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If one gives an agent to yeast that inhibits the enzyme that converts intermediate D to intermediate E in the biochemical pathway below, which is the first intermediate whose concentration will increase? A B C D E A) A B) B C) C D) D E) E Where Are We?
I have discussed: How nutrients and oxygen enter our blood, how the blood circulates throughout the body to bring nutrients and oxygen to each cell, and how cells use the nutrients and oxygen for energy and biosynthesis. How the kidneys filter the blood and produce a hormone that stimulates red blood cell formation in bone marrow. Today I will discuss: The Internal Milieu According to Claude Bernard, each cell is free to live and respire in the body because it is surrounded by an internal milieu that is in equilibrium with the blood. In His Own Words...
"The living body, though it has need of the surrounding environment, is nevertheless relatively independent of it. This independence which the organism has of its external environment, derives from the fact that in the living being, the tissues are in fact withdrawn from direct external influences and are protected by a veritable internal environment which is constituted, in particular, by the fluids circulating in the body." Keeping the Internal Milieu Constant
The lungs keep the oxygen/carbon dioxide composition of the internal milieu constant and the kidneys (as well as the endocrine glands I will discuss next time) help keep everything else (e.g. water, acidity, Na+, K+, and glucose) constant. The kidneys perform their function by filtering the blood, reabsorbing the necessary components from the urinary duct back to the blood, secreting wastes from the blood into the urinary duct, and excreting the wastes as urine. Structure of Kidney The Kidney's Blood Supply
Blood enters the kidney through arterioles that branch of from the renal artery. The renal artery branches off from the aorta. The blood returns to the body through renal venules that lead to renal veins that lead to the vena cava. The renal arteriole elaborates into a netlike structure known as the glomerulus. The blood passing through the glomerulus is under pressure. The pressure forces some of the fluid and solutes (excluding cells and proteins) out of the blood and into a tubule whose "opening" surrounds the glomerulus and is known as Bowman's capsule. The Filtrate
The filtrate passes into the proximal convoluted tubule, the loop of Henle and the distal convoluted tubule before it passes into the collecting duct, through the ureter and into the bladder and urethra, from which it is excreted. The Blood
The blood that does not pass out of the glomerulus continues through the renal arteriole and capillaries from which additional wastes are secreted into the tubule and valuable constituents are reabsorbed into the capillaries that will eventually empty into the renal vein. The Nephron
The functioning unit of the kidney, which includes the tubule and the associated blood vessels is known as the nephron. Each kidney contains approximately 1 million nephrons that make up about 176 miles (80 km) of tubules that function in the cleansing and homeostatic regulation of the blood. The Function of the Kidneys
Remove nitrogenous wastes (urea) that result from the breakdown of amino acids and nucleic acids Maintain the correct balance of glucose, salts (e.g. Na+ and K+) and water in the blood. Maintain the correct blood pH (H+ and HCO3). Maintain the correct blood volume and pressure. Secrete a hormone that causes the bone marrow to synthesize red blood cells. The Formation of Urea
The breakdown (deamination) of amino acids in the liver results in the formation of ammonia. Ammonia is toxic and is converted in a cyclic reaction in the liver to the less toxic urea. The urea is filtered out of the blood by the kidneys and is excreted in the urine. More Than 1000 Liters Blood /Day Pass Through the Kidneys
The kidneys receive about 2025% of the arterial blood that comes from the heart. If the volume of blood pumped by the heart is 75 ml/beat and the heart beats 70 beats/minute, then the heart pumps 7560 liters/day. If 22% of that blood goes to the kidneys to be filtered, then the kidneys pass about 1663 liters/day. The Numbers
>1000 liters blood/day flow into the kidneys. Approximately 200 liters of fluid/day pass out of the blood and into the tubules. Luckily, about 198 liters of fluid/day is reabsorbed by the blood stream and we only eliminate about 2 liters a day as urine. The Inside of Thomas Jefferson's Outhouse How do we figure out how any organ (e.g. the kidney) works?
According to Ernest Starling, "there are two main avenues of approach in the attempt to unravel the complicated processes which determine the function of any individual organ." Two Approaches
"...we may study its reaction in the intact animal to comparatively small environmental changes--a method of inestimable value, since it is one which may readily be applied to man;" "...we may remove the organ and study its reaction under grossly artificial conditions." Every Technique Has Merits and Demerits
"In the former case, we sacrifice simplicity and full control to a close approximation to normality in environment; in the latter case, we sacrifice normality in environment in order to obtain greater simplicity and a higher degree of experimental control." Every Technique Has Merits and Demerits
When isolating organs, "...we attempt to dissociate the medley of influences which share in determining the normal function of the organ, and to relegate to each its particular office in maintaining this normality...we attempt to associate these influences...in such a manner as to bring the isolated organ back to an environment and function comparable to the normal." An isolated organ needs plenty of oxygen for the oxidation of glucose. An isolated organ needs plenty of chemical energy in the form of glucose, not only to perform its function, but to maintain the cells and their membranes that perform the functions. Depending on how long an organ is isolated, it may need, in part, vitamins necessary to make the cofactors required for the burning of glucose, the amino acids required to make enzymes and the lipids necessary to make the membranes. How do you keep an isolated kidney "alive"? Attempts in Obtaining Isolated and Functional Kidneys
Carl Ludwig (mid 1800s) perfused an isolated kidney with 3% gum, 1% NaCl. The kidney did nothing. Jacoby (1892) perfused an isolated kidney with aerated blood and obtained a very slow urine flow. The urine contained a lot of protein, indicative of tissue breakdown. By adding amyl nitrite to dilate the arteries through which the aerated blood was perfused, Pfaff (1903) was able to get isolated kidneys to produce 16 ml of urine in 15 minutes. Ernest Starling, the discoverer of secretin, and the person who coined the term "hormone" also worked on the kidney Ernest Starling (1924), taking into consideration the importance of convection, developed a fast moving aerated perfusion system that allowed an isolated kidney to produce over 30 ml of urine in 15 minutes, which was sufficient to begin to look for the localization of various functions in the tubules of the kidney. Using an Isolated Kidney, Starling Discovered that Filtration Occurred at the Glomerulus
He observed that the rate of urine formation directly depended on the blood pressure. He compared the concentration of protein, CO2, urea, NH3, NaCl and Na2SO4 in the blood serum and in the urine and found that the small molecules entered the tubules and the large molecules (e.g. protein) and cells remained in the blood. Starling Discovered that Filtration is a Passive Process
He added cyanide, which inhibits the production of ATP during cellular respiration, to the perfusion solution in the renal artery. Then he compared the concentration of protein in the blood serum and the urine. After short treatment times with cyanide, the urine still had no protein in it, indicating that filtration is a passive process that does not require ATP. Protein appeared in the urine after long treatment times because the kidney tissue itself began to break down. Filtration
The epithelial layer of the glomerulus and of Bowman's capsule have pores. The pores are large enough to pass water, salts, sugar, amino acids, vitamins, and nitrogenous wastes, such as urea. The pores are too small to pass proteins and blood cells. Active Secretion from the Capillaries to the Tubules
When the kidneys were perfused with cyanide, the amount of urea eliminated into the urine decreased. Therefore urea in the capillaries must be actively secreted in an ATPdependent manner from the capillaries into the tubules. Active Re-absorption from the Tubules to the Capillaries
Starling also found that the amount of NaCl eliminated into the urine increased. Therefore NaCl must be actively reabsorbed from the tubules and passed back to the capillaries in an ATP dependant manner. Summary of Kidney Function Filtration Secretion Reabsorption Excretion Determination of the Function of Specific Regions of the Tubule
It is now possible to isolate small regions of the renal tubule, perfuse them with solutions of various radioactive tracers and measure the properties of the transport proteins responsible for moving the radioactive solutes across the epithelium of the tubule. Re-absorption of Glucose at the Proximal Tubule
The proximal tubule can transport up to 375 mg glucose/min out of the tubule. This is a high enough rate to reabsorb all the glucose from the renal artery and send it all back to the renal vein. But, this rate is not high enough to reabsorb the high levels of glucose that occurs in the blood of diabetics. Thus diabetics end up with "sugary urine", which is the literal meaning of diabetes mellitus. Diabetes and the Kidney
The glucose in the tubule of diabetics pulls in water by osmosis. This leads to the production of more urine and the need to urinate frequently. It also causes diabetics to get thirsty and they to need to drink more often. Re-absorption of NaCl
Experiments show that the proximal tubule, the ascending loop of Henle and the distal tubule are capable of actively pumping NaCl out of the tubule at such a rate that almost all the NaCl from the renal artery is reabsorbed and sent back to the renal vein. Specifically, the positively charged sodium ion is actively pumped and the negatively charged chloride ion follows it. Transport at the Distal Tubule
The distal tubule has membrane proteins that transport HCO3 out of the tubule so it can be re absorbed and sent back to the renal vein. The distal tubule also has membrane proteins that transport H+, K+ and ammonia (NH3) into the tubule so they will leave the blood and end up in the urine. The pH of the blood is maintained by balancing the transport of HCO3 out of the tubule and H+ into the tubule. The Blood Pressure Increases During Times of Fight or Flight
Water moves by osmosis into regions high in sodium. The greater the concentration of sodium in the blood, the greater the volume of water. The greater the volume of water in the arteries with limited elasticity, the greater the arterial blood pressure. This is why sodium influences blood pressure. The kidneys control how much sodium is reabsorbed into the blood. Hormonal Control of Kidney Function: Aldosterone
During a prolonged "fight or flight" response, the adrenal glands secrete the mineralocorticoid, aldosterone which stimulates the re absorption of sodium from the distal tubule into the blood. The increased blood pressure gives you the speed and power you need to escape an attacking lion. 3Cs: Conservation, Concentration and Convenience
The NaCl that is actively pumped out of the tubules causes a passive osmotic flow of water out of the collecting duct and back into the capillaries. In this way the body conserves water and concentrates the urine. Concentrating the urine, reduces the volume that needs to be excreted from about 200 liters to about 2 liters, which is a real convenience. Dehydration: Hormonal Control
If the body becomes dehydrated, the osmotic pressure of the blood rises. Dehydration causes the pituitary gland to secrete antidiuretic hormone (ADH). Diuresis is the production of urine. ADH prevents the production of urine. Dehydration: Hormonal Control
ADH stimulates the insertion of proteinaceous water channels known as aquaporins into the collecting duct. This helps water move out of the collecting duct faster so it moves back into the blood fluid instead of becoming urine and entering the ureters. If the blood gets too dilute, ADH release is reduced, the water channels are removed by endocytosis. Then the water is not reabsorbed but becomes urine. The kidneys connect to the ureters, which connect to the bladder. Double ureters occur in 1 out of 150 people. The bladder is drained via the urethra. The Convenient Control of Urination
A sphincter, made from skeletal muscle, occurs at the exit of the bladder where the urethra is attached. This sphincter is under neuronal control. Thankfully this allows the occasional release of stored urine instead of a continuous dribble. The stretched bladder wall activates stretch receptors in the bladder wall that send a message to the brain. The brain sends an impulse that relaxes the sphincter and contracts the smooth muscle of the bladder wall, which empties the contents of the bladder. The Color of Urine
Urobilins are a class of chemicals that are derived from the breakdown product of hemoglobin. They give urine its yellowish color. The Smell of Urine About forty percent of the population has the gene that codes for an enzyme that produces either methyl mercaptan from methionine or asparagine-aminosuccinic-acid monoamide from the asparagine found in asparagus What happens when your kidneys can no longer filter your blood? Dialysis
Small molecules like urea are removed from the blood because they are free to diffuse between the blood and the bath fluid which contains the ideal mixture of salts and nutrients. Large molecules (e.g., plasma proteins) and cells remain confined to the blood. Kidney Transplants
Since a person only needs one working kidney, kidney transplants can come from living or dead donors. Are you an organ donor? Check the back of your driver's license. Dr Joseph Murray (1990) of the Peter Bent Brigham Hospital in Boston won the Nobel Prize for working out the immunosuppressant techniques necessary for successful transplants between immunologically different people. Erythropoietin (EPO) is a hormone produced by the kidneys and secreted into the blood stream in response to lowered oxygen levels. Erythropoietin stimulates the bone marrow to make more oxygen carrying red blood cells. The Kidneys Also Regulate Red Blood Cell Production Genetically-engineered human erythropoietin is used to help people with chronic kidney disease fight anemia that results from too few red blood cells. Cheating (and Testing) in Sports Cheats inject EPO, which increases the oxygencarrying capacity of the blood. Athletes are now screened and tested for EPO. You Can Make Money from Anything From Fish to Philosopher: Homer W. Smith
"No less than his lowly predecessors, he continues in the search of the free and independent life, for it is in the nature of all life to move into that equilibrium where the totality of desire is balanced against the totality of restraint. But because he is the highest vertebrate he can do what no other vertebrate can do: when, out of whatever desire and knowledge may be his, he makes a choice, he can say `I will...' And knowing how and why he says `I will" he comes into his own as a philosopher." In Part, Our Freedom Depends on Our Kidneys Working Hard to Ensure the Constancy of Our Internal Milieu
Have You Thanked Your Kidneys Today? ...
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This note was uploaded on 09/24/2007 for the course BIO G 110 taught by Professor Wayne,r. during the Spring '07 term at Cornell University (Engineering School).
- Spring '07