renal objectives

8/7/2019 renal objectives

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GFR & RPF1. Define the terms filtration, reabsorption, secretion and excretion.

Describe how changes in filtration, reabsorption and secretion affect the

amount of a substance excreted.

Filtration- Input into Bowman¶s space = Px*GFR

Reabsorption- Output of a substance from the tubules, back into the blood stream via the peritubular capillaries.

Secretion- Input of a substance into the tubules from the blood stream, via the peritubular capillaries.

Excretion- The amount of a substance expelled in the urine = Ex = Fx ± R x + Sx

Increases in filtration and secretion will result in greater substance excretion, whereas an increasein reabsorption will lead to a decline in substance excreted.

Source: Boron p.759

2. Given the capillary and Bowman¶s capsule hydrostatic and oncotic

pressures, calculate net filtration pressure at the glomerular capillaries.

Predict changes in GFR caused by increases or decreases in any of these parameters.

NFP= (PGC+BC)-(PBC+GC)

Glomerular filtration rate will increase with an increase in the hydrostatic pressure of theGlomerular Capillaries. GFR will decrease with either a rise in the hydrostatic pressure of

Bowman¶s Capsule or a decrease in the oncotic pressure of the Glomerular Capillaries. It is



important to note that there is virtually no oncotic pressure in Bowman¶s Capsule, so BC canactually be taken out of the equation.

Source: Dr. Averil¶s first renal lecture, slides 15 & 16

3. Predict changes in renal plasma flow and glomerular filtration ratefollowing selective changes in renal afferent or efferent arteriolar

resistance.

As chart B shows an increase in renal afferent arteriolar resistance results in a decrease in

renal plasma flow (RPF) as well as the glomerular filtration rate. The RPF declines because thereis an inverse relationship between flow and resistance, so as R increases the flow decreases

(F=P/R ). The hydrostatic pressure of the glomerular capillary will decline as well because theconstriction of the afferent arteriole is before the glomerulus, so there is very little flow in the

glomerulus and pressure and flow have a direct relationship (F=P/R). There will be a decline inGFR because of the decreases in PGC and RPF.

Chart C shows that an increase in renal efferent arteriolar resistance results in a decreasein RPF and an initial increase in GFR, but at higher pressures a decrease in GFR. Renal plasma

flow will decline again because there is an increase in resistance across the capillary beds. As theefferent arteriole is located after the glomerulus, the flow is inhibited right after the glomerulus



which explains the increase in PGC, as the blood flow is pooling there. At first the increase in PGC outweighs the decline in RPF when determining the GFR. This explains the initial increase in

GFR, but eventually the RPF will outweigh the PGC so GFR declines.

Source: Boron p.774

4. Describe the effects of changes in peritubular capillary hydrostatic

pressure and colloid osmotic pressure on net proximal tubular fluid

reabsorption.

Net Proximal Tubular Fluid Reabsorption will decrease with a higher peritubular capillaryhydrostatic pressure and increase with a higher colloid osmotic pressure. This is because

reabsorption is the return of fluid to the peritubular capillary so a hydrostatic pressure pushingfluid outwards will not favor reabsorption and inversely an oncotic pressure pulling fluid inwards

will favor reabsorption.

5. Define autoregulation and describe the myogenic and

tubuloglomerular feedback mechanisms that mediate autoregulation.

Autoregulation is the stability of renal blood flow and glomerular filtration rate, despite a wide

range of mean arterial pressures. This is done through a myogenic and tubuloglomerular feedback mechanisms. The myogenic response is the afferent arterioles ability to contract or

relax in response to vessel circumference. The tubuloglomerular feedback is when the maculadensa cells detect an increase in GFR and provide feedback inhibition by constricting the afferent

arteriole. The macula densa does not detect an increase in flow directly, but rather an increase in[Na

+] and [Cl

-] ions, which is a direct result of the increased GFR. Vasoconstrictive chemicals

(ATP, adenosine, thromboxane) are released from the macula densa and trigger contraction of the SM cells of the afferent arteriole. Note in the diagram below how Efferent Arteriolar

Resistance, Renal Blood Flow and GFR remain relatively constant with changing Renal ArterialPressures and it is only the Afferent Arteriolar Pressure that changes drastically.

Source: Boron p.777 & 778

6. Predict the change in renal blood flow and glomerular filtration rate

caused by an increase in each of the following: renal sympathetic nerve



activity; angiotensin II synthesis; release of atrial natriuretic petide;

prostaglandin formation.

Renal sympathetic nerve activity: Norephinephrine is released into the interstitial space and potentially both the afferent and efferent arteriolar resistances can increase in response. RBF and

GFR decrease. If stimulation isn¶t maximal there is actually a preference for efferentconstriction which explains why RBF falls more quickly than the GFR. Also triggers release of

renin and consequently ANG II.

Angiotensin II synthesis: Multiple effects, most importantly reduced RBF and GFR .

ANP: Vasodilates afferent and efferent arterioles, which can increase the blood flow whilelowering sensitivity of the TGF mechanism. RBF and GFR increase. ANP also inhibits renin,

which prevents production of ANG II.

Prostaglandin: Synthesized from SM, endothelial, mesangial, tubule and interstitial cells of the

renal medulla. Acts to prevent excessive vasoconstriction of ANG II. Maintains RBF and GFR during conditions where levels of ANG II are very high( during surgery, blood loss and saltdepletion).

Source: Boron p. 779-781

CLEARANCE

7. Explain the clearance principle.

The clearance principle is used to evaluate the kidneys ability to handle solutes and water.Clearance compares the rate of filtration of a substance with the rate of excretion. If the kidneysare properly functioning, one can determine if the substance is being reabsorbed or secreted as

well, assuming the kidney does not store, produce or use the substance. Clearance is specificallydefined as the amount of blood plasma needed to supply the amount of solute that appears in

solute. The equations below define renal clearance with the principle of mass balance applied,the input of substance X into the kidney equals the ouput of X.

PX,a*RPFa = PX,c*RPFv + UX*VArterial input Venous Output Urine Ouput

If clearance is maximal than their will be no venous output, so the equation can be rewritten.

PX,a*CX= UX*V or CX= UX*V/PX

Two important limitations to keep in mind are clearance is the sum of several transportoperations throughout the nephron and clearance measures output of two million nephrons in

parallel, not a specific site.



8. Use the clearance equation and an appropriate compound to estimate the glomerular filtrationrate, renal plasma flow and renal blood flow.

Clearance: the rate at which fluid is completely removed of a substance. It¶s found by the urinary

excretion rate of the substance divided by the plasma concentration of the substance.

Cx = (V x Ux)/Px V = vol of urine, Ux = conc of X in urine, Px = conc of X in plasmaGFR = Cx à Px x GFR = V x Ux à GFR = (V x Ux )/ Px

Example: Ux is 4g/mL, Px is 10mg/mL, V is 2mL/min à

[(GFR = 4000mg/mL) x (2mL/min)]/10mg/mL = 800mL/min

Effective Renal Plasma Flow: can be estimated from PAH clearance.CPAH = RPF = (V x UPAH)/PPAH

Renal Blood Flow: can be measured using RPF and hematocrit

RBF = RPF/(1 ± Hct)

Example: UPAH is 650mg/mL, PPAH is 1.1mg/mL, V is 1mL/min, Hct is 0.45 àRPF = (1mL/min x 650mg/mL)/1.1mg/mL = 591mL/min

RBF = (591mL/min)/(1-0.45) = 1075mL/min

Source: Medical Physiology ± Boron & Boulpaep; Physiology Cases & Problems ± Costanzo

9. Calculate free-water clearance, filtration fraction, filtered load and fractional excretion rate

from provided data.

Free-Water Clearance: the measure of the volume of plasma from which a substance iscompletely removed by kidneys per unit time. Since it cannot be measured directly, it¶s found

using the rate that osmolar molecules are cleared.V = Cosm + CH20 à Cosm = (Uosm x V)/ Posm à CH20 = V ± Cosm

Example: Uosm is 140mOsm/L, Posm is 280mOsm/L, V is 4mL/min à

CH20 = 4mL/min ± [(140mOsm/L)/280mOsm/L)] x 4mL/min = 2mL/minSource: Renal physiology lecture ± Averill; Wikipedia (example)

Filtration Fraction: the fraction of the renal plasma flow that is filtered across the glomerular

capillaries.Filtration fraction = GFR/RPF

Example: GFR is 120mL/min, RPF is 591mL/min àFiltration fraction = (120mL/min)/(591mL/min) = 0.20

Source: Physiology Cases & Problems ± Costanzo



Filtered Load: the total amount of substance filtered per unit time. It¶s found by multiplying GFR by the plasma concentration of the substance. If the excretion rate is less than the filtered load,

the substance was reabsorbed. If the excretion rate is greater than the filtered load, the substancewas secreted.

Filtered load = GFR x Px

Example: GFR is 120mL/min, Px is 10mg/mL à filtered load = 120mL/min x 10mg/mL =1200mg/min


Excretion Fraction Rate: the fraction of the filtered load that is excreted in the urine. It¶s found

by excretion rate divided by filtered load.Excretion rate = V x Ux

Filtered load = GFR x Px

Excretion fraction rate = (V x Ux)/( GFR x Px)

Example: using filtered load from above; V is 1mL/min, Ux is 2g/mL à

Excretion fraction rate = (1mL/min x 2g/mL)/1200mg/min = 1.67 (or 167%)


RENAL HANDLING OF SOLUTES

10. Contrast the structural and functional properties of the four renal tubule segments: proximal,

loop of Henle, distal and collecting.Proximal: simple cuboidal epithelium with brush border, prominent glycocalyx, major site of

glomerular filtrate, basal striations; reabsorbs NaCl, NaHCO3, filtered nutrients (glucose, aminoacids), Ca

2+, HPO4

2-( PTH reduces reabsorption), SO4

2-, K

+, H2O urea; secretes NH4

+

Loop of Henle: descending thick limb ± looks like PCT, thin limb ± simple squamousepithelium, ascending thick limb ± looks like DCT, impermeable to water; concentrates or

dilutes urine; pumps NaCl into interstitium of medulla making it hypertonic ; regulates Cl-, Mg

2+,

Ca2+ and water reabsorption; secretes urea

Distal: simple cuboidal epithelium with some brush border; regulates pH by absorbing andsecreting bicarbonate and protons; regulates K

+and Na

+(aldosterone causes Na

+absorption);

regulates Ca2+ ( PTH causes Ca2+ reabsorption); vasopressin receptors expressed in DCTCollecting: simple columnar epithelium, principal and intercalated cells, nonmotile primary cilia

with polycystin 1 and 2; vasopressin receptors expressed; reabsorbs of Cl-, Na+, water, urea;

secretes K +

11. Describe the function of the renal transporters and their predominant localization with regardto nephron segment and apical versus basolateral membrane.

This is focused on transcellular reabsorption, which involves two steps. 1) movement from the

lumen to the epithelial cell (apical membrane) 2) movement from epithelial cell to the interstitial



space (basolateral membrane). This is very complicated, I tried to simplify it as much as possible.

Name of Transport Type of Transport Location in Nephron

Membrane Type Purpose

Na+

/K +

ATPase S1, TAL, DCT,CNT/CCT

Basolateral Na+

reabsorption

H+/K

+ATPase -intercalated

cells of CCT and

MCT

Apical K +

reabsorptionduring potassium

deficiency

H+

ATPase CCT (-intercalated cell)

Apical Acid Secretion

Na+

Ion Channel Principal Cell of CNT/CCT

Apical Na+

reabsorption

K +

Ion Channel S1(AM &BM),S3(AM&BM),

TAL (BM), CCT(AM & BM)

Apical (AM) /Basolateral (BM)

K +

reabsorption(principal cells)

and secretion (-intercalated cells)

Cl-

Ion Channel S3, TAL, DCT,

CCT

Basolateral Cl-reabsorption

Na+/H

+antiporter Coupled

Transporter

S1, TAL Apical Na+

reabsorption

Acid excretion

Cl-/HCO3

-

antiporter

Coupled

Transporter

TAL (BM)

CCT (AM)

Basolateral/ Apical HCO3-

reabsorption andCl- reabsorption in

-intercalated cell

Na+/K

+/Cl

-

symporter

Coupled

Transporter

TAL Apical Na+

reabsorption

Na+/glucose

symporter CoupledTransporter

S1 Apical Na+

and Glucosereabsorption

Na+/phosphate

symporter

Coupled

Transporter

S1 Apical Na+ and Phosphate

reabsorption

Na+/Cl

-symporter Coupled

Transporter DCT Apical Na

+and Cl

-

Reabsorption

Na+/HCO3

-

symporter CoupledTransporter

S1 Basolatearal Na+

reabsorption

S1- Early PCT

S3- Late PCTTAL- Thick Ascending Limb

DCT- Distal Convoluted TubuleCNT- Principal Cell of Connecting Tubule

CCT- Cortical Collecting Tubule



Source: Boron Chapters 35-3712. Describe the cellular mechanisms for the transport of Na

+, Cl

-, K

+, HCO3

-, H

+, Ca

++,

phosphate, glucose and amino acids by major tubular segments.

The two major types of transports for these substances are paracellular and transcellular.

Paracellular pathways are a way for ions to travel extracellularly. Transcellular pathways involvemovement through the epithelial cell. The epithelial cell has two membranes, one is the apicalmembrane between the lumen and epithelial cell. The other is the basolateral membrane between

the epithelial cell and the interstitial space.

Paracellular transport is always passive and only involves ion channels. Two things determine if an ion will move through the channel, the chemical gradient and the electrical gradient. It is

possible for an ion to move uphill against one of these gradients if the other gradient dominates.

Transcellular transport involves not only ion channels, but also facilitated diffusion and activetransport. Facilitated diffusion involves numerous symports and antiports that can allow for a

substance to move uphill against its gradient, e.g. glucose goes against its chemical gradient inthe Na+/Glucose symport in the PCT. There is also active transport, which appear as ATPases. A

crucial one being the Na+/K

+pump which is the final step in transcellular Na

+reabsorption.

Source: Boron p. 782 & 783

13. Describe the impact of changes in filtered load on reabsorption and excretion of substancesreabsorbed via carrier-mediated transport processes.

There is a direct relationship between the filtered load and reabsorption of a substance in the

proximal convoluted tubules. The fraction remains constant as a protection mechanism againstsudden changes, e.g. changes in Na

+due to extreme exercise, severe pain or anaesthesia. This

constant fractional reabsorption is independent of external neural and hormonal control in thePCT. It is important to note that the distal nephron is under control by the neural and hormonal

control, so there will not be a constant fraction between the sodium reabsorbed and filteredsodium load.

Source: Boron p. 791

Countercurrent mechanisms of the kidney

Countercurrent system: a system in which the inflow runs parallel to, and in close proximity

to the outflow for some distance. This occurs for both the loops of Henle and the vasa recta inthe renal medulla



Countercurrent mechanisms of the kidney

Countercurrent system: a system in which the inflow runs parallel to, and in close proximity to the

outflow for some distance. This occurs for both the loops of Henle and the vasa recta in the renal

medulla

14.Describe the mechanism by which the ascending limb of the loop of Henle produces a high

medullary interstitial osmolarity.

Background information to answer question:

y The Loops of Henle of the juxtamedullary nephrons dip deeply into the medullary pyramids.

y The thin descending limb is permeable to water, therefore, filtrate is

y The thin ascending limb of the LOH is impermeable to water, but is permeable to NaCl

o Solutes move out of the ascending limb, water does not

y The thick ascending limb contains the Na+ K+ 2Cl- Pump

o Reabsorbs NaCl without water w qtubular fluid concentration

But how does the LOH produce high medullary interstitial osmolarity?

The process of generation of the gradient is illustrated as occurring in hypothetical steps, starting at A,

where osmolality in both limbs and the interstitium is 300 mOsm/kg of water. The pumps in the thick

ascending limb move Na+ and Cl into the interstitium, increasing its osmolality to 400 mOsm/kg, and

this equilibrates with the fluid in the thin descending limb. However, isotonic fluid continues to flow into

the thin descending limb and hypotonic fluid out of the thick ascending limb. Continued operation of the

pumps makes the fluid leaving the thick ascending limb even more hypotonic, while hypertonicity

accumulates at the apex of the loop.

15.Describe the inter-relationship between the loop of Henle, the collecting duct and the vasa recta

that allows dilute or concentrated urine to be produced.



All 3 of these structures dip down into the medulla of the kidney, in doing so, are capable of

concentrating urine.

y Loop of Henle:

y C ollecting duct: Principal cellso R eabsorb Na+ and H20 and secrete K+o A

ldosterone ± increases Na+ reabsorption (and subsequent H2O in presence of AD

H)o ADH ± increases H2O permeability through aquaporin channel insertion into the luminal

membrane

y V asa R ecta: The vasa recta acts as countercurrent exchangers in the kidney. NaC l and urea diffuseout of the ascending limb of the vessel and into the descending limb, whereas water diffuses out of the descending and into the ascending limb of the vascular loop.

16.Describe how tubular flow rate, vasa recta blood flow, tubular fluid osmolarity and

antidiuretic hormone influence the ability of the kidney to form concentrated urine.

y Tubular (peritubular) flow rate: When there is an increase in tubular flow rate, hydrostatic pressure inthe peritubular capillary blood increases and there is a concurrent decrease in oncotic pressure (inthe peritubular capillary)

o This decreases the amount of filtrate that is reabsorbed to the peritubular capillaries fromthe filtrate at the level of the proximal tubule.

y ADH: ADH causes the insertion of aquaporin channels into the apical membrane of epithelial cells of the collecting duct.

o S ince filtrate at this point is hypotonic, water flows down its osmotic gradient to theinterstitium of the cortex, and subsequently the medulla.

o This dramatically increases the osmolality of urine to as much as 1400 mOsm/kg of H2O.

17. Describe the nephron sites and molecular mechanisms of action of the following classes of

diuretics: osmotic, carbonic anhydrase inhibitors, loop, thiazide, K-sparing.



Class of diuretic Site of action Mechanism

Osmotic Proximal tubule/descending limb Promote diuretic dieresis

(increase osmolarity of filtrate to

increase oncotic pressure)

Carbonic anhydrase inhibitor Proximal tubule Inhibition of carbonic anhydrase

Loop Thick ascending limb of LoH Inhibition of Na/K/2Clcotransport

Thiazide Early distal tubule Inhibition of Na-Cl cotransport

K-sparing Late distal tubule/collecting duct Inhibition of Na reabsorption/K

secretion/H secretion

18. Contrast the quantitative differences in sodium and water reabsorption in the major tubular

segments.

Na:

PCT = 67%

Thick ascending limb = 25%

Distal convoluted tubule = 5%

Collecting duct = 3%

Water:

PCT = 67% (water follows Na+)

Descending loop of Henle = 15%

Ascending limb of LoH (thick and thin) = impermeable to water (only Na and Cl move)

Distal tubule and collecting tubule = water follows Na, but permeability is regulated by ADH; if no

ADH is secreted, no water will be reabsorbed; 5% during water loading (low ADH, >24% during

dehydration (high ADH)

19. Define renal interstitial hydraulic pressure and describe its importance in water reabsorption in

the proximal tubule.

Renal interstitial hydraulic pressure (glomerular capillary oncotic pressure) is determined by the

protein concentration of glomerular capillary blood. It is a force that opposes filtration.

Along the length of the glomerular capillary,RIHP normally increases because filtration of water

increases the protein concentration of glomerular capillary blood. Thus, as glomerular blood

empties into the efferent glomerular arteriole and subsequently the peritubular capillaries,

solute/water reabsorption is proportionately increased at the proximal convoluted tubule.

Conversely, a decrease in filtration fraction causes an increase in RIHP and eventually a decrease in

solute/water reabsorption at the proximal convoluted tubule.

20. Predict how changes in peritubular capillary hydrostatic and oncotic pressures alter renal

interstitial hydraulic pressure and subsequent water reabsorption.



The Starling forces (hydrostatic and oncotic pressures) in peritubular capillaries determines how

much Na+ and water will be resorbed in the proximal tubule. The hydrostatic and oncotic pressures

of the peritubular capillaries determine how much of the isosmotic fluid is resorbed directly

affecting interstitial hydraulic pressure and water resorption.

- An increase in peritubular capillary oncotic pressure increases fluid reabsorption into the

capillaries causing a decrease in hydraulic pressure- A decrease in peritubular oncotic pressure decreased fluid reabsorption into the capillaries

causing an increase in hydraulic pressure

Heres a flow chart giving one example:

21. Define pressure natriuresis and describe the underlying mechanism that accounts for it.

Pressure natiuresis is the excretion of sodium by the body (typically used when referring to excess

excretion) as a compensatory mechanism for increased arterial pressure. There are several

mechanisms which account for this:

1. Increased BP leads to increased GFR, so Na+ filtered load would be greater, therefore Na+

excreted would also increase

2. Increased circulatory volume would cause an decrease in rennin production, leading to

reduced resorption of Na+ by the distal tubule

3. Increased blood pressure increases volume of blood following through the vasa recta,

leading to a decrease in hypotonicity of the medulla, and a decrease in Na+ resorption by

the loop of henle

4. Increased BP leads to decreased number of Na+-H+ exchangers in proximal tubule

5. Increased BP leads to increased pressure in peritubular capillaries, which reduces proximal

tubule resorption

22. Explain the inter-relationship between pressure natriuresis, tubuloglomerular balance and

autoregulation.



Tubuloglomerular balance involves the ability of the macula densa to determine GFR, and respond

to an increase in GFR by increasing the resistance of the afferent arterioles, thereby effectively

reducing the renal plasma flow and glomerular capillary pressure, and lowering the increased GFR

towards normal. Also, the macula densa can respond to a decrease in GFR by causing the initiation

of the renin-angiotensin cascase, resulting in increased Na+ resorbtion and an increase in blood

pressure. Pressure naturesis occurs when the increased pressure causes the macula densa to sense

the increased Na and Cl levels, and therefore signal a reduction in the production of renin

eventually leading to increased excretion of Na (and therefore water) and a decreased BP

This is a great figure explaining the cascade I found:

Response of the kidneys to an increase in blood pressure (natriuresis /diuresis). Part of the intermediate-

term response to increases in blood pressure is to reduce blood volume (in an attempt to match blood

volume with the capacity of the vascular tree). There are several mechanisms for this response. By far, the

most important is a reduction in proximal tubular sodium reabsorption because of a reduction in the number

of functional transporters (Na-H antiporters) in the apical membrane of the proximal tubule epithelial cells.

The reduction is probably in response to reduced levels of angiotensin II. There is also an increase (usually

small) in glomerular filtration rate (GFR) and an increase in peritubular hydrostatic pressure and renal

interstitial pressure that favor reduced absorption of salt and water in the cortex (particularly from the

proximal nephron). ECF, extracellular fluid

23. Describe the effect of each of the following on sodium reabsorption: aldosterone, angiotensin

II, arterial pressure, antidiuretic hormone, atrial natriuretic hormone, prostaglandins, renalinterstitial hydraulic pressure, and sympathetic nerve activity.



Aldosterone: stimulates Na+

reabsorption by the initial tubule and the cortical collecting tubule,and by medullary collecting ducts. Early cellular actions of aldosterone action include

upregulation of apical ENaCs, apical K +

channels, the basolateral Na-K pump, and mitochondrialmetabolism. The effects on ENaC involve an increase in the product of channel number and open

probability (NPo), and thus apical Na+

permeability.

Angiotensin II: promotes Na

+

reabsoption. Binds to AT1 receptors at the apical and basolateralmembranes of proximal tubule cells and, predominantly through protein kinase C, stimulatesapical NHE3s. ANG II also stimulates Na-H exchange in the TAL and stimulates apical Na

+

channels in the initial collecting tubule.Arterial pressure: decreases Na

+reabsorption. First, the increased effective circulating volume

inhibits the renin-angiotensin-aldosterone axis and thus reduces Na+

reabsorption (see Chapter 35). Second, the high blood pressure augments blood flow in the vasa recta, washes out

medullary solutes and reduces interstitial hypertonicity in the medulla, and ultimately reduces passive Na+ reabsorption in the thin ascending limb (see Chapter 38). Third, an increase in

arterial pressure leads, by an unknown mechanism, to prompt reduction in the number of apical Na-H exchangers in the proximal tubule. Normalizing the blood pressure rapidly reverses this

effect. Finally, hypertension leads to increased pressure in the peritubular capillaries, therebyreducing proximal tubule reabsorption (physical factors; see Chapter 35).

Anti diuretic hormone (arginine vasopressin): stimulates Na+

reabsorption. In principal cells of the initial collecting tubule and the CCT, antidiuretic hormone stimulates Na

+transport by

increasing the number of open Na+

channels (NPo) in the apical membrane.Atrial natriuretic hormone: decreases Na

+reabsorption. It causes renal vasodilation, by

massively increasing blood flow to both the cortex and the medulla. Increased blood flow to thecortex raises GFR and increases the Na+ load to the proximal tubule and to TAL (see Chapter

34). Increased blood flow to the medulla washes out the medullary interstitium, thus decreasingosmolality and ultimately reducing passive Na

+reabsorption in the thin ascending limb (see

Chapter 38). The combined effect of increasing cortical and medullary blood flow is to increasethe Na

+load to the distal nephron and thus to increase urinary Na

+excretion. In addition to its

hemodynamic effects, ANP directly inhibits Na+ transport in the inner medullary collecting duct, perhaps by decreasing the activity of nonselective cation channels in the apical membrane.

Prostaglandins: inhibits Na+

reabsorption. these agents act through protein kinase C (see Chapter 3) to inhibit Na

+reabsorption, probably by phosphorylating K

+or Na

+channels. In addition, the

transepithelial voltage becomes less lumen positive, thus decreasing the driving force for passive paracellular reabsorption of Na+ and other cations. In the CCT, both PGE2 and bradykinin inhibit

ENaCs (Fig. 35-4D).Renal interstitial hydraulic pressure: hydrostatic pressure in bowman¶s space opposes filtration

(bowman¶s space is equivalent to interstitial space). I believe the objective is looking for this, Icould not find hydraulic pressure, only hydraulic conductivity which relates driving force and

permeability.Sympathetic nerve activity: enhances Na+ reabsorption. The varicosities of the sympathetic fibers

release norepinephrine and dopamine into the loose connective tissue near the smooth musclecells of the vasculature (i.e., renal artery as well as afferent and efferent arterioles) and near the

proximal tubules. Sympathetic stimulation to the kidneys has three major effects. First, thecatecholamines cause vasoconstriction. Second, the catecholamines strongly enhance Na

+

reabsorption by proximal tubule cells. Third, as a result of the dense accumulation of



sympathetic fibers near the granular cells of the JGA, increased sympathetic nerve activitydramatically stimulates renin secretion.

Regulation of ECFV and whole body osmolarity 24. Describe the sensors and effector systems that are involved in maintaining a constant

extracellular volumeThe maintenance of the ECF volume, or Na+ balance, depends on signals that reflect theadequacy of the circulation-the so-called effective circulating volume, discussed later. Low- and

high-pressure baroreceptors send afferent signals to the brain (see Chapter 23), which translatesthis volume signal into several responses that can affect ECF over either the short term or the

long term. The short-term effects (over a period of seconds to minutes) occur as the autonomicnervous system and humoral mechanisms modulate the heart and blood vessels to control blood

pressure. The long-term effects (over a period of hours to days) consist of nervous, humoral, andhemodynamic mechanisms that modulate renal Na+ excretion. In the first part of this chapter, we

discuss the entire feedback loop, of which Na+

excretion (see Chapter 35) is the effector.Why is the Na

+content of the body the main determinant of the ECF volume? Na

+, with its

associated anions, Cl

-

and, is the main osmotic constituent of the ECF volume; when Na saltsmove, water must follow. Because the body generally maintains ECF osmolality within narrow

limits (e.g., 290 mOsmol/kg or mOsm), it follows that whole-body Na+

content-which the

kidneys control-must be the major determinant of the ECF volume. A simple example illustratesthe point. If the kidney were to enhance the excretion of Na

+and its accompanying anions by

145 mEq each-the amount of solute normally present in 1 L of ECF-the kidneys would have toexcrete an additional liter of urine to prevent a serious fall in osmolality. Alternatively, adding

145 mmol of "dry" NaCl to the ECF necessitates adding 1 L of water to the ECF; this additioncan be accomplished by drinking water or by reducing renal excretion of solute-free water.

Relatively small changes in Na+

excretion lead to marked alterations in the ECF volume. Thus, precise and sensitive control mechanisms are needed to safeguard and regulate the body's contentof Na

+.

25. Define the concept, ³effective circulating volume´, and contrast how it changes in heart

failure and hemorrhageThe effective circulating volume cannot be identified anatomically. Rather, it is a f unctional

blood volume that reflects the extent of tissue perfusion in specific regions, as evidenced by thefullness or pressure within their blood vessels. Normally, changes in the effective circulating

volume parallel those in total ECF volume. However, this relationship may be distorted in certaindiseases. For example, in patients with congestive heart failure (see earlier), nephrotic syndrome,

or liver cirrhosis, total ECF volume is grossly expanded (e.g., edema or ascites). In contrast, thee ff ective circulating volume is low, resulting in Na

+retention.

26. Describe the sensors and effector systems that are involved in maintaining a constant

extracellular osmolarity.



Direct control of water excretion in the kidneys is exercised by vasopressin, or anti-diuretichormone (ADH), a peptide hormone secreted by the hypothalamus. ADH causes the insertion of

water channels into the membranes of cells lining the collecting ducts, allowing water reabsorption to occur. Without ADH, little water is reabsorbed in the collecting ducts and dilute

urine is excreted.

ADH secretion is influenced by several factors (note that anything that stimulates ADH secretionalso stimulates thirst):1. By special receptors in the hypothalamus that are sensitive to increasing plasma osmolarity

(when the plasma gets too concentrated). These stimulate ADH secretion.2. By stretch receptors in the atria of the heart, which are activated by a larger than normal

volume of blood returning to the heart from the veins. These inhibit ADH secretion, because the body wants to rid itself of the excess fluid volume.

3. By stretch receptors in the aorta and carotid arteries, which are stimulated when blood pressure falls. These stimulate ADH secretion, because the body wants to maintain enough

volume to generate the blood pressure necessary to deliver blood to the tissues.ADH plays a role in lowering osmolarity (reducing sodium concentration) by increasing water

reabsorption in the kidneys, thus helping to dilute bodily fluids. To prevent osmolarity fromdecreasing below normal, the kidneys also have a regulated mechanism for reabsorbing sodium

in the distal nephron. This mechanism is controlled by aldosterone, a steroid hormone produced by the adrenal cortex. Aldosterone secretion is controlled two ways:

1.The adrenal cortex directly senses plasma osmolarity. When the osmolarity increases abovenormal, aldosterone secretion is inhibited. The lack of aldosterone causes less sodium to be

reabsorbed in the distal tubule. Remember that in this setting ADH secretion will increase toconserve water, thus complementing the effect of low aldosterone levels to decrease the

osmolarity of bodily fluids. The net effect on urine excretion is a decrease in the amount of urineexcreted, with an increase in the osmolarity of the urine.

2. The kidneys sense low blood pressure (which results in lower filtration rates and lower flowthrough the tubule). This triggers a complex response to raise blood pressure and conserve

volume. Specialized cells (juxtaglomerular cells) in the afferent and efferent arterioles producerenin, a peptide hormone that initiates a hormonal cascade that ultimately produces angiotensin

II. Angiotensin II stimulates the adrenal cortex to produce aldosterone.27. Outline the compensatory responses to the following: infusion of 2 liters of isotonic NaCl,

infusion of ½ isotonic NaCl, and the loss of 2 L of hypotonic fluid.

Micturition28. Describe the efferent and afferent innervation of the urinary bladder.

The urinary bladder is innervated by the vesicle nervous plexus which arises from the forefrontof the pelvis plexus. The urinary bladder wall is composed of a layer of smooth muscle fibers

called the detrusor muscle. When the bladder is stretched afferent the vesicle nervous plexussignals the parasympathetic nervous system which returns a signal to the detrusor muscle to

contract. The detrusor muscle contraction induces the expulsion of urine from the bladder through the urethra and out of the body. For the urine to exit the bladder the autonomically

controlled internal sphincter and voluntarily controlled external sphincter must open.

Micturition



28. Describe the efferent and afferent innervations of the urinary bladder.

The afferent innervations are sent by stretch receptors that detect urine storage in the bladder.The signal is continued to the brain by pelvic splanchnic nerves. The efferent innervation is

controlled by the pontine micturition center, which inhibits the presynaptic parasympathetic

neurons from firing due to a learned reflex. Once someone consciously decides to void, theinhibition stops and the parasympathetic preganglionic nerves innervate the detrusor muscle.Micturition is controlled by a spinal reflex arch. Here is the general info from the text on the

arch:

Bladder tone is defined by the relationship between bladder volume and internal (intravesical) pressure. One can measure the volume-pressure relationship by first inserting a catheter through

the urethra and emptying the bladder and then recording the pressure while filling the bladder with 50-mL increments of water. The record of the relationship between volume and pressure is

a cystometrogram (Fig. 33-13, blue curve). Increasing bladder volume from 0 to 50 mL

produces a moderately steep increase in pressure. Additional volume increases up to 300 mL

produce almost no pressure increase; this high compliance reflects relaxation of bladder smoothmuscle. At volumes higher than 400 mL, additional increases in volume produce steep rises in"passive" pressure. Bladder tone, up to the point of triggering the micturitionreflex, is

independent of extrinsic bladder innervation.

Cortical and suprapontine centers in the brain normally inhibit the micturition reflex, whichthe pontine micturition center coordinates. The pontine micturition center controls both the

bladder detrusor muscle and the urinary sphincters. During the storage phase, stretch receptorsin the bladder send afferent signals to the brain through the pelvic splanchnic nerves. One first

senses the urge for voluntary bladder emptying at a volume of 150 mL and senses fullness at400 to 500 mL. Nevertheless, until a socially acceptable opportunity to void presents itself,

efferent impulses from the brain, in a learnedreflex, inhibit presynaptic parasympathetic neuronsin the sacral spinal cord that would otherwise stimulate the detrusor muscle. Voluntary

contraction of the external urinary sphincter probably also contributes to storage.

The voiding phase begins with a voluntary relaxation of the external urinary sphincter, followed

by the internal sphincter. When a small amount of urine reaches the proximal (posterior) urethra,afferents signal the cortex that voiding is imminent. The micturition reflex now continues as

pontine centers no longer inhibit the parasympathetic preganglionic neurons that innervate thedetrusor muscle. As a result, the bladder contracts, expelling urine. Once this micturition

reflex has started, the initial bladder contractions lead to further trains of sensory impulses fromstretch receptors, thus establishing a self-regenerating process (Fig. 33-13, red spikes moving to

the left). At the same time, the cortical centers inhibit the external sphincter muscles. Voluntaryurination also involves the voluntary contraction of abdominal muscles, which further raises

bladder pressure and thus contributes to voiding and complete bladder emptying.

The basic bladder reflex that we have just discussed, although inherently an autonomic spinal

cord reflex, may be either facilitated or inhibited by higher centers in the central nervous system



that set the level at which the threshold for voiding occurs. Because of the continuous flow of urine from the kidneys to the bladder, the function of the various sphincters, and the nearly

complete emptying of the bladder during micturition, the entire urinary system is normallysterile.

29. Describe the role of somatic, sympathetic and parasympathetic nerves in the micturitionreflex

· Somatic

o The somatic innervation originates from motor neurons arising from segments S2 to S4.Through the pudendal nerve, these motor neurons innervate and control the voluntary skeletal

muscle of the external sphincter.· Sympathetic

o Innervates the bladder and internal sphincter o Arises from neurons in the intermediolateral cell column of the tenth thoracic to second

lumbar spinal cord segment.§ The preganglionic fibers then pass through lumbar splanchnic nerves to the superior

hypogastric plexus, where they give rise to the left and right hypogastric nerves. These nerveslead to the inferior hypogastric/pelvic plexus, where preganglionic sympathetic fibers synapse

with postganglionic fibers.§ The postganglionic fibers continue to the bladder wall through the distal portion of the

hypogastric nerve.· Parasympathetic

o Originates from the intermediolateral cell column in segments S2 through S4 of the sacralspinal cord.

o The parasympathetic fibers approaching the bladder via the pelvic splanchnic nerve are still preganglionic. They synapse with postganglionic neurons in the body and neck of the urinary

bladder.

30. For the nerves involved in the micturition reflex identify the neurotransmitter, the receptor onwhich it acts and the tissue response.

Sympathetic input (through aortic, hypogastric, and ovarian or spermatic plexuses) modulates

ureteral contractility as norepinephrine acts by excitatory -adrenergic receptors and inhibitoryß-adrenergic receptors. Parasympathetic input enhances ureteral contractility through

acetylcholine, either by directly stimulating muscarinic cholinergic receptors (see Chapter 3) or by causing postganglionic sympathetic fibers to release norepinephrine, which then can stimulate

-adrenoceptors. Some autonomic fibers innervating the ureters are afferent pain f ibers. In fact,the pain of renal colic associated with violent peristaltic contractions proximal to an obstruction

is one of the most severe encountered in clinical practice.

31. Describe the three major classes of lesions that affect micturition



1. Combined aff erent and eff erent lesions. Severing both afferent and efferent nervesinitially causes the bladder to become distended and flaccid. In the chronic state of the so-

called "decentralized bladder," many small contractions of the progressivelyhypertrophied bladder muscles replace the coordinated micturition events. Although

small amounts of urine can be expelled, a residual volume of urine remains in the bladder

after urination.2. Aff erent lesions. When only the sacral dorsal roots (sensory fibers) are interrupted,reflex contractions of the bladder, in response to stimulation of the stretch receptors, are

totally abolished. The bladder frequently becomes distended, the wall thins, and bladder tone decreases. However, some residual contractions remain because of the intrinsic

contractile response of smooth muscle to stretch. As a rule, a residual urine volume is present after urination.

3. Spinal cord lesions. The effects of spinal cord transection (e.g., in paraplegic patients)include the initial state of spinal shock in which the bladder becomes overfilled and

exhibits sporadic voiding ("overflow incontinence"). With time, the voiding reflex is re-established, but with no voluntary control. Bladder capacity is often reduced and reflex

hyperactivity may lead to a state called "spastic neurogenic bladder." Again, the bladder cannot empty completely, resulting in the presence of significant residual urine. Urinary

tract infections are frequent because the residual urine volume in the bladder serves as anincubator for bacteria. In addition, during the period of "overflow incontinence," before

the voiding reflex is re-established, these patients have to be catheterized frequently,further predisposing to urinary tract infections.

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