARTERIAL PRESSURE

3) ANGIOTENSIN II (acts on the organum vasculosum - outside the blood-brain barrier)

4) Dryness of the mouth and mucous membranes of the esophagus

5) GI and pharyngeal stimuli influence thirst

Threshold for osmolar stimulus of drinking

-When the sodium concentration increases only about *2 mEq/L above normal*, the thirst mechanism is activated, causing a desire to drink water. This is called the threshold for drinking. Thus, even small increases in plasma osmolarity are normally followed by water intake, which restores extracellular fluid osmolarity and volume toward normal. In this way, the extracellular fluid osmolarity and sodium concentration are precisely controlled.

angiotensin II and aldosterone have ____ effect on sodium concentration, except under extreme conditions

-little (for 2 reasons)
First, although these hormones increase the amount of sodium in the extracellular fluid, they also increase the extracellular fluid volume by increasing reabsorption of water along with the sodium.

-Second, as long as the ADH-thirst mechanism is functional, any tendency toward increased plasma sodium concentration is compensated for by increased water intake or increased plasma ADH secretion, which tends to dilute the extracellular fluid back toward normal

EXTREME SITUATIONS in which plasma sodium concentration may change significantly, even with a functional ADH-thirst mechanism

-Under extreme conditions, caused by complete LOSS of aldosterone secretion because of adrenalectomy or in patients with Addison's disease (severely impaired secretion or total lack of aldosterone), there is tremendous loss of sodium by the kidneys, which can lead to reductions in plasma sodium concentration.
-One of the reasons for this is that large losses of sodium eventually cause SEVERE VOLUME DEPLETION and DECREASED BLOOD PRESSURE, which can activate the THIRST MECHANISM through the cardiovascular reflexes.
-->This leads to a further DILUTION of the plasma sodium concentration, even though the increased water intake helps to minimize the decrease in body fluid volumes under these conditions.

Salt-appetite mechanism

*In general, the primary stimuli that increase salt appetite are those associated with sodium deficits and decreased blood volume or decreased blood pressure, associated with circulatory insufficiency.
-i.e Addison's disease ( can't reabsorb sodium and water)

-The neuronal mechanism for salt appetite is analogous to that of the thirst mechanism. Some of the same neuronal centers in the AV3V region of the brain seem to be involved because lesions in this region frequently affect both thirst and salt appetite simultaneously in animals

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