ex4 - renal

List the transmembrane transport mechanisms found in the GI tract

Active transporters (ATPase's) Na+-dependent co-transporters H+-coupled co-transporters Antiporters Uniporters Ion channels Aquaporins Receptor-mediated endocytosis

Receptor-mediated endocytosis Provide specific example and their location on the cell and along the GI tract.

B12/intrinsic factor complex receptor - ileum luminal membrane Fe2+/transferrin receptor - small intestine luminal membrane

The GI tract contains longitudinal and circular smooth muscle and some skeletal muscle. In the *small intestine:* List the type of muscle located in this section of GI tract and the role(s) it plays in the process of digestion and/or movement of the chyme down the alimentary canal.

1) Contraction-relaxation of circular smooth muscle (segmentation). Initiated by pacemaker cells (Interstitial Cells of Cajal). Helps digest food while moving it slowly down the small intestine 2) Post-absorption segmentation stops and is replaced by peristaltic waves of smooth muscle contraction (migrating myoelectrical complex: MMC) which moves residual material into the large intestine. Controlled by the hormone motilin

The GI tract contains longitudinal and circular smooth muscle and some skeletal muscle. In the *stomach:* List the type of muscle located in this section of GI tract and the role(s) it plays in the process of digestion and/or movement of the chyme down the alimentary canal.

1) Initial relaxation of stomach wall smooth muscle to receive food from the esophagus (receptive relaxation) 2) Closure of the lower esophageal and pyloric sphincters (smooth muscle) 3) Stomach contents mixed by peristaltic waves of smooth muscle contraction (retropulsion). Rhythm dictated by pacemaker cells in longitudinal muscle.

The GI tract contains longitudinal and circular smooth muscle and some skeletal muscle. In the *large intestine:* List the type of muscle located in this section of GI tract and the role(s) it plays in the process of digestion and/or movement of the chyme down the alimentary canal.

1) Intense waves of smooth muscle contraction 3-4 times per day (mass movement) moving material into the rectum 2) Internal anal sphincter (smooth muscle) closed; external anal sphincter (skeletal muscle) open to this point 3) Distension of rectum triggers smooth muscle contraction (defecation reflex); Internal anal sphincter opens

The greatest amount of the sodium filtered by the kidney is reabsorbed by A. the proximal tubule B. the loop of Henle C. the distal tubule D. the collecting tubule

A

Which of the following should DECREASE glomerular filtration rate (GFR)? A. An increase in Bowman's space hydrostatic pressure. B. A decrease in plasma colloid oncotic pressure. C. Dilation of the afferent arteriole. D. Constriction of the efferent arteriole.

A

Which of the following statements is CORRECT? A. Absorption of calcium will be reduced after parathyroidectomy. B. Absorption of fat is dependent on micelles containing resynthesized triglyceride being taken up by the lacteals. C. Absorption of heme is dependent on binding to transferrin which is secreted by the intestinal epithelial cells. D. Absorption of vitamin B12 is dependent on intrinsic factor synthesis by the ileum.

A

Which of the following statements is correct? A. Pepsinogen secretion by chief cells increases during the cephalic phase. B. Enterogastrones stimulate HCl secretion by parietal cells. C. At low stomach lumen pH, somatostatin stimulates the secretion of gastrin and histamine. D. Gastrin potentiates the stimulatory effects of histamine and acetylcholine on HCl secretion by parietal cells.

A

All of the following clinical findings are associated with chronic renal failure EXCEPT: A. Hypokalemia B. Anemia C. Azotemia D. Edema

A hyperkalemia is associated with chronic renal failure

In the renal section of the course we will discuss diuretics which are used to increase the excretion of salt and water. One (of many) diuretics is acetazolamide; if a patient was given this drug over a period of time, what effect(s) might you expect on GI tract function?

Acetazolamide is a carbonic anhydrase inhibitor. This enzyme is located in stomach parietal cells and catalyzes the conversion of CO2 and H2O to carbonic acid and subsequently to H+ and HCO3-. The H+ is then transported across the luminal membrane via the H+/K+ ATPase to form HCl. Recall the low stomach lumen pH directly promotes initial breakdown of luminal contents AND converts the zymogen, pepsinogen, to the active proteolytic enzyme pepsin. In the presence of acetazolamide, HCl production will be suppressed, pepsin will not be activated and thus there will be little to no digestion of ingested material. Although not covered to this point in class, we will see that carbonic anhydrase is also required for HCO3- synthesis and secretion by the pancreas.

In the renal section of the course we will discuss diuretics which are used to increase the excretion of salt and water. One (of many) diuretics is acetazolamide; if a patient was given this drug over a period of time, what may be a consequence of this treatment?

Although of little consequence in this treatment scenario, recall that epithelial cells located at the opening of the gastric glands synthesize mucus and HCO3- which form a thin protective layer across the epithelial lining of the stomach. The proteinaceous content of the mucus acts as an H+ chelator and the HCO3- neutralizes HCl in close proximity to the luminal membrane. Generation of HCO3- in these cells also requires carbonic anhydrase.

In a state of maximum antidiuresis, human urine output could be: A. 20 liters/day B. 500 ml/day C. 50 ml/day D. 5 liters/day

B

ADH acts on the nephron to A. stimulate Na-K-ATPase in the collecting duct B. insert sodium channels in the collecting duct C. insert water channels in the collecting duct D. increase the potassium permeability of the collecting duct

C

An increase in efferent arteriole diameter might be expected to: A. increase glomerular filtration rate and increase renal blood flow B. Increase glomerular filtration rate and decrease renal blood flow C. decrease glomerular filtration rate and increase renal blood flow D. decrease glomerular filtration rate and decrease renal blood flow

C

In an experimental animal model, total renal plasma flow is 100 ml/min. You would estimate glomerular filtration rate to be: A. 180 ml/min B. 33 ml/min C. 20 ml/min D. 5 ml/min

C

In the ABSENCE of amylase (pancreatic and salivary): A. absorption of all ingested disaccharide will cease. B. absorption of all ingested carbohydrate will cease. C. absorption of all ingested polysaccharide will cease. D. absorption of all ingested monosaccharide will cease.

C

In the pancreas: A. CCK stimulates HCO3- secretion. B. all digestive enzymes are secreted as zymogens. C. inhibition of monitor peptide production should lead to a decrease in digestive enzyme secretion. D. cephalic phase stimuli increase carbonic anhydrase activity.

C

The appearance of which of the following substances in the urine is most consistent with a diagnosis of chronic renal failure? A. HCO3- B. Creatinine C. Serum albumin D. Glucose

C

Which of the following combinations should INCREASE ADH secretion to the greatest extent? A. Decreased plasma osmolarity; increased plasma volume B. Decreased plasma osmolarity; decreased plasma volume C. Increased plasma osmolarity; decreased plasma volume D. Increased plasma osmolarity; increased plasma volume

C

Which of the following determines the concentration of angiotensin II in the plasma? A. activity of converting enzyme in the lungs B. concentration of angiotensinogen substrate made by the liver C. renin secretion rate by the kidney D. the clearance of angiotensin II from the blood

C

Which of the following is the most likely consequence of an impaired ability to secrete saliva (xerostomia)? A. Increased taste discrimination. B. Decreased absorption of fats. C. Increased incidence of oral infections and tooth decay. D. Decreased absorption of carbohydrates.

C

Which of the following statements is CORRECT? A. Synthesis of new HCO3- occurs predominantly in the loop of Henle. B. An increase in plasma pH will stimulate respiration. C. The kidneys can generate HCO3- by metabolizing glutamine. D. CO2 is considered a fixed, non-volatile acid.

C

Which of the following will increase renal renin secretion the most? A. Increased sympathetic nervous system activity and increased NaCl delivery to the macula densa. B. Increased NaCl delivery to the macula densa and increased blood pressure C. Decreased blood pressure and increased sympathetic nervous system activity D. Decreased sympathetic nervous system activity and decreased NaCl delivery to the macula densa

C

Which of the following would lead to a decrease in glomerular filtration rate? A. Increased glomerular hydrostatic pressure B. Decreased glomerular capillary colloid osmotic pressure C. Increased Bowman's space hydrostatic pressure D. Increased Bowman's space colloid osmotic pressure

C

Which one of the following is NOT a site of protein/peptide digestion? A. The brush border membrane of small intestine epithelial cells. B. The cytosol of small intestine epithelial cells. C. The basolateral membrane of small intestine epithelial cells. D. The lumen of the stomach. E. The lumen of the small intestine.

C

Which of the following statements is correct? A. Emetics inhibit the vomiting center. B. Increasing GIP secretion suppresses insulin secretion. C. Bile duct obstruction can lead to clotting problems and hypercholesterolemia. D. Cholera is associated with osmotic diarrhea.

C A: emetics stimulating vomiting center B: GIP stimulates insulin secretion D. cholera is secretory diarrhea

Ion channels Provide specific example and their location on the cell and along the GI tract.

Cl-, K+ - luminal membrane of stomach parietal cells Cystic fibrosis transmembrane regulator (CFTR) - luminal membrane of pancreatic duct cells

Antiporters Provide specific example and their location on the cell and along the GI tract.

Cl-/HCO3- exchanger - basolateral membrane of stomach parietal cells Na+/H+ exchanger - pancreas basolateral membrane

You have developed a conditional, GI-tract specific CCK receptor knock-out mouse. How will GI tract function change in these mice? In your answer please address why the model in question is a conditional knock-out.

Consider the multiple roles of CCK which will all be suppressed/eliminated in the absence of a CCK receptor. CCK 1) stimulates the secretion of all digestive enzymes by the pancreas, 2) potentiates the stimulatory effect of secretin on HCO3- secretion by the pancreas, 3) causes the smooth muscle surrounding the gall bladder to contract, forcing bile into the bile duct 4) causes relaxation of the Spincter of Oddi which allows the bile to flow into the lumen of the small intestine. Recall that CCK also participates in intestinal phase control of stomach function. As stomach chyme enters the small intestine, CCK levels increase and leads to both a reduction in HCl secretion by parietal cells and a reduction in stomach motility. This helps ensure that both the pH and the rate of delivery of chyme to the small intestine is optimal for subsequent digestion by pancreatic enzymes. This feedback control would be lost in the receptor knock-out.

C

Considering the unique characteristics of inulin, the tubular fluid concentration of inulin at point C will be: A. the same as the plasma concentration of inulin. B. lower than the plasma concentration of inulin. C. higher than the plasma concentration of inulin.

When we consider fluid reabsorption from the proximal tubule, it is really a two stage process. Stage one involves transporting the solute and water through the proximal tubule cell (the transcellular route). Stage two involves uptake of the fluid into the peritubular capillaries, and this is dependent on a favorable balance of Starling forces. What will happen to a) glomerular filtration rate and b) proximal tubule fluid reabsorption if the efferent arteriole is constricted (provide explanations for your answers)?

Constriction of the efferent arteriole will lead to an increase in glomerular capillary hydrostatic pressure and therefore an increase in glomerular filtration rate (GFR). In addition, the increase in constriction leads to increased resistance and therefore renal plasma flow (RPF) decreases. As a consequence, the filtration fraction (GFR ÷ RPF) will increase, leading to a higher plasma protein concentration and thus oncotic pressure within the peritubular capillaries. The increased constriction of the efferent arteriole will also lead to a greater decrease in hydrostatic pressure within the peritubular capillaries. As discussed in part 1 of this question, both of these changes will lead to increased proximal tubule fluid reabsorption.

The GI tract contains longitudinal and circular smooth muscle and some skeletal muscle. For the process of *chewing* List the type of muscle located in this section of GI tract and the role(s) it plays in the process of digestion and/or movement of the chyme down the alimentary canal.

Controlled by skeletal muscle of the jaws

A test subject is treated with an experimental drug (Drug Q) that decreases GFR and increases renal plasma flow. What is the MOST LIKELY mechanism of action of Drug Q? A. It decreases glomerular capillary KF. B. It selectively constricts the afferent arteriole. C. It decreases systemic blood pressure. D. It selectively dilates the efferent arteriole.

D

GI tract smooth muscle: A. is the primary component of both the upper and lower esophageal sphincter. B. contains more troponin than skeletal muscle. C. is regulated exclusively by the autonomic nervous system. D. is described as single-unit smooth muscle because cells function as a syncytium.

D

Intravenous injection of a hormone initiates a phase of intense sequential contractions of the proximal duodenum that migrate slowly towards the cecum. Which of the following hormones was most likely injected? A. Somatostatin B. CCK C. Gastrin D. Motilin E. Secretin

D

The proximal tubule: A. reabsorbs approximately 50% of the filtered load of glucose and HCO3-. B. is the only site for tubular secretion. C. is the primary site of action of aldosterone. D. reabsorbs approximately 2/3 of the filtered load of water and solutes.

D

Which of the following would lead to the greatest increase in Antidiuretic Hormone secretion? A. Increased plasma osmolarity and increased blood volume B. Decreased plasma osmolarity and decreased blood volume C. Decreased plasma osmolarity and increased blood volume D. Increased plasma osmolarity and decreased blood volume

D

Which sphincter is composed of striated muscle and is normally tonically relaxed? A. Upper esophageal sphincter B. Internal anal sphincter C. Lower esophageal sphincter D. External anal sphincter

D A is tonically contracted B and C are smooth muscle (not striated)

Recall that filterability is governed by molecular size and by charge. Solutes with a MW of 5000 or less are freely filterable, As MW increases above that point filterability (fractional clearance) decreases. The charge effect is caused primarily by the basement membrane which, because of its composition, has a net negative charge. According to the laws of repulsion/attraction then, a large negatively charged solute would be repelled by the basement membrane i.e. filtration would be impeded, while the filtration of a positively charged molecule might be potentiated. Hence, in the graph the center line represents dextrans with no charge, the lower line represents dextrans with a negative charge and the upper line dextrans with a positive charge. In the right-hand NSN model notice that there is no longer any charge selectivity. The disease has likely affected the structure/composition of the basement membrane resulting in the loss of negative charge.

Dextrans are molecules that are available in different sizes (here plotted in angstroms on the x-axis) and with different associated charge (positive, negative and neutral). The left-hand graph below plots the filterability of dextrans as a function of size and charge (a fractional clearance of 1.0 = completely filterable). Explain the outcome of the experiment, predicting (and explaining) what charge is associated with each line. In the right-hand graph, the experiment is repeated in rats with nephrotoxic serum nephritis (NSN), a disease that affects the glomerulus. What effect has the disease had on the glomerulus to produce the observed results?

A substance such as Inulin can be used to measure glomerular filtration rate (GFR) because A. it is not reabsorbed by the kidney B. it is not secreted by the kidney C. it is not synthesized by the kidney D. it is not metabolized by the kidney E. it meets all of the above conditions

E

A patient presents at the emergency room complaining of frequent urination. The osmolarity of a sample of urine is 75 mOsm/L. What are the potential causes of this problem, and what could you do to identify the specific cause?

Excretion of large volumes of very dilute (hypotonic) urine is consistent with a diagnosis that the patient has diabetes insipidus (DI). The issue to be resolved is whether this is hypothalamic (central) or nephrogenic DI. The best way to distinguish between the two options is to administer exogenous antidiuretic hormone. A rise in urine osmolarity (and decrease in volume) would be consistent with hypothalamic DI; you would not expect a change in urine output with nephrogenic DI (renal unresponsiveness to ADH). .

Based on our discussion of the principal components of renal function, describe three ways by which excretion of a substance in the urine could be reduced. The urinary sodium concentration in patient A is 50 mEq/L and 150 mEq/L in patient B. Based on this information alone, can you determine which patient is excreting more sodium?

Excretion of substance X could be hypothetically reduced a) by decreasing GFR b) by increasing the rate of reabsorption or c) by decreasing the rate of secretion. The simple answer to part B is that you cannot tell which patient is excreting more sodium based simply on the concentration information provided. With a higher concentration, it may appear that patient B is excreting more sodium BUT the amount excreted is calculated by multiplying concentration by urine flow rate. So say patient A had a flow rate of 3 L/day while patient B produced 1 L/day, the amount of sodium excreted would be the same in both patients ... 150 mEq/day.

Uniporters Provide specific example and their location on the cell and along the GI tract.

GLUT transporters (fructose) - luminal membrane of small intestine epithelial cells GLUT transporters (fructose, galactose, glucose) - basolateral membrane of small intestine epithelial cells

Na+-dependent co-transporters Provide specific example and their location on the cell and along the GI tract.

Glucose, galactose, amino acids - luminal membrane of small intestine epithelial cells

H+-coupled co-transporters Provide specific example and their location on the cell and along the GI tract.

H+-small peptide - luminal membrane of small intestine epithelial cells

Your patient has been diagnosed with cystic fibrosis. What is the impact of dysfunctional CFTR:?

If CFTR function is impaired 1) HCO3- synthesis and secretion will be reduced. As a consequence the acidic stomach chyme cannot be efficiently neutralized as it enters the small intestine and thus digestion by pancreatic enzymes (which act at neutral-alkaline pH) will not occur; this will result in malabsorption of most of the ingested food. The reduced CFTR activity will also lead to decreased water movement into the lumen of the pancreatic duct. Continued synthesis and secretion of proteinaceous digestive enzymes into the lumen containing less water, will lead to the generation of a much more viscous fluid, which can often block the pancreatic duct. As a consequence delivery of digestive enzymes to the small intestine lumen will be impaired and lead to further malabsorption. The CFTR is also located on the luminal membrane of small intestine epithelial cells. Similar to the mechanism described above, the primary transport of Cl- into the lumen of the small intestine is followed by the paracellular flux of Na+. This accumulation of NaCl provides the osmotic driving force for water movement into the lumen. An impaired CFTR will reduce this fluid secretion; since this normally helps lubricate the wall of the intestine, movement of the stool will be impeded and could lead to blockage

A patient presents at the emergency room complaining of frequent urination. The osmolarity of a sample of urine is 75 mOsm/L. You narrow it down to either hypothalamic DI or nephrogenic Di. how do you determine which is occurring?

If this was indeed hypothalamic DI and the patient was given a maximally effective dose of synthetic ADH, you might expect that urine osmolality would increase to 1200 mOsm/L. In fact this wouldn't be the case; it might be only 600 mOsm/L at best. The reason is that the magnitude of the medullary interstitial hypertonic gradient is dependent on circulating ADH levels. If levels are high the gradient will be maximal (1200-1400 mOsm/L at the tip of the papilla). In a patient with hypothalamic DI, ADH may have been effectively zero for some time. Therefore, the interstitial gradient will have decreased. When a maximal dose of ADH is administered urine can only be concentrated to the existing osmolarity within the medulla, in this case 600 mOsm/L. With continued treatment with exogenous ADH the osmotic gradient will increase and after several days urine concentration will again be maximal.

What are the four starling sources that determine the volume and direction of fluid movement between plasma and interstitial across systemic capillaries

JV = KF [(PC - PI) - (πC - πI)] JV = flux of fluid across the capillary wall (volume/time) KF = the filtration coefficient PC= hydrostatic pressure within the capillary πC= oncotic pressure within the capillary PI=hydrostatic pressure within the interstitium πI = interstitial oncotic pressure (oncotic pressure is osmotic pressure due to protein)

1. glomerular filtration 2. tubular secretion 3. tubular reabsorption

Label (1), (2), and (3), on the diagram

What are some of the functional limitations of hemodialysis? Compare and contrast the effectiveness of hemo- versus peritoneal dialysis.

The primary limitation of hemodialysis is that it cannot maintain perfect homeostasis; there will inevitably be oscillations in ECF composition as discussed in class. Also, dialysis (of any kind) cannot maintain erythropoietin levels or activated vitamin D ... these must be administered exogenously. Since dialysis is continuous with the peritoneal option, the oscillations will be blunted. The challenge is for the patient to have the determination to exchange the dialysis fluid on a consistent basis.

A patient presents with a total block of the common bile duct. What will be the effect on small intestine function?

Liver ... impaired bile salt delivery will impact fat digestion/absorption. Recall that their amphipathic nature is essential to the emulsification process and the subsequent delivery of monoglyceride and free fatty acids to the luminal membrane in micelles. Pancreas ... pancreatic 'juice' contains enzymes responsible for the digestion of essentially all principal materials within the luminal chyme (carbohydrates, proteins, fats, nucleic acids). An inability to digest leads to an inability to absorb. There may still be some limited protein digestion/absorption since the lack of HCO3- from the pancreas will mean that the chyme delivered from the stomach will remain acidic and as a consequence the pepsin contained within the chyme will continue to digest proteins/peptides.

Aquaporins Provide specific example and their location on the cell and along the GI tract.

Luminal and basolateral membrane of most intestinal epithelial cells

Active transporters (ATPase's) Provide specific example and their location on the cell and along the GI tract.

Na+-K+-ATPase - basolateral membrane of mucosal epithelial cells from stomach → small intestine H+-K+-ATPase - luminal membrane of stomach parietal cells Ca2+ ATPase - basolateral membrane of small intestine epithelial cells

I stated on several occasions that the GI system is detrimental to body fluid homeostasis. Based on what you now know about this organ system do you agree with this statement (provide evidence for your answer)? Are there elements of GI tract function that actually help maintain body fluid homeostasis?

Overall I would stand by that statement; for the most part the GI tract is designed to digest and absorb as much of the ingested material as possible, with little or no consideration for how the addition of this absorbed material into the extracellular fluid (ECF) will affect overall fluid homeostasis. There are however examples of 'homeostasis-friendly' processes including: 1. iron absorption 2. calcium absorption 3. GI tract incretins

We made the statement that there is a direct correlation between total body sodium chloride content and extracellular fluid volume. Why does this relationship exist? Why does a reduction in plasma protein content lead to edema (expansion of the interstitial fluid volume)?

Recall that the majority of the Na(Cl) in the body is contained within the extracellular fluid (ECF) space. This is because of the activity of the plasma membrane Na+-K+-ATPase which pumps Na+ out of and K+ into the cells. As an example, if you eat 3 salt tablets, the NaCl will be absorbed from the GI tract and added to the ECF; this will increase the osmolarity of the ECF and thus draw water from the intracellular fluid space. Water flux will stop when the osmolarities of the ICF and ECF are equal. Four Starling forces determine the volume and direction of fluid movement between plasma and interstitium across systemic capillaries. Directionally protein in the plasma creates an osmotic force that tends to draw fluid from the interstitium into the capillary, or viewed another way, opposes the filtration of fluid into the interstitium. If plasma protein concentration decreases this oncotic force decreases, thus more fluid will accumulate in the interstitial space resulting in edema.

Patient #1 has lost vagal innervation to the GI tract. Patient #2 is being treated with a muscarinic receptor antagonist. How would the muscarinic receptor antagonist work?

Recall that with delivery of food to the stomach, wall distension/stretch detected by sensory nerve endings triggers short and long neural reflexes which normally stimulate HCl secretion. In the presence of a muscarinic receptor antagonist, 1) the direct stimulatory effect of ACh on the parietal cell will be lost, and 2) the stimulatory effect of ACh on histamine release will be lost. Neural stimulation of gastrin release may not be affected since this pathway utilizes gastrin releasing peptide (GRP) as the neurotransmitter and muscarinic antagonists will likely not block this post-synaptic receptor. In addition, gastrin release can be stimulated directly by stomach lumen contents which in turn can increase histamine release. The net effect is that total HCl secretion will be reduced (but not completely blocked) and as a consequence luminal content digestion will be less effective. Note that since it is controlled by essentially the same factors as HCl, the release of pepsinogen from chief cells will be similarly impacted.

The GI tract contains longitudinal and circular smooth muscle and some skeletal muscle. For the process of *swallowing* List the type of muscle located in this section of GI tract and the role(s) it plays in the process of digestion and/or movement of the chyme down the alimentary canal.

Requires: 1) relaxation of upper esophageal sphincter (skeletal muscle) 2) peristaltic waves of esophageal smooth muscle contraction 3) relaxation of lower esophageal sphincter (smooth muscle)

A drug is administered that decreases NaCl reabsorption by the thick ascending limb of the loop of Henle. What would you predict will happen 1) to the medullary interstitial gradient 2) to the osmolarity of tubular fluid delivered to the ascending from the descending limb and 3) to the osmolarity of tubular fluid delivered to the distal nephron. With prolonged drug treatment will NaCl reabsorption change in the distal nephron; if so, why?

The NaCl reabsorbed from the thick ascending limb is the source of the NaCl deposited in the medulla to create the hypertonic gradient. Reducing this rate of reabsorption will decrease NaCl deposition and therefore the medullary osmolarity. A reduction in medullary osmolarity will decrease water reabsorption from the thin descending limb, therefore the osmolarity of the fluid delivered to the ascending limb will not be as concentrated. A reduced rate of NaCl reabsorption from the ascending limb will not dilute the tubular fluid to the same extent therefore the osmolarity of the fluid delivered to the distal nephron will be higher (closer to isotonic). Reduced NaCl reabsorption from the ascending limb will lead to a decrease in total body NaCl and therefore a reduction in extracellular fluid volume. This will activate the renin-angiotensin-aldosterone system. The high aldosterone levels will stimulate NaCl reabsorption from one sub-section of the distal nephron, the cortical collecting tubule.

You have developed a conditional, GI-tract specific CCK receptor knock-out mouse. Why is the model in question is a conditional knock-out.?

The concept of a conditional knock-out is that you (the investigator) can determine when the gene/gene product in question is knocked out in for example an experimental mouse model. If the CCK receptor gene was knocked out at birth, the multiple adverse effects described above would likely mean that the pups would not survive.

PGC remains relatively constant along the glomerular capillary primarily because of the high resistance maintained by the efferent arteriole (downstream of the capillaries). Anatomically it is probably a narrower diameter that the afferent arteriole and is typically tonically constricted. Recall that πGC is the osmotic pressure due to protein. As the plasma flows down the glomerular capillary fluid but not protein is being filtered. Consequently the concentration of protein in the plasma progressively increases and thus the oncotic pressure generated progressively increases. At a net filtration pressure (NFP) of zero, the primary driving force for filtration (PGC) and the two forces opposing filtration (πGC and PBC) are equal, thus glomerular filtration stops. KF is fundamentally an index of the water permeability of the glomerular capillary. If it increased, fluid would be filtered more rapidly across the capillary, πGC would therefore rise more rapidly and you would achieve an NFP of zero before the end of the glomerular capillary.). No filtration (and no reuptake) of fluid will occur along the remainder of the capillary.

The filtration of fluid across glomerular capillaries is dependent on Starling forces. The left hand graph is plotting the status of each of the three primary forces along the length of the glomerular capillary. Why does PGC not change appreciably? Why does πGC increase along the capillary? What is happening when you achieve a net filtration pressure (NFP) of zero? What do you think would happen to the πGC line if the KF increased?

A new drug has been developed that selectively targets and suppresses the activity of Na+-K+-ATPase in the GI tract. What effects will this drug have on GI tract function?

The goal here is to recognize the importance of this pump for transepithelial transport, particularly in the small intestine. We have emphasized that it is located exclusively on the basolateral membrane of enterocytes and is responsible for the maintenance of a low intracellular Na+ concentration (10-15 mEq/L compared to 140 mEq/L in the extracellular fluid). This low intracellular Na+ provides the driving force for the extensive series of Na+-coupled co-transporters located on the luminal membrane of these cells; this includes the Na+-monosaccharide and Na+-amino acid family of transporters. This transport across the luminal membrane is often described as 'secondary-active' transport because is it absolutely dependent on the active (energy-dependent) transport of Na+ out of the cells across the basolateral membrane. In the presence of ATPase inhibitor then, intracellular Na+ concentration will increase and as a consequence co-transporter activity on the luminal membrane will decrease. Carbohydrate and protein absorption will thus be inhibited. There may be little effect on fat absorption since this process is ATPase-independent, with movement across the luminal membrane being a pure diffusive process.

Your patient has been diagnosed with cystic fibrosis. What is the underlying cause?

The underlying cause of cystic fibrosis is a defective chloride channel, the cystic fibrosis transmembrane regulator (CFTR). The CFTR is located at two primary sites in the GI tract. The first is on the luminal membrane of pancreatic duct cells, which are responsible for the synthesis of HCO3-. Recall that HCO3- is synthesized by the duct cells in a reaction catalyzed by carbonic anhydrase, and is transported across the luminal membrane by a HCO3-/Cl- exchanger; the Cl- that enters the cell is then returned to the lumen by the CFTR. The flux of Cl- into the lumen creates a local lumen-negative electrical potential which promotes the paracellular (between the cells) movement of Na+ into the lumen. This in turn creates a favorable osmotic gradient for the movement of water into the lumen of the pancreatic duct.

A drug is administered that decreases proximal tubule fluid reabsorption. What effect if any will this have on renin release (be sure to provide an explanation for your answer)?

There are three mechanisms that regulate renin release from the granular cells located on the afferent arteriole 1) pressure within the arteriole itself 2) sympathetic nervous system activity and 3) (key to this question) the macula densa .. a cluster of early distal tubule cells that can detect changes in tubular fluid flow. If a drug is given that decreases proximal tubule fluid reabsorption, the rate of fluid flow through the remainder of the nephron will increase. This increased fluid flow rate is detected by the macula densa cells resulting in a signal being sent to the granular cells to decrease renin release.

A 30-year-old male comes to the ER in a severely dehydrated state; he states he has been suffering from diarrhea for several days. What are the underlying potential causes of diarrhea (be sure to explain the mechanisms involved?).

There are two primary forms of diarrhea 1) osmotic and 2) secretory. In the case of osmotic diarrhea the underlying causes include an inability to fully digest and subsequently absorb material in the small intestine (for example due to decreased digestive enzyme activity (lactose intolerance) or a blocked common bile duct) or due to ingestion of non-absorbable solutes such as mannitol and sorbitol. The increased osmotic load within the lumen prevents the normal absorption of water, resulting in the excretion of large volumes of watery stool. The underlying cause of secretory diarrhea is a primary inappropriate increase in salt transport into the lumen of the small intestine which then leads to the osmotic flux of water into the lumen. Cholera is a disease that triggers secretory diarrhea

How are GI tract incretins 'homeostasis-friendly'?

These are hormones (glucose-dependent insulinotropic peptide (GIP); glucagon-like peptide (GLP)) released from the GI tract in response to food intake that stimulate insulin secretion prior to absorption of glucose from the GI tract. They participate in so-called feed-forward control of plasma glucose.

How is Ca++ absorption a 'homeostasis-friendly' process?

This process is controlled by 1,25 (OH)2-vitaminD (1,25-D), which in turn is regulated by parathyroid hormone (PTH). For example, a decrease in plasma Ca2+ below normal, leads to increased PTH, increased 1,25-D, and therefore increased Ca2+ absorption, which will help return plasma Ca2+ to normal.

A 30-year-old male comes to the ER in a severely dehydrated state; he states he has been suffering from diarrhea for several days. What are the underlying potential causes of diarrhea (be sure to explain the mechanisms involved?). How might you be able to determine which form of diarrhea this patient is suffering from? What are the systemic consequences of prolonged diarrhea?

To distinguish between the two diarrhea forms 1) a stool sample from a patient suffering from osmotic diarrhea should contain larger amounts of undigested carbohydrates, proteins, and fats (steattorhea), and 2) osmotic diarrhea should cease after a patient is fasted. The primary systemic consequence of prolonged diarrhea is dehydration. Several liters of fluid can be lost in the stool each day; recall that this fluid originates in the extracellular fluid space.

Filtered load = GFR X plasma glucose [ ] Control: FL = 100 ml/min X 1.0 mg/ml = 100 mg/min Experimental: FL = 100 ml/min X 3.0 mg/ ml = 300 mg/min CORRECT

You are conducting a clinical trial of a new drug (Expo) to determine if it has any effects on renal function. You make the following measurements before (control) and after (experimental) administration of Expo. Use the following information to answer questions below: 2. Is the following statement CORRECT? The filtered load of glucose is higher after Expo treatment.

When we consider fluid reabsorption from the proximal tubule, it is really a two stage process. Stage one involves transporting the solute and water through the proximal tubule cell (the transcellular route). Stage two involves uptake of the fluid into the peritubular capillaries, and this is dependent on a favorable balance of Starling forces. How might the events that have occurred upstream at the glomerulus affect Starling forces so that they promote fluid uptake into the peritubular capillaries?

Two Starling forces will promote the uptake of fluid reabsorbed from the proximal tubule into the peritubular capillaries: 1. Recall that 20% of the plasma flowing through the glomerular capillaries is filtered; proteins contained within the plasma are however not filtered; consequently, the concentration of protein in the plasma flowing into the peritubular capillaries will much higher. The resultant high oncotic pressure created (osmotic pressure due to proteins) will promote fluid uptake into the capillaries. 2. As a result of having two upstream resistance points in series (the afferent and efferent arterioles), hydrostatic pressure in the peritubular capillaries will be very low. This is normally a force that opposes fluid uptake, so the lower this pressure the more it favors fluid uptake.

Patient #1 has lost vagal innervation to the GI tract. Patient #2 is being treated with a muscarinic receptor antagonist. How would stomach function and its control differ in these two patients?

Vagal innervation is particularly important for cephalic phase control of the stomach. Recall that the primary stimuli for this phase of GI tract control include, sight, smell and taste of the food. The excitatory efferents resulting from these external and oral stimuli are carried to the stomach via the vagal nerve fibers. In patient #1, with a blocked or cut vagus the stimulatory effects of these stimuli on HCl secretion from parietal cells and pepsinogen secretion from chief cells would be lost. This would be due to: 1. Loss of direct stimulatory effect of parasympathetics on the parietal (and chief) cells 2. Loss of stimulatory effect of parasympathetics on gastrin and histamine secretion The primary neurotransmitter released at target cells within the GI tract is acetylcholine which post-synaptically binds predominantly to cholinergic muscarinic receptors. In patient #2, binding to these receptors will be blocked (for example with atropine). Consequently, as for patient #1, cephalic phase control of the stomach will be lost but in addition, there will be likely be suppression of gastric phase control. In particular, the vagovagal reflex will for the most part be lost.

We use what is known as the dilution principal to measure the volume of a body fluid space. I. Add known amount of a measurable substance X to unknown volume in the beaker ii. Mix until substance X distributes throughout the fluid iii. Fluid Volume = Amount of X Added/Concentration of X at Equilibrium To apply the dilution principle to directly measuring body fluid volumes: I. Marker must be distributed only in the compartment(s) to be measured (see below) ii. Volume to be measured should include the plasma volume (because marker usually injected i.v. and only plasma can be sampled at equilibrium) iii. Any losses (e.g. in urine, sweat) should ideally be quantifiable iv. Compartment Volume = [(Amount of X Given) - (Amount of X Lost)]/Concentration of X at Equilibrium

We assigned absolute values to the volumes of each of the major body fluid compartments. How are these measurements made? Use example in image to determine how much liquid is in the flask

The markedly reduced partial pressure of oxygen at high altitude will lead to an increased. If you remain in this environment for some time, what effect will it have on your acid-base status (consider renal compensation in your answer)? Can you think of another change in renal function that will occur as a result of extended exposure to a hypoxic (low O2) environment?

With sustained hyperventilation arterial pCO2 will decrease. Let's say it decreases from the normal value of 40 mmHg to 20 mmHg. Converting this to dissolved CO2 the value would be 0.6 mmol/L. At this point, pH would be greater than 7.4, a state of respiratory alkalosis. The renal compensation for this state involves excretion of HCO3 in order to lower plasma HCO3 concentration (in this case to 12 mmol/L) and thereby restore the normal 20:1 ratio of HCO3:CO2. Recall that CO2 is a controlling factor for HCO3 reabsorption. A reduced pCO2 will result in decreased proximal tubule HCO3 reabsorption; in addition there will be no stimulus either for generation of new HCO3 via glutamine metabolism, or via the production of distal tubule titrateable acid. As with the model of respiratory acidosis discussed in class, this renal compensatory mechanism will be slow onset. In this hypoxic state you would expect renal synthesis and secretion of erythropoietin to increase, leading to an increase in red blood cell production.

GFR = urine flow X urine inulin [ ] / plasma inulin [ ] Control: GFR = 1.0 ml/min X 0.4 mg/ml / 0.004 mg/ml = 100 ml/min Experimental: GFR = 2.0 ml/min X 0.2 mg/ml / 0.004 mg/ml = 100 ml/min Conclusion: Expo has no effect on GFR

You are conducting a clinical trial of a new drug (Expo) to determine if it has any effects on renal function. You make the following measurements before (control) and after (experimental) administration of Expo. Use the following information to answer questions below: 1. What effect does Expo have on GFR?

The TM is the maximum reabsorptive capacity for (in this case) glucose. In the control period there is no glucose in the urine meaning all filtered glucose has been reabsorbed; the TM has not been exceeded. In contrast after Expo, glucose does appear in the urine meaning the filtered load exceeds the TM. CORRECT

You are conducting a clinical trial of a new drug (Expo) to determine if it has any effects on renal function. You make the following measurements before (control) and after (experimental) administration of Expo. Use the following information to answer questions below: 3. Is the following statement CORRECT? The TM for glucose has been exceeded after Expo treatment.

By definition, the plasma threshold is the plasma (glucose) concentration which leads to a filtered load that exceeds TM i.e. glucose appears in the urine. In the control period there is no glucose in the urine therefore the plasma threshold must be greater than 1 mg/ml. CORRECT

You are conducting a clinical trial of a new drug (Expo) to determine if it has any effects on renal function. You make the following measurements before (control) and after (experimental) administration of Expo. Use the following information to answer questions below: 4. Is the following statement CORRECT? The plasma threshold for glucose is greater than 1 mg/mL.

How does cholera trigger secretory diarrhea?

mechanistically the pathogen stimulates cyclic AMP generation in small intestine epithelial cells which stimulates CFTR activity and therefore Cl- flux into the lumen. The accumulation of Cl- and Na+ osmotically draws water into the lumen.

How is iron absorption a 'homeostasis-friendly' process?

recall that a significant amount of the iron absorbed from the lumen of the small intestine is sequestered within the cell (complexed to ferritin and transferrin). The amount released basolaterally into the ECF is determined by ECF iron levels; if lower than normal, more will be released and if higher than normal less will be released.