Phys II Exam I readings .docx

Assignment 1 The vestibular apparatus is the sensory organ for detecting sensations of equilibrium. It is enclosed in a system of bony tubes and chambers located in a part of the temporal lobe called the membranous labyrinth. The membranous labyrinth is the functional part of the vestibular apparatu...

Assignment 1 The vestibular apparatus is the sensory organ for detecting sensations of equilibrium. It is enclosed in a system of bony tubes and chambers located in a part of the temporal lobe called the membranous labyrinth. The membranous labyrinth is the functional part of the vestibular apparatus that is composed mainly of the cochlea, three semicircular canals, and two large chambers (utricle and saccule) The cochlea is the major sensory organ for hearing and has little to do with equilibrium The semicircular canals,the utricle, and the saccule are all integral parts of the equilibrium mechanism Maculae - sensory organs located on the inside of the utricle and saccule that detect orientation of the head with respect to gravity The macula of the utricle is located on a horizontal plane and determines orientation of the head when it is upright The macula of the saccule is on a vertical plane and determines head orientation when one is lying down Each macula is covered by a gelatinous layer that contain small calcium carbonate crystals called statoconia which due to its weight and specific gravity can bend the cilia in the direction of gravitational pull The macula also contains many hair cells that project cilia up into the gelatinous layer. The perimeter of the hair cells synapse with sensory endings of the vestibular nerve. Each hair cell has small cilia called stereocilia, and one large cilium, the kinocilium. The kinocilium is always located to one side, and the stereocilia become progressively shorter toward the other side of the cell. Very small filamentous attachments connect the tip of each stereocilium to the next longer stereocilium and finally, to the kinocilium. When the stereocilia bend in the direction of the kinocilium, these attachments tug in sequence on the stereocilia, pulling them outward from the cell body. This movement opens cation channels in the neuronal cell membrane around the bases of hate stereocilia, and these channels are capable of conducting large numbers of positive ions. Therefore, positive ions pour into the cell from the surrounding Endo lymphatic fluid, causing receptor membrane depolarization. If you bend the stereocilia in the opposite direction (away from the kinocilium) it reduces the tension on the attachments; this movement closes the ion channels, causing receptor hyperpolarization. Under normal resting conditions, the nerve fibers leading from the hair cells transmit continuous nerve impulses. The impulse traffic increases when the stereocilia are bent toward the kinocilium, and decreases when bent away, often turning it off completely. Therefore, orientation of the head in space changes and the weight of the statoconia bends the cilia, appropriate signals are transmitted to the brain to control equilibrium. Different patterns of excitation occur in the macular nerve fibers for each orientation of the head in the gravitational field. This pattern is what apprises the brain of the head’s orientation in space The three semicircular ducts in each vestibular apparatus are known as anterior, posterior, and lateral (horizontal). They are arranged at right angles to one another so that they represent all three planes in space. If the head is bent forward 30 degrees, the lateral duct is horizontal with respect to the surface of the earth, the anterior and posterior ducts are both in vertical planes but one projects forward and the other backwards respectively both 45 degrees outward. Each semicircular duct has an enlargement at one of its ends called the ampulla. The ducts and the ampulla are filled with endolymph which flows through one of the ducts and through its ampulla which excites the sensory organ of the ampulla. Each ampulla has a small crest called a crista ampullaris On top of it is a loose gelatinous tissue mass, the cupula When a person’s head rotates in any direction, the inertia of the fluid in one or more of the semicircular ducts causes the fluid to remain stationary while the semicircular duct rotates with the head This process causes fluid to flow from the duct and through the ampulla, bending the cupula to one side and rotation of the head in the opposite direction causes it to bend to the opposite side Many cilia from hair cells located on the ampullary crest are projected into the cupula. The kinocilium of these hair cells are all oriented in the same direction in the cupula, and bending the cupula in that direction causes depolarization of the hair cells, whereas bending the hair in the opposite direction causes hyperpolarization. From these hair cells, appropriate signals are sent via the vestibular nerve to apprise the central nervous system of a change in rotation of the head and the rate of change in each of the three planes of space. Assignment 2 When a muscle contracts against a load it performs work which means that energy is transferred from the muscle to the external load to lift an object to a greater height or overcome resistance to movement W= l x d W is work output, l is load, and d is distance of movement against load Energy for work comes from chemical reactions in the muscle cells during contraction There are three sources of energy for muscle contraction Most of the energy is used to trigger the walk-along mechanism whereby the cross-bridges pull the actin filaments Small amount of energy are required for: pumping calcium ions from the sarcoplasm into the sarcoplasm in reticulum after the contraction is over pumping Na/K ions through the muscle fiber to maintain ionic environment for propagation of muscle fiber AP’s The concentration of ATP in the muscle fiber is sufficient to maintain full contraction for only 1-2 seconds. The ATP is split to form ADP, which transfers energy from the ATP molecule to the contraction machinery of the muscle fiber. The ADP is then rephosphorylated to form new ATP to continue the contraction. Here are the three sources of energy for this rephosphorylation First source used to remake ATP is phosphocreatine, which carries a high-energy phosphate bond that has a slightly higher amount of free energy than each ATP bond. However the amount of phosphocreatine in the muscle fiber is small, therefore the combined energy of both the stored ATP and the phosphocreatine in the muscle is capable of causing maximal contraction. The second source is used to remake both ATP and phosphocreatine, and it is glycolysis. This is the breakdown of glycogen which was stored in the muscle cells. Rapid breakdown of glycogen to pyruvic acid and lactic acid liberates energy that is used to convert ADP -> ATP which then causes additional muscle contraction and reforms phosphocreatine. First, glycolysis reactions can occur even in the absence of oxygen, so muscle contractions can be sustained even when oxygen is not available. Second, the rate of ATP formation by glycolysis is 2.5 times faster than formation in response to cellular foodstuff reacting with oxygen. However, a lot of end products of glycolysis accumulate in the muscle cells so glycolysis also loses its capability to sustain maximum muscle contraction after about a minute. The first source is oxidative metabolism, which means combining oxygen with the end products of glycolysis and with other cellular foodstuff to liberate ATP. More than 95% of all energy used to sustain long-term contractions come from oxidative metabolism. The consumed foods are carbs, fats, and proteins. The longest energy for muscle activity comes from fats and then carbs last for a few hours. The percentage of input energy to muscle (chemical energy in nutrients) that can be converted into work, is less than 25%, with the rest becoming heat. The reason for this low efficiency is that about one-half of the energy in food is lost during formation of ATP and only 40-45% of energy can be later converted into work. Maximum efficiency can be realized only when the muscle contracts at a moderate velocity. If the muscle contracts slowly or without any movement, small amounts of maintenance heat are released during contraction, even though little or no work is performed, thereby decreasing the conversion efficiency to as little as zero. Conversely, if contraction is too rapid, much of the energy is used to overcome viscous friction within the muscle itself, and this too reduces the efficiency of contraction. Ordinarily, maximum efficiency occur when the velocity of contraction is about 30% of maximum. Assignment 3 Fast versus slow muscle fibers Muscles that react rapidly are fast fibers Muscles that react slowly are slow fibers Slow fibers (Type 1, red muscle) Slow fibers are smaller than fast fibers Slow fibers are innervated by smaller nerve fibers These fibers have a more extensive blood vessel system and more capillaries compared to fast fibers Have increased numbers of mitochondria to support high levels of oxidative metabolism Contain a large amount of myoglobin which gives it its red appearance Fast fibers (Type II, white muscle) Larger for great strength of contraction Extensive sarcoplasmic reticulum for rapid release of calcium ions to initiate contraction Large amounts of glycolytic enzymes for rapid release of energy Have a less extensive blood supply compared to slow fibers (oxidative metabolism not as important) With fewer mitochondria than slow fibers, a deficit of red myoglobin gives it its white appearance Assignment 4 Remodeling of muscle to match function Muscles of the body are continuously remodeled to match the functions required of them The process is rapid occurring within a few weeks Muscle contactile proteins in some smaller more active muscles can be replaced in as little as two weeks Muscle hypertrophy and muscle atrophy The increase of total muscle mass is called hypertrophy When the total muscle mass decreases, the process is called atrophy Hypertrophy results in the increase in the number of actin and myosin filaments in each muscle fiber causing enlargement in individual muscle fibers Called fiber hypertrophy Caused when muscle is loaded leading to strong contractions The rate of synthesis of muscle contractile proteins is far greater when hypertrophy is developing, leading also to greater numbers of both actin and myosin filaments in the myofibrils, often increasing as much as 50% Along with the increasing size of myofibrils, the enzyme systems that provide energy also increase, especially the enzymes for glycolysis, allowing for a rapid supply of energy during short-term forceful muscle contraction. When a muscle is unused for many weeks the rate of degradation of the contractile proteins is more rapid than rate of replacement so muscle atrophy occurs The ATP-dependent ubiquitin-proteasome pathway accounts for protein degradation Adjustment of muscle length Hypertrophy can occur when muscles are stretched to greater length than normal Stretching causes new sarcomeres to be added at the ends of the muscle fibers where they attach to tendons In fact, new sarcomeres can be added as rapidly as several per minute in newly developing muscle Conversely, when a muscle continually remains shortened to less than its normal length, sarcomeres at the ends of the muscle fibers can actually disappear. Hyperplasia of muscle fibers Under rare conditions of extreme muscle force the number of muscle fibers has been observed to increase in addition to the fiber hypertrophy process, this increase in fiber number is called fiber hyperplasia Muscle denervation causes rapid atrophy When a muscle loses its nerve supply, it no longer receives the contractile signals to maintain normal muscle size Atrophy begins immediately Degenerative changes begin to appear after two months But if nerve supply is returned to the muscle, it can return to normal in 3 months but from then on the capability of functional return becomes less and less with no return of function after 1 to 2 years In the final stage of denervation atrophy most of the muscle tissue is destroyed and replaced by fibrous and fatty tissue The fibers that remain have few to no contractile properties even if nerve grows back. Fibrous tissue that replaces muscle fibers has a tendency to continue to shorten for months, this is called contracture Recovery of muscle contraction in Poliomyelitis: development of macromotor units When some but not all nerve fiber to a muscle are destroyed, the remaining nerve fibers branch off to form new axons that then innervate many of the paralyzed muscle fibers, this causes large motor units called macromotor units This happens in poliomyelitis Formation of large motor units decreased fineness of control one has over muscles but allows the muscles to regain strength Rigor mortis Several hours after death, all muscles in the body go into a state of contracture called rigor mortis, muscles contract and go ridgid Caused by the loss of all ATP required to separate cross bridges from the actin filaments during relaxation The muscles remain in rigor until the proteins deteriorate hours later resulting in autolysis caused by enzymes released by lysosomes Occurs more rapidly at higher temps Muscular dystrophy Inherited disorders that cause progressive muscle weakness and degeneration. The muscles are replaced by fatty tissue and collagen Most common form is Duchenne muscular dystrophy X-linked recessive Mutation in the gene that encodes for dystrophin which links actins to proteins in the muscle cell membrane Lack of dystrophin or mutated forms cause muscle cell membrane destabilization and aberrant membrane repair after injury One important effect of abnormal dystrophin is an increase in membrane permeability to calcium, thus allowing extracellular calcium ions to enter the muscle fiber and initiate changes in intracellular enzymes that ultimately lead to proteolysis and muscle fiber breakdown. Symptoms of DMD include muscle weakness that begins in early childhood and rapidly progresses, the patient is usually in wheelchairs by age 12 years and dies of respiratory failure before age 30. A milder form of this disease, called Becker muscular dystrophy (BMD), is also caused by mutations of the gene that encodes for dystrophin but has a later onset and longer survival. Assignment 5 The three important metabolic systems for understanding the limits of physical activity are: Phosphocreatine system Glycogen-lactic acid system Aerobic system The source of energy used to cause muscle contraction is ATP. The bonds attaching the last 2 phosphate radicals to the molecule are designated by the symbol ~. They are high energy bonds. The removal of the first phosphate makes ADP, and the removal of the second phosphate makes AMP. New ATP needs to be formed continuously even during athletic events, because the amount present in the muscles, even in a well trained athlete, is sufficient to sustain maximal muscle power for only about 3 seconds. Phosphocreatine system Phosphocreatine is another chemical compound that has a high-energy phosphate bond Phosphocreatine can decompose to creative and a phosphate ion and in doing so release large amounts of energy This bond has more energy than an ATP bond, therefore it can easily provide enough energy to reconstitute the high-energy bond of ATP More cells also have 2-4x more phosphocreatine than ATP All the energy stored in muscle phosphocreatine is almost instantaneously available for muscle contraction The combined amounts of cell ATP and phosphocreatine are called the phosphagen energy system Together they can provide maximal power for 8-10 seconds so the energy from the phosphagen energy system is used for maximal short bursts of muscle power Glycogen-Lactic Acid system The stored glycogen in muscle can be split into glucose which can then be used for energy. The initial stage is called glycolysis which occurs without use of oxygen (anaerobic metabolism) During glycolysis, each glucose molecule is split into two pyruvic acid molecules, and energy is released to form 4 ATP molecules for each cell original glucose Usually pyruvic acid then enters the mitochondria of the muscle cells and reacts with oxygen to form more ATP, however, when there is not enough oxygen for the oxidative stage to occur, most of the pyruvic acid is converted into lactic acid which diffuses out of the muscle cells, Into the interstitial fluid and blood Much of glycogen is transformed to lactic acid and considerable amount of ATP are formed without the consumption of oxygen This system also forms ATP about 2.5x faster than the oxidative mechanism of mitochondria So when large amounts of ATP are required for short to moderate periods of muscle contraction, this anaerobic glycolysis mechanism can be used as a rapid source of energy However, it is only half as fast as the phosphagen system Aerobic system The aerobic system is the oxidation of food in the mitochondria to provide energy Glucose, fatty acids, and amino acids from the food combine with oxygen after some intermediate processing, to release a lot of energy that is used to convert AMP and ADP into ATP The aerobic system produces the least moles of ATP/min out of all three systems, however when it comes to endurance it lasts as long as nutrients last unlike the other two systems So this system is required for prolonged athletic activity, the phosphagen system is used for muscle power surges of a few seconds, and the glycogen-lactic acid system is important for providing extra power during intermediate activity Phosphocreatine can be used to reform ATP and energy from the glycogen-lactic acid cycle system can be used to reform phosphocreatine and ATP. Energy from oxidative metabolism of the aerobic system can then be used to reconstitute all the other systems. Reconstitution of the lactic acid system means mainly the removal of the excess lactic acid that has built up in body fluids. Removal of the excess lactic acid is especially important because buildup of this acid contributes to fatigue and the burning sensation in active muscles during intense exercise. When enough energy is available from oxidative metabolism, lactic acid is removed in two ways: A small portion of is it converted back into pyruvic acid and the metabolized oxidatively by tissues The remaining acid is reconverted into glucose, mainly in the liver, and the glucose in turn is used to replenish the glycogen store of the muscles Even during the early stages of heavy exercise, a portion of one’s aerobic energy capability is depleted. This depletion results from two effects: the so-called oxygen debt Depletion of glycogen stores of the muscles The body normally contains ~ 2 L of stored oxygen that can be used for aerobic metabolism even without breathing in new oxygen. The stored oxygen consists of the following: 0.5 L in lungs 0.25 L dissolved in body fluids 1 L combined with hemoglobin 0.3 L stored in muscle fibers, combined mainly with myoglobin In heavy exercise, almost all oxygen is used for aerobic metabolism. After exercise is over, this stored oxygen must be replenished by breathing extra amounts of oxygen above normal levels. Also, about 9 L of oxygen must be consumed to reconstitute the phosphagen system and the lactic acid system. All the extra oxygen that must be repaid is called oxygen debt. The early portion of oxygen debt is called the alactacid oxygen debt (3.5 L). The later portion is called the lactic acid oxygen debt (8 L). Recovery of muscle glycogen Recovery often requires days and there are three conditions: in people who consume a high-carbohydrate diet In people who consume a high-fat, high-protein diet In people who consume no food For the high-carbohydrate diet, full recovery occurs in 2 days, whereas for the high-fat, high-protein diet, and no food at all show little recovery, even after 5 days. This shows that high-carbohydrate diets are important before hard athletic activities. Athletes should not participate in exhaustive exercise 48 hours preceding the event. Muscles use large amounts of fat for energy in the form of fatty acids and acetoacetic acid, as well as proteins in the form of amino acids (to a much lesser extent). Even under the best conditions, in endurance athletic activities that take longer hours the glycogen stores are depleted and the muscle now depends on fats. Not all the energy from carbs comes from the stored muscle glycogen. Almost an equal amount is stored in the liver. This glycogen can be released into the blood in the form of glucose and then taken up by the muscles as an energy source. Assignment 6 Fast-Twitch and Slow-Twitch muscle fibers All muscles have a varying percentage of fast-twitch and slow-twitch muscle fibers For example, gastrocnemius has more fast-twitch and the soleus muscles have more slow-twitch Fast twitch fibers are large in diameter compared to slow-twitch fibers Enzymes that promote rapid release of energy from the phosphagen and glycogen-lactic acid are more active in fast-twitch fibers than in slow-twitch fibers Better for power in short periods of time Slow-twitch fibers are mainly for endurance they have more mitochondria and myoglobin better for aerobic metabolism than fast-twitch The number of capillaries is greater in slow-twitch than fast-twitch fibers In summary fast-twitch good for extreme power for a short period of time, and slow-twitch is good for endurance Hereditary differences among athletes for fast-twitch versus slow-twitch muscle fibers Some people have more fast-twitch than slow-twitch and vice versa which can determine the extent of athletic abilities You can train to develop one fiber but it is greatly determined by genetics This can determine which sport is the best for the person Assignment 7 Intro The maintenance of a constant volume and stable composition of the body fluids is essential for homeostasis Some of the most common problems in clinal medicine happen because of abnormalities in the control systems that maintain the stable composition body fluids Fluid intake and output are balanced during steady-state conditions Fluid added to the body is highly variable and must be matched by an equal output of water from the body to prevent body fluid volumes from increasing or decreasing Daily intake of water Water is ingested in the form of liquids or water in food and is synthesized in the body by oxidation of carbs These mechanisms provide a total water intake of about 2300 ml/day but it can vary Daily Loss of Body water Some water loss can’t be regulated Insensible water loss is loss that we are not consciously aware of Occurs independently of sweating Occurs in people who are born without sweat glands For example continuous water loss by evaporation from the respiratory tract and diffusion through the skin Loss is minimized by cholesterol-filled cornified layer of the skin Barrier against excessive loss by diffusion When the cornified layer is destroyed by an extensive burn the person must be given large amounts of fluid Water is continuously lost through the lungs with respiration EX As air enters the respiratory tract, it becomes saturated with moisture to a vapor pressure of about 47 mm Hg before it is expelled. Because the vapor pressure of the inspired air is usually less than 47 mm Hg, water is lost More water loss in cold weather which is why respiratory passages feel dry in the cold Fluid loss in sweat Amount of water loss variable due to physical activity and environmental temperature This fluid loss can deplete body fluids if intake is not increased by thirst mechanism Water loss in feces Only a small amount of water lost Can increase with severe diarrhea and can be life threatening Water loss by the kidneys Water loss from the body as urine excreted by the kidneys Multiple mechanisms control rate of urine excretion Controlling the rate at which the kidneys excrete substances is the most important means of how the body maintains balance between water intake and output as well as intake and output of electrolytes The kidneys adjust the excretion rate of water and electrolytes to match the intake of these substances as well as compensating for excessive losses of fluids and electrolytes that occur in certain disease states Body fluid compartments The total body fluid is distributed mainly between two compartments The extracellular fluid Divided into the interstitial fluid and the blood plasma Intracellular fluid There is another small compartment of fluid called trancellular fluid Includes fluid in synovial, peritoneal, pericardial, and intraocular spaces, as well as cerebrospinal fluid As a person grows older, the percentage of total body weight that is fluid gradually decreases Due to increased body fat Women have a greater percentage of body fat so their total body water percentage is less than men’s Intracellular fluid compartment Intracellular fluid are liters of fluid inside cells of the body About 40% of total body weight in average person The fluid of each cell contains its individual mixture of different constituents, but the concentrations of these substances are similar from one cell to another. The composition of cell fluids is similar, even in different animals. The intracellular fluid of all the different cells together is considered to be one large fluid compartment. Extracellular fluid compartment All fluids outside of the cell About 20% of body weight Two largest compartments Interstitial fluid ¾ of extracellular fluid Plasma ¼ of extracellular fluid the noncellular part of the blood; it exchanges substances continuously with the interstitial fluid through the pores of the capillary membranes. These pores are highly permeable to almost all solutes in the extracellular fluid, except the proteins. the extracellular fluids are constantly mixing, so the plasma and interstitial fluids have about the same composition except for proteins, which have a higher concentration in the plasma Blood volume Blood contains extracellular fluid (the fluid in plasma) and intracellular fluid (the fluid in the red blood cells). Blood is considered to be a separate fluid compartment because it is contained in a chamber of its own, the circulatory system The blood volume is especially important in the control of cardiovascular dynamics. The average blood volume of adults is about 7% of body weight, or about 5 liters. About 60% of the blood is plasma and 40% is red blood cells, but these percentages can vary Hematocrit (packed red blood cell volume) The fraction of the blood composed of red blood cells Determied by centrifuge In men, the measured hematocrit is normally about 0.40, and in women, it is about 0.36. In people with severe anemia , the hematocrit may fall as low as 0.10, a value that is barely sufficient to sustain life. Conversely, in persons with some conditions, excessive production of red blood cells occurs, resulting in polycythemia In these persons, the hematocrit can rise to 0.65. Constituents of Extracellualr and intracellular fluids Similar ionic composition of plasma and interstitial fluid Because the plasma and interstitial fluid are separated only by highly permeable capillary membranes, their ionic composition is similar. Higher concentration of proteins in the plasma is the main difference between the two capillaries have a low permeability to the plasma proteins Because of the Donnan effect, the concentration of positively charged ions (cations) is slightly greater in plasma than in interstitial fluid. Plasma proteins have a net negative charge and therefore tend to bind cations such as sodium and potassium ions, thus holding extra amounts of these cations in the plasma, along with the plasma proteins. Conversely, negatively charged ions (anions) tend to have a slightly higher concentration in interstitial fluid compared with plasma because the negative charges of the plasma proteins repel the negatively charged anions. Intracellular fluid constituents The intracellular fluid is separated from the extracellular fluid by a cell membrane that is highly permeable to water but is not permeable to most electrolytes in the body. In contrast to the extracellular fluid, the intracellular fluid contains only small quantities of sodium and chloride ions and almost no calcium ions. It contains large amounts of potassium and phosphate ions plus moderate quantities of magnesium and sulfate ions, all of which have low concentrations in the extracellular fluid. Also, cells contain large amounts of protein—almost four times as much as in the plasma. Assignment 8 The relative amounts of extracellular fluid distributed between the plasma and interstitial spaces are determined mainly by the balance of hydrostatic and colloid osmotic forces across the capillary membranes. The distribution of fluids b/w intra and extracellular compartments, in contrast, is determined mainly by the osmotic effect of smaller solutes (especially Na, Cl, and other electrolytes) acting across the cell membrane. The reason for this is that the cell membranes are highly permeable to water but relatively impermeable to even small ions. Therefore, water moves across the cell membrane rapidly, and the intracellular fluid remains isotonic with the extracellular fluid. Because cell membranes are relatively impermeable to most solutes but are highly permeable to water, whenever there is a higher concentration of solute on one side of the cell membrane, water diffuses across the membrane toward the region of higher solute concentration. Thus, if a solute such and NaCl is added to the extracellular fluid, water rapidly diffuses from the cells through the cell membranes into the extracellular fluid until the water concentration on both sides of the membrane becomes equal. Conversely, if a solute such as NaCl is removed from the extracellular fluid, water diffuses from the extracellular fluid through the cell membranes into the cells. Osmolality concentration is expressed as osmoses per kilogram of water; it is osmolarity when it is expressed as osmoles per liter of solution. In dilute solutions, these two terms can be used almost synonymously because the differences are small. Using the van’t Hoff law, one can calculate the potential osmotic pressure of a solution, assuming that the cell membrane is impermeable to the solute. The example they used was a NaCl solution having an osmotic pressure of 0.9% which = 0.9 g of NaCl pers 100 mL of solution or 9 g/L. They then divided 9 g/L by the molecular weight of NaCl which is 58.5 g/mol which gave them 0.154 mol/L. For each molecule of NaCl it is equal to 2 osmoles, so 0.154 x 2 gave them 0.308 Osm/L. The osmolarity of this solution is 308 mOsm/L. One can correct for the deviations by using a correction factor called the osmotic coefficient. About 80% of the total osmolarity of the interstitial fluid and plasma is due to NaCl ions, whereas for intracellular fluid, almost half of the osmolarity is due to potassium ions, and the remainder is divided among many other intracellular substances. The slight difference between plasma and interstitial fluid is caused by the osmotic effects of the plasma proteins which maintain about 20 mm Hg greater pressure in the capillaries than in the surrounding interstitial spaces. Corrected osmolar activities of plasma, interstitial fluid, and intracellular fluid can be shown because cations and anions exert interionic attraction which can cause a slight decrease in the osmotic activity of the dissolved substances. High osmotic pressures can develop across the cell membrane with small changes in the concentration of solutes in the extracellular fluid. Isotonic - When the water concentration in the intracellular and extracellular fluids is equal, and the solutes cannot enter or leave the cell so neither shrinking or swelling occurs Hypertonic - Cell shrinks due to being placed in a hypertonic solution (higher concentration of impermeable solutes), water leaves the cell to dilute the extracellular fluid until both fluid concentrations become equal Hypotonic - cell swells due to being put in a hypotonic solution (lower concentration of impermeable solutes), water will diffuse inside the cell to dilute the intracellular fluid until the intracellular and extracellular fluids have about the same osmolarity The terms isotonic, hypotonic, and hypertonic refer to whether solutions will cause a change in cell volume. The toxicity of solutions depends on the concentration of impermeant solutes. Some solutes can permeate the cell membrane. Solutions with an osmolarity the same as the cell are called isosmotic, regardless of whether the solute can penetrate the cell membrane. The terms hyperosmotic and hypo-osmotic refer to solutions that have a higher or lower osmolarity, respectively compared with normal extracellular fluid, without regard for whether the solute permeates the cell membrane. Highly permeating substances, such as urea, can cause transient shifts in fluid volume between the intracellular and extracellular fluids but, given enough time, the concentrations these substances eventually become equal in the two compartments and have little effect on intracellular volume under steady-state conditions. Transfer of fluid across the cell membrane occurs so rapidly that any differences in osmolarities b/w these two compartments are usually corrected within seconds or, at the most, minutes. This rapid movement of water across the cell membrane does not mean that complete equilibrium occurs b/w the intracellular and extracellular compartments throughout the whole body in the same period. This is because fluid usually enters the body through the gut and must be transported by the blood to all tissues before complete osmotic equilibrium can occur. Some of the different factors that can cause extracellular and intracellular volumes to change are excess ingestion or renal retention of water, dehydration, intravenous infusion of different types of solutions, loss of large amounts of fluid from the gastrointestinal tract, and loss of abnormal amounts of fluid by sweating or through the kidneys. The changes intracellular and extracellular fluid volumes and the types of therapy that should be instituted can be calculated if the following basic principles are kept in mind: Water moves rapidly across cell membranes (osmolarities of both fluids remain almost exactly equal) Cell membranes are almost completely impermeable to many solutes (the number of osmoles remains relatively constant) If isotonic saline is added to the extracellular fluid compartment, the osmolarity of the extracellular fluid does not change The main effect is an increase in extracellular fluid If a hypertonic solution is added to the extracellular fluid, the extracellular osmolarity increases and causes osmosis of water out of the cells and into the extracellular compartment. Net result is an increase in extracellular volume and a decrease in intracellular volume. If a hypotonic solution is added to the extracellular fluid, the osmolarity decreases, and some of the extracellular water diffuses into the cells until both have the same osmolarity. Both intracellular and extracellular volumes are increased although the intracellular volume increases to a greater extent Assignment 9 There are several solutions that are given intravenously to people who cannot ingest enough nutrition. Glucose solutions are widely used while amino acids and homogenized fat solutions are used less. When the solutions are given, their concentrations of osmotically active substances are isotonic, or they are given slowly enough that they do not upset the osmotic equilibrium of the body fluids. After glucose/nutrients are metabolized, an excess of water remains The kidneys excrete this fluid as dilute urine and the net result is the addition of only nutrients to the body The 5% glucose solution (isosmotic) is used to treat dehydration and it can be infused intravenously without causing red blood cell swelling since it is isosmotic. Glucose from the solution is quickly transported into the cells and metabolized, therefore, infusion of this glucose solution reduces extracellular fluid osmolarity and helps correct the increase in extracellular fluid osmolarities associated with dehydration. The plasma sodium concentration is a measurement that evaluates a patient’s fluid status. Plasma osmolarity is not routinely measured but, because sodium and its associated anions (mainly chloride) account for more than 90% of the solute in the ECF, the plasma sodium concentration is a reasonable indicator of plasma osmolarity. When plasma sodium is below normal, that person is said to have hyponatremia, and when it is above normal they have hypernatremia. Decreased plasma sodium concentration can result from a loss of sodium from the ECF or an addition of water to the ECF. This results in hyponatremia and dehydration and is associated with a decrease in ECF volume. Conditions that can cause hyponatremia are diarrhea and vomiting. Overuse of diuretics that inhibit the kidneys ability to conserve sodium and certain sodium-wasting kidney diseases can also cause hyponatremia. Addison disease, which results from decreased aldosterone secretion, which impairs the kidneys ability to reabsorb sodium can also cause hyponatremia. Hyponatremia is also associated with excess water retention, which dilutes the sodium in the ECF, a condition called hyponatremia-over hydration. Excessive secretion of ADH for example, increases water reabsorption by the kidney tubules, and leads to this. Rapid changes in cell volume as a result of hyponatremia can have profound effects on tissue and organ function, especially the brain. A rapid reduction in plasma sodium concentration, can cause brain cell edema and neurological symptoms, including headache, nausea, lethargy, and disorientation. If plasma sodium rapidly falls below 115 -120 mmol/L, brain swelling may lead to seizures, coma, permanent brain damage, and death. Because the skull is rigid, the brain cannot increase its volume by more than about 10% without it being forced down the neck (herniation), which can lead to permanent brain injury and death. When hyponatremia evolves slowly, over days, the brain and other tissues respond by transporting sodium, chloride, potassium, and organic solutes, such as glutamate, from the cells into the extracellular compartment. This response attenuates osmotic flow of water into the cells and swelling of the tissues. Transport of solutes from the cells during slowly developing hyponatremia, however, can make the brain vulnerable to injury if corrected too rapidly. When hypertonic solutions are added too quickly to correct it, this can outpace the brain’s ability to recapture the solutes lost from the cells and may lead to osmotic injury of the neurons that is associated with demyelination. We can avoid demyelination by limiting the correction of chronic hyponatremia. This slow rate of correction permits the brain to recover the osmoles that were lost from the cells as a result of adaptation to chronic hyponatremia Hyponatremia is the most common electrolyte disorder encountered An increased plasma sodium concentration, which increases osmolarity, can be due to loss of water from ECF, which concentrates the sodium ions, or excess sodium in the ECF. Loss of water from ECF results in hypernatremia and dehydration. This condition can occur from an inability to secrete ADH. As a result the kidneys excrete large amounts of dilute urine which causes dehydration and increased salt concentration in the ECF. This happens with certain renal diseases as well, causing a type of nephrogenic diabetes insipidus. A more common cause is simple dehydration which can be due to excess sweating, or too little consumption of water. It can also occur when excessive amounts of salt is added to the ECF which can cause hypernatremia-over hydration. This happens because when there is too much salt the water follows it so there will be water retention in the kidneys. This can happen with excessive aldosterone secretion. The only reason hypernatremia is not severe is because the sodium retention also stimulates secretion of ADH and causes the kidneys to reabsorb more water. Hypernatremia is less common than hyponatremia and it usually promotes intense thirst and stimulates ADH secretion, which both protect against a large increase in plasma and ECF sodium. However, severe hypernatremia can occur in patients with hypothalamic lesions that impair their sense of thirst, in infants who may not have ready access to water, in older patients with altered mental status, or in persons with diabetes insipidus. Correction of hypernatremia can be achieved by giving a hypo-osmotic salt or dextrose solution. It must be corrected slowly in patients who have had chronic increases in their plasma sodium concentration because hypernatremia also activates defense mechanisms that protect the cell from changes in volume. These defenses are the opposite of those that occur for hyponatremia and consist of mechanisms that increase the intracellular concentration of sodium and other solutes. Edema - excess fluid in body tissues ( mainly in the ECF but can also involve ICF accumulation) The conditions that cause intracellular swelling: Hyponatremia Depression of the metabolic systems of the tissues Lack of adequate nutrition to the cells For example, when blood flow to a tissue is decreased, the delivery of oxygen and nutrients is reduced. If blood flow becomes too low to maintain normal tissue metabolism, the cell membrane ionic pumps become depressed, and sodium ions that normally leak into the interior of the cell can no longer be pumped out of the cells. The excess intracellular Na ions then cause osmosis of water into the cells. Sometimes this process can increase the intracellular volume of a tissue area. When such an increase in intracellular volume occurs, it is usually a prelude to death of the tissue. Intracellular edema can also occur in inflamed tissues. Inflammation usually increases cell membrane permeability, allowing Na and other ions to diffuse into the interior of the cell, with subsequent osmosis of water into the cells. Extracellular edema occurs when excess fluid accumulates in the extracellular spaces. There are two general causes for this: Abnormal leakage of fluid from the plasma to the interstitial spaces across the capillaries Failure of the lymphatics to return folding from the interstitium back into the blood, often called lymphedema. The most common clinical cause of interstitial fluid accumulation is excessive capillary fluid filtration. Capillary filtration rate can increase through: Increased capillary hydrostatic pressure Increased capillary filtration coefficient Decreased plasma colloid osmotic pressure When lymphatic function is impaired as a result of blockage or loss of the lymph vessels, edema can become especially severe because plasma proteins that leak into the interstitium cannot be removed in any other way. The rise in protein concentration raises the colloid osmotic pressure of interstitial fluid, which draws even more fluid out the capillaries. Blockage of lymph flow can be especially severe with infections of the lymph nodes, such as occurs with infection by filariasis nematodes, which are microscopic threadlike worms. The adult worms live in the human lymph system and are spread from person to person by mosquitoes. People with filarial infections can have severe lymphedema and elephantiasis and men can have swelling of the scrotum, called hydrocele. Lymphedema can also occur in persons who have certain types of cancer or after surgery in which lymph vessels are removed or obstructed. For example, large numbers of lymph vessels are removed during a radical mastectomy, imparting the removal of protein and fluid from the breast and arm areas and causing edema and swelling of the tissue spaces. A few lymph vessels eventually regrow after this type of surgery; thus interstitial edema is usually temporary. One of the most serious and common causes of edema is heart failure. The heart fails to pump blood normally from veins into the arteries, which raises venous and capillary pressures, causing increased capillary filtration. The arterial pressure also tends to fall, causing decreased excretion of salt and water by the kidneys, which causes more edema. Blood flow to the kidneys is reduced in persons with heart failure, and this reduced blood flow stimulates secretion of renin, causing increased formation of angiotensin 2 and aldosterone, which both cause additional salt and water retention in the kidneys. In advanced heart failure, increased secretion of ADH stimulates water reabsorption by the renal tubules, leading to hyponatremia as well as intracellular and extracellular edema. In patients with left-sided heart failure but without significant failure of the right side of the heart, blood is pumped into the lungs normally by the right side of the heart but cannot escape easily from the pulmonary veins to the left side of the heart because this part of the heart has been weakened. All the pulmonary vascular pressures, including pulmonary capillary pressure, rise far above normal, causing serious life-threatening pulmonary edema. When untreated, fluid accumulation in the lungs can rapidly progress, causing death within a few hours. Most salt added to the blood remains in the extracellular compartment, and only a small amount enters the cells. Therefore, in kidney disease the compromise urinary excretion of salt and water, large amounts are added to the ECF. Most of this leaks from the blood into the interstitial spaces, but some remains. The main effects of this are: Widespread increases in interstitial fluid volume Hypertension due to increased blood volume An example: in children who have acute glomerulonephiritis, in which the renal glomeruli are injured by inflammation and fail to filter enough fluid, serious extracellular fluid edema develops and severe hypertension. Failure to produce normal amounts of proteins or leakage of proteins from the plasma causes the plasma colloid osmotic pressure to fall. This leads to increased capillary filtration throughout the body and extracellular edema. One of the most important causes of decreased plasma protein concentration is the loss of proteins in the urine in certain kidney diseases (nephrotic syndrome). Multiple types of renal diseases can damage the membranes of the renal glomeruli, causing the membranes to become leaky to the plasma proteins and often allowing large quantities of these proteins to pass into the urine. When this loss exceeds the ability of the body to synthesize proteins, a reduction in plasma protein concentration occurs. Cirrhosis of the liver is another condition that reduces plasma protein concentration. Cirrhosis means the development of large amounts of fibrous tissue among the liver parenchyma cells. One result is failure of these cells to produce sufficient plasma proteins, leading to decreased plasma colloid osmotic pressure and the generalized edema that accompanies this condition. Another way that cirrhosis causes edema is that the liver fibrosis sometimes compresses the abdominal portal venous drainage vessels as they pass through the liver before emptying back into the general circulation. Blockage of this portal venous outflow raises capillary hydrostatic pressure throughout the gastrointestinal area and further increases fluid filtration out of the plasma into the intra-abdominal areas. When this occurs, the combined effects of decreased plasma protein concentration and high portal capillary pressure cause transduction of large amounts of fluid and protein into the abdominal cavities, a condition referred to as ascites. Assignment 10 Hydrogen Ion Concentration is Precisely Regulated Precise H + regulation is essential because the activities of almost all enzyme systems in the body are influenced by H + concentration. Therefore, changes in H + concentration alter virtually all cell and body functions. Compared with other ions, the H + concentration of the body fluids normally is kept at a low level. For example, the concentration of sodium in extracellular fluid (142 mEq/L) is about 3.5 million times as great as the normal concentration of H + , which averages only 0.00004 mEq/L. Equally important, the normal variation in H + concentration in extracellular fluid is only about one millionth as great as the normal variation in sodium ion (Na + ) concentration. Thus, the precision with which H + is regulated emphasizes its importance to the various cell functions. Acids and Bases—Definitions and Meanings A hydrogen ion is a single free proton released from a hydrogen atom. Molecules containing hydrogen atoms that can release hydrogen ions in a solution are referred to as acids. An example is hydrochloric acid (HCl), which ionizes in water to form hydrogen ions (H + ) and chloride ions (Cl − ). Likewise, carbonic acid (H 2 CO 3 ) ionizes in water to form H + and bicarbonate ions (HCO 3 − ). A base is an ion or a molecule that can accept an H +. For example, HCO 3 − is a base because it can combine with H + to form H 2 CO 3. Likewise, HPO 4 = is a base because it can accept an H + to form H 2 PO 4 −. The proteins in the body also function as bases because some of the amino acids that make up proteins have net negative charges that readily accept H +. The protein hemoglobin in the red blood cells and proteins in the other cells of the body are among the most important of the body’s bases. The terms base and alkali are often used synonymously. An alkali is a molecule formed by the combination of one or more of the alkaline metals—such as sodium, potassium, and lithium—with a highly basic ion such as a hydroxyl ion (OH − ). The base portion of these molecules reacts quickly with H + to remove it from solution and are, therefore, typical bases. For similar reasons, the term alkalosis refers to the excess removal of H + from the body fluids, in contrast to the excess addition of H + , which is referred to as acidosis. Strong and Weak Acids and Bases A strong acid, such as HCl, rapidly dissociates and releases especially large amounts of H + in solution. Weak acids such as H 2 CO 3 are less likely to dissociate their ions and, therefore, release H + with less vigor. A strong base is one that reacts rapidly and strongly with H + and, therefore, quickly removes H + from a solution. A typical example is OH − , which reacts with H + to form water (H 2 O). A typical weak base is HCO 3 − because it binds with H + much more weakly than OH −. Most acids and bases in the extracellular fluid that are involved in normal acid–base regulation are weak acids and bases. The most important ones that we discuss are carbonic acid (H 2 CO 3 ) and HCO 3 − base. Normal H + Concentration and pH of Body Fluids and Changes That Occur in Acidosis and Alkalosis The blood H + concentration is normally maintained within tight limits around a normal value of about 0.00004 mEq/L (40 nEq/L). Normal variations are only about 3 to 5 nEq/L but, under extreme conditions, the H + concentration can vary from as low as 10 nEq/L to as high as 160 nEq/L without resulting in death. Because H + concentration normally is low, and because these small numbers are cumbersome, it is customary to express H + concentration on a logarithm scale using pH units. pH is related to the actual H + concentration by the following formula (H + concentration [H + ] is expressed in equivalents per liter): pH=log1[H+]=−log[H+]pH=log1[H+]=−log[H+] For example, normal [H + ] is 40 nEq/L (0.00000004 Eq/L). Therefore, the normal pH is as follows: pH=−log[0.00000004]pH=7.4pH=−log[0.00000004]pH=7.4 From this formula, one can see that pH is inversely related to the H + concentration; therefore, a low pH corresponds to a high H + concentration, and a high pH corresponds to a low H + concentration. The normal pH of arterial blood is 7.4, whereas the pH of venous blood and interstitial fluids is about 7.35 because of the extra amounts of carbon dioxide (CO 2 ) released from the tissues to form H 2 CO 3 in these fluids ( Table 31-1 ). Because the normal pH of arterial blood is 7.4, a person is considered to have acidemia when the pH falls significantly below this value and alkalemia when the pH rises above 7.4. The lower limit of pH at which a person can live more than a few hours is about 6.8, and the upper limit is about 8.0. Intracellular pH usually is slightly lower than plasma pH because cell metabolism produces acid, especially H 2 CO 3. Depending on the type of cells, the pH of intracellular fluid has been estimated to range between 6.0 and 7.4. Hypoxia of the tissues and poor blood flow to the tissues can cause acid accumulation and decreased intracellular pH. The terms acidosis and alkalosis describe the processes that lead to acidemia and alkalemia, respectively. The pH of urine can range from 4.5 to 8.0, depending on the acid–base status of the extracellular fluid. As discussed later, the kidneys play a major role in correcting abnormalities of extracellular fluid H + concentration by excreting acids or bases at variable rates. An extreme example of an acidic body fluid is the HCl secreted into the stomach by the oxyntic (parietal) cells of the stomach mucosa, as discussed in Chapter 65. The H + concentration in these cells is about 4 million times greater than the hydrogen concentration in blood, with a pH of 0.8. In the remainder of this chapter, we discuss the regulation of extracellular fluid H + concentration. Defending Against Changes in H + Concentration: Buffers, Lungs, and Kidneys Three primary systems regulate the H + concentration in the body fluids: (1) the chemical acid–base buffer systems of the body fluids , which immediately combine with an acid or a base to prevent excessive changes in H + concentration; (2) the respiratory center , which regulates the removal of CO 2 (and, therefore, H 2 CO 3 ) from the extracellular fluid; and (3) the kidneys , which can excrete acidic or alkaline urine, thereby readjusting the extracellular fluid H + concentration toward normal during acidosis or alkalosis. When there is a change in H + concentration, the buffer systems of the body fluids react within seconds to minimize these changes. Buffer systems do not eliminate H + from or add H + to the body but only keep them tied up until balance can be re-established. The second line of defense, the respiratory system , acts within a few minutes to eliminate CO 2 and, therefore, H 2 CO 3 from the body. These first two lines of defense keep the H + concentration from changing too much until the more slowly responding third line of defense, the kidneys , can eliminate the excess acid or base from the body. Although the kidneys are relatively slow to respond compared with the other defenses, over a period of hours to several days, they are by far the most powerful of the acid–base regulatory systems. Buffering of H + in the Body Fluids A buffer is any substance that can reversibly bind H +. The general form of the buffering reaction is as follows: Buffer+H+⇄HBufferBuffer+H+⇄HBuffer In this example, a free H + combines with the buffer to form a weak acid (H buffer) that can either remain as an unassociated molecule or dissociate back to the buffer and H +. When the H + concentration increases, the reaction is forced to the right, and more H + binds to the buffer, as long as buffer is available. Conversely, when the H + concentration decreases, the reaction shifts toward the left, and H + is released from the buffer. In this way, changes in H + concentration are minimized. The importance of the body fluid buffers can be quickly realized if one considers the low concentration of H + in the body fluids and the relatively large amounts of acids produced by the body each day. About 80 milliequivalents of H + is ingested or produced each day by metabolism, whereas the H + concentration of the body fluids normally is only about 0.00004 mEq/L. Without buffering, the daily production and ingestion of acids would cause lethal changes in the body fluid H + concentration. The action of acid–base buffers can perhaps best be explained by considering the buffer system that is quantitatively the most important in the extracellular fluid—the bicarbonate buffer system. Bicarbonate Buffer System The bicarbonate buffer system consists of a water solution that contains two ingredients: (1) a weak acid, H 2 CO 3 ; and (2) a bicarbonate salt, such as sodium bicarbonate (NaHCO 3 ). H 2 CO 3 is formed in the body by the reaction of CO 2 with H 2 O: CO2+H2O⇄carbonicanhydraseH2CO3CO2+H2O⇄carbonicanhydraseH2CO3 This reaction is slow, and exceedingly small amounts of H 2 CO 3 are formed unless the enzyme carbonic anhydrase is present. This enzyme is especially abundant in the walls of the lung alveoli, where CO 2 is released; carbonic anhydrase is also present in the epithelial cells of the renal tubules, where CO 2 reacts with H 2 O to form H 2 CO 3. H 2 CO 3 ionizes weakly to form small amounts of H + and HCO 3 − : H2CO3↔H++HCO−3H2CO3↔H++HCO3− The second component of the system, bicarbonate salt, occurs predominantly as NaHCO 3 in the extracellular fluid. NaHCO 3 ionizes almost completely to form HCO 3 − and Na + , as follows: NaHCO3↔Na++HCO−3NaHCO3↔Na++HCO3− Now, putting the entire system together, we have the following: CO2+H2O↔H2CO3↔H++HCO−3+Na+CO2+H2O↔H2CO3↔H++HCO3−︸+Na+ Because of the weak dissociation of H 2 CO 3 , the H + concentration is extremely low. When a strong acid such as HCl is added to the bicarbonate buffer solution, the increased H + released from the acid (HCl → H + + Cl − ) is buffered by HCO 3 − : ↑⏐H++HCO−3→H2CO3→CO2+H2O↑H++HCO3−→H2CO3→CO2+H2O As a result, more H 2 CO 3 is formed, causing increased CO 2 and H 2 O production. From these reactions, one can see that H + from the strong acid HCl reacts with HCO 3 − to form the very weak acid H 2 CO 3 , which in turn forms CO 2 and H 2 O. The excess CO 2 greatly stimulates respiration, which eliminates the CO 2 from the extracellular fluid. The opposite reactions take place when a strong base, such as sodium hydroxide (NaOH), is added to the bicarbonate buffer solution. NaOH+H2CO3→NaHCO3+H2ONaOH+H2CO3→NaHCO3+H2O In this case, the OH − from the NaOH combines with H 2 CO 3 to form additional HCO 3 −. Thus, the weak base NaHCO 3 replaces the strong base NaOH. At the same time, the concentration of H 2 CO 3 decreases (because it reacts with NaOH), causing more CO 2 to combine with H 2 O to replace the H 2 CO 3 : The net result, therefore, is a tendency for the CO 2 levels in the blood to decrease, but the decreased CO 2 in the blood inhibits respiration and decreases the rate of CO 2 expiration. The rise in blood HCO 3 − concentration that occurs is compensated for by increased renal excretion of HCO 3 −. Assignment 11 Proteins are important intracellular buffers Proteins are plentiful buffers in the body because of their high concentrations in the cells The pH of cells changes in proportion to extracellular fluid changes There is a slight diffusion of H + and HCO 3 − through the cell membrane, but these ions require several hours to reach equilibrium with the extracellular fluid But rapid equilibrium occurs in the red blood cells. CO2 can rapidly diffuse through all the cell membranes This diffusion of the elements of the bicarbonate buffer system causes the pH in intracellular fluid to change when there are changes in extracellular pH The buffer systems in cells help prevent changes in the pH of the extracelluar fluid but may take several hours be become effective In red blood cells, hemoglobin (Hb) is an important buffer Most of the total chemical buffering results from the intracellular proteins Except for blood cells, the slow rate at which H + and HCO 3 −move through the cell membranes delays the ability of the intracellular proteins to buffer extracellular acid Another thing that contributes to proteins buffering power is that the pKas are close to intracellular pH Assignment 12 Respiratory regulation of Acid-Base balance The second line of defense against acid-base disturbances is control of extracellular fluid CO2 concentration by the lungs Increase of ventilation eliminates CO2 from ECF which reduces the H+ concentration Decresed ventilation increases CO2 and H+ concentrations in ECF Pulmonary expiration of CO2 balances metabolic formation of CO2 CO2 is continously formed in the body by intracellular metabolic processes After formed, it diffuses from the cells into interstitial fluids and blood, and the flowing blood transports to the lungs, where it diffuses into the alveoli and then is transferred to the atmosphere by pulmonary ventilation If the rate of metabolic formation of CO 2 increases, the P co 2 of the extracellular fluid is also increased. A decreased metabolic rate lowers the P co 2. If the rate of pulmonary ventilation is increased, CO 2 is blown off from the lungs, and the P co 2 in the extracellular fluid decreases. Changes in pulmonary ventilation or the rate of CO 2 formation by the tissues can change the extracellular fluid P co 2. Increasing alveolar ventilation decreases extracellular fluid H+ concentration and raises pH If the metabolic formation of CO 2 remains constant, the only other factor that affects P co 2 in extracellular fluid is the rate of alveolar ventilation. The higher the alveolar ventilation, the lower the P co 2. Again, when CO 2 concentration increases, the H 2 CO 3 concentration and H + concentration also increase, lowering extracellular fluid pH. Figure shows changes in blood pH that are casued by increasing or decreasing the alveolar ventilation rate Increasing alveolar ventilation raises extracellular fluid pH decrease in alveolar ventilation reduces the pH Increased H+ concentration stimulates alveolar ventilation Not only does the alveolar ventilation rate influence H + concentration by changing P co 2 of the body fluids, but the H + concentration affects the rate of alveolar ventilation. Alveolar ventilation rate increases as pH decreases, alveolar ventilation rate decreased as pH increases as the alveolar ventilation rate decreases, from an increase in pH (decreased H + concentration), the amount of oxygen added to the blood decreases, and the partial pressure of oxygen (P o 2 ) in the blood also decreases, which stimulates the ventilation rate. The respiratory compensation for an increase in pH is not nearly as effective as the response to a reduction in pH. Feedback control of H+ concentration by the respiratory system Increased H + concentration stimulates respiration and because increased alveolar ventilation decreases H + concentration, the respiratory system acts as a typical negative feedback controller of H + concentration When H+ is too high respiratory system is stimulated and alveolar ventilation increases This mech decreases the Pco2 in extracellular fluid and reduces H+ concentration back toward normal If H+ concentration falls below normal the respiratory center becomes depressed. Alveolar ventilation decreases and H+ concentration increases Alkalosis tends to depress the respiratory centers, the response is less robust and less predictable than the response to metabolic acidosis; the hypoxemia associated with reduced alveolar ventilation eventually activates oxygen-sensitive chemoreceptors that tend to stimulate ventilation and limit the respiratory compensation for metabolic alkalosis. Efficiency of respiratory control of H+ concentration Respiratory control cannot return the H + concentration all the way back to normal when a disturbance outside the respiratory system changed the pH. The respiratory mechanism for controlling H + concentration is effective but not 100% If the pH is suddenly decreased by adding acid to the extracellular fluid, and the pH falls from 7.4 to 7.0, the respiratory system can return the pH to a value of about 7.2 to 7.3. This response occurs within 3 to 12 minutes. The respiratory responses to metabolic alkalosis are limited by hypoxemia associated with reduced alveolar ventilation. Buffering power of the respiratory Respiratory regulation of acid–base balance is a physiological type of buffer system because it acts rapidly and keeps the H + concentration from changing too much until the slowly responding kidneys can eliminate the imbalance. The overall buffering power of the respiratory system is one to two times as great as the buffering power of all other chemical buffers in the extracellular fluid combined. One to two times as much acid or base can normally be buffered by this mechanism as by the chemical buffers. Impairment of the lung function can cause respiratory acidosis The role of the normal respiratory mechanism is a means of buffering changes in H + concentration. Issues of respiration can also cause changes in H + concentration. Impairment of lung function decreases the ability of the lungs to eliminate CO2 , which causes a buildup of CO2 in the extracellular fluid and/or respiratory acidosis. Also, the ability to respond to metabolic acidosis is impaired because the reductions in P co 2 that would normally occur by iincreased ventilation are prevented. When this happens, the kidneys have a physiological mechanism for returning pH toward normal Renal control of acid-base balance The kidneys control acid–base balance by excreting acidic or basic urine. Excreting acidic urine reduces the amount of acid in extracellular fluid, excreting basic urine removes base from the extracellular fluid. The overall mechanism of how the kidneys excrete acidic or basic urine. Large amounts of HCO 3 − are filtered continuously into the tubules and, if excreted into the urine, remove base from the blood. Large numbers of H + are also secreted into the tubular lumen by the tubular epithelial cells, removing acid from the blood. If more H + is secreted than HCO 3 − is filtered, there will be a net loss of acid from the extracellular fluid. Conversely, if more HCO 3 − is filtered than H + is secreted, there will be a net loss of base. Each day, the body produces about 80 mEq of nonvolatile acids, mainly from metabolism of proteins. These acids are called nonvolatile because they are not H2CO3 and cannot be excreted by the lungs. The primary mechanism for removal of these acids from the body is renal excretion. The kidneys must also prevent the loss of bicarbonate in the urine, a task that is more important than the excretion of nonvolatile acids. The reabsorption of HCO 3 − and excretion of H + are accomplished through the process of H + secretion by the tubules. HCO 3 − must react with a secreted H + to form H 2 CO 3 before it can be reabsorbed When there is a reduction in the extracellular fluid H + concentration (alkalosis), the kidneys usually secrete less H + and fail to reabsorb all the filtered HCO 3 − , thereby increasing the excretion of HCO 3 −. Because HCO 3 − normally buffers H + in the extracellular fluid, this loss of HCO 3 − is the same as adding an H + to the extracellular fluid. Therefore, in alkalosis, the removal of HCO 3 − raises the extracellular fluid H + concentration back toward normal. In acidosis, the kidneys secrete additional H + and do not excrete HCO 3 − into the urine but reabsorb all the filtered HCO 3 − and produce new HCO 3 − , which is added back to the extracellular fluid. This action reduces the extracellular fluid H + concentration back toward normal. The kidneys regulate extracellular fluid H + concentration through three mechanisms: (1) secretion of H + ; (2) reabsorption of filtered HCO 3 − (3) production of new HCO 3 - Secretion of H+ and reabsorption of HCO3– by the renal tubules Hydrogen ion secretion and HCO 3 − reabsorption occur in all parts of the tubules except the descending and ascending thin limbs of the loop of Henle. Figure 31-4 summarizes HCO 3 − reabsorption along the tubule. Keep in mind that for each HCO 3 − reabsorbed, an H + must be secreted. Reabsorption of HCO 3 − in different segments of the renal tubule. The percentages of the filtered load of HCO 3 − absorbed by the various tubular segments are shown, as well as the number of milliequivalents reabsorbed per day under normal conditions. About 80% to 90% of the HCO 3 − reabsorption (and H + secretion) occurs in the proximal tubule, so only a small amount of HCO 3 − flows into the distal tubules and collecting ducts. In the thick ascending loop of Henle, another 10% of the filtered HCO 3 − is reabsorbed, and the remainder of the reabsorption takes place in the distal tubules and collecting ducts. The mechanism whereby HCO 3 − is reabsorbed also involves tubular secretion of H + , but different tubular segments accomplish this task differently. H + Secreted by Secondary Active Transport in Early Tubular Segments The epithelial cells of the proximal tubule, the thick segment of the ascending loop of Henle, and the early distal tubule all secrete H + into the tubular fluid by sodium-hydrogen counter-transport This secondary active secretion of H + is coupled with the transport of Na + into the cell at the luminal membrane by the sodium-hydrogen exchanger protein And the energy for H + secretion against a concentration gradient is from the sodium gradient favoring Na + movement into the cell. This gradient is established by the sodium-potassium adenosine triphosphatase (Na + -K + ATPase) pump in the basolateral membrane. About 95% of the bicarbonate is reabsorbed in this manner, requiring about 4000 mEq of H + to be secreted each day by the tubules. This mechanism can establish a minimum pH of only about 6.7; the tubular fluid becomes very acidic only in the collecting tubules and collecting ducts, which can establish a urine pH as low as about 4.5. The figure shows how the process of H + secretion achieves HCO3 − reabsorption. The secretory process begins when CO2 either diffuses into the tubular cells or is formed by metabolism in the tubular epithelial cells. Under the influence of the enzyme carbonic anhydrase , CO 2 , combines with H 2 O to form H 2 CO 3 , which dissociates into HCO 3 − and H +. The H + is secreted from the cell into the tubular lumen by sodium-hydrogen counter-transport. That is, when Na + moves from the lumen of the tubule to the interior of the cell, it first combines with a carrier protein in the luminal border of the cell membrane; at the same time, a H + in the interior of the cells combines with the carrier protein. The Na + moves into the cell down a concentration gradient that has been established by the Na + -K + ATPase pump in the basolateral membrane. The gradient for Na + movement into the cell then provides the energy for moving H + in the opposite direction from the interior of the cell to the tubular lumen. The HCO 3 − generated in the cell (when H + dissociates from H 2 CO 3 ) then moves downhill across the basolateral membrane, into the renal interstitial fluid and peritubular capillary blood. The net result is that for every H + secreted into the tubular lumen, an HCO 3 − enters the blood. Filtered HCO 3 − IS Reabsorbed by Interaction with H + in the Tubules Bicarbonate ions do not readily permeate the luminal membranes of the renal tubular cells; therefore, HCO 3 − that is filtered by the glomerulus cannot be directly reabsorbed. Instead, HCO 3 − is reabsorbed by a special process in which it first combines with H + to form H 2 CO 3 , which eventually becomes CO 2 and H 2 O. This reabsorption of HCO 3 − is initiated by a reaction in the tubules between HCO 3 − filtered at the glomerulus and H + secreted by the tubular cells. The H 2 CO 3 formed then dissociates into CO 2 and H 2 O. The CO 2 can move easily across the tubular membrane; therefore, it instantly diffuses into the tubular cell, where it recombines with H 2 O, under the influence of carbonic anhydrase, to generate a new H 2 CO 3 molecule. This H 2 CO 3 dissociates to form HCO 3 − and H + ; the HCO 3 − then diffuses through the basolateral membrane into the interstitial fluid and is taken up into the peritubular capillary blood. The transport of HCO 3 across the basolateral membrane is facilitated by two mechanisms: (1) Na + -HCO 3 − co-transport in the proximal tubules; (2) Cl − -HCO 3 − exchange in the late segments of the proximal tubule, thick ascending loop of Henle, and collecting tubules and ducts. Each time a H + is formed in the tubular epithelial cells, an HCO 3 − is also formed and released back into the blood. The net effect of these reactions is “reabsorption” of HCO 3 − from the tubules, although the HCO 3 − that actually enters the extracellular fluid is not the same as that filtered into the tubules. The reabsorption of filtered HCO 3 − does not result in net secretion of H + because the secreted H + combines with the filtered HCO 3 − and is therefore not excreted. HCO 3 − Is Titrated Against H + in the Tubules Under normal conditions, the rate of tubular H + secretion is about 4400 mEq/day, and the rate of filtration by HCO 3 − is about 4320 mEq/day. The quantities of these two ions entering the tubules are almost equal, and they combine with each other to form CO 2 and H 2 O. HCO 3 − and H + normally “titrate” each other in the tubules. The titration process is not exact because there is usually a slight excess of H + in the tubules to be excreted in the urine. This excess H + (≈80 mEq/day) rids the body of nonvolatile acids produced by metabolism. most of this H + is not excreted as free H + but is in combination with other urinary buffers, especially phosphate and ammonia. When there is an excess of HCO 3 − over H + in the urine, as occurs in metabolic alkalosis, the excess HCO 3 − cannot be reabsorbed. Therefore, the excess HCO 3 − is left in the tubules and eventually excreted into the urine, which helps correct the metabolic alkalosis. In acidosis, there is excess H + relative to HCO 3 − , causing complete reabsorption of the HCO 3 − ; the excess H + passes into the urine in combination with urinary buffers, especially phosphate and ammonia, and eventually is excreted as salts. The basic mechanism where the kidneys correct acidosis or alkalosis is incomplete titration of H + against HCO 3 − , leaving one or the other to pass into the urine and be removed from the extracellular fluid. Primary Active Secretion of H + in the Intercalated Cells of Late Distal and Collecting Tubules Beginning in the late distal tubules and continuing through the remainder of the tubular system, the tubular epithelium secretes H + by primary active transport The mechanism for primary active H + secretion It occurs at the luminal membrane of the tubular cell, where H + is transported directly by specific proteins, a hydrogen-transporting ATPase and a hydrogen-potassium-ATPase transporter. The energy required for pumping the H + is derived from the breakdown of ATP to adenosine diphosphate. Primary active secretion of H + occurs in special types of cells called the type A intercalated cells of the late distal tubule and in the collecting tubules. Hydrogen ion secretion in these cells is accomplished in two steps: (1) the dissolved CO 2 in this cell combines with H 2 O to form H 2 CO 3 ; and (2) the H 2 CO 3 then dissociates into HCO 3 − , which is reabsorbed into the blood, plus H + , which is secreted into the tubule by means of the hydrogen-ATPase and the hydrogen-potassium-ATPase transporters. For each H + secreted, a HCO 3 − is reabsorbed, similar to the process in the proximal tubules. The main difference is that H + moves across the luminal membrane by an active H + pump instead of by counter-transport, as occurs in the early parts of the nephron. Although secretion of H + in the late distal tubule and collecting tubules accounts for only about 5% of the total H + secreted, this mechanism is important in forming acidic urine. In the proximal tubules, H + concentration can be increased only about threefold to fourfold and the tubular fluid pH can be reduced to only about 6.7, although large amounts of H + are secreted by this nephron segment. However, H + concentration can be increased as much as 900-fold in the collecting tubules. This mechanism decreases the pH of the tubular fluid to about 4.5, which is the lower limit of pH that can be achieved in normal kidneys. Combination of Excess H + with Phosphate and Ammonia Buffers In the Tubule Generates “New” HCO 3 − When H + is secreted in excess of the HCO 3 − filtered into the tubular fluid, only a small part of the excess H + can be excreted in the ionic form (H + ) in the urine. This is because the minimal urine pH is about 4.5, corresponding to an H + concentration of 10 −4.5 mEq/L, or 0.03 mEq/L. Thus, for each liter of urine formed, a maximum of only about 0.03 mEq of free H + can be excreted. To excrete the 80 mEq of nonvolatile acid formed by metabolism each day, about 2667 liters of urine would have to be excreted if the H + remained free in solution. The excretion of large amounts of H + (on occasion as much as 500 mEq/day) in the urine is accomplished primarily by combining the H + with buffers in the tubular fluid. The most important buffers are phosphate buffer and ammonia buffer. Other weak buffer systems, such as urate and citrate, are much less important. When H + is titrated in the tubular fluid with HCO 3 − , this leads to reabsorption of one HCO 3 − for each H + secreted, as discussed earlier. However, when there is excess H + in the tubular fluid, it combines with buffers other than HCO 3 − , and this leads to generation of new HCO 3 − that can also enter the blood. When there is excess H + in the extracellular fluid, the kidneys not only reabsorb all the filtered HCO 3 − but also generate new HCO 3 − , thereby helping replenish the HCO 3 − lost from the extracellular fluid in acidosis. Phosphate Buffer System Carries Excess H + Into the Urine and Generates New HCO3− The phosphate buffer system is composed of HPO 4 =. Both become concentrated in the tubular fluid because water is normally reabsorbed to a greater extent than phosphate by the renal tubules. Therefore, although phosphate is not an important extracellular fluid buffer, it is much more effective as a buffer in the tubular fluid. Another factor that makes phosphate important as a tubular buffer is the fact that the pK of this system is about 6.8. Under normal conditions, the urine is slightly acidic, and the urine pH is near the pK of the phosphate buffer system. Therefore, in the tubules, the phosphate buffer system normally functions near its most effective pH range. Figure shows the sequence of events where H + is excreted in combination with phosphate buffer and the mechanism whereby new HCO 3 − is added to the blood. As long as there is excess HCO 3 − in the tubular fluid, most of the secreted H + combines with HCO 3 −. However, once all the HCO 3 − has been reabsorbed and is no longer available to combine with H + , any excess H + can combine with HPO 4 = and other tubular buffers. After the H + combines with HPO 4 = to form H 2 PO 4 − , it can be excreted as a sodium salt (NaH 2 PO 4 ), carrying with it the excess H +. There is one important difference in this sequence of H + excretion from that discussed previously. In this case, the HCO 3 − that is generated in the tubular cell and enters the peritubular blood represents a net gain of HCO 3 − by the blood, rather than merely a replacement of filtered HCO 3 −. Therefore, whenever an H + secreted into the tubular lumen combines with a buffer other than HCO 3 − , the net effect is the addition of a new HCO 3 − to the blood. This process demonstrates one of the mechanisms whereby the kidneys can replenish the extracellular fluid stores of HCO 3 −. Under normal conditions, much of the filtered phosphate is reabsorbed, and only 30 to 40 mEq/day are available for buffering H +. Therefore, much of the buffering of excess H + in the tubular fluid in acidosis occurs through the ammonia buffer system. Excretion of Excess H + and Generation of New HCO 3 − by Ammonia Buffer System A second buffer system in the tubular fluid that is even more important quantitatively than the phosphate buffer system is composed of ammonia (NH 3 ) and the ammonium ion (NH 4 + ). Ammonium ion is synthesized from glutamine, which comes mainly from metabolism of amino acids in the liver. The glutamine delivered to the kidneys is transported into epithelial cells of the proximal tubules, thick ascending limb of the loop of Henle, and distal tubules Once inside the cell, each molecule of glutamine is metabolized in a series of reactions to ultimately form two NH 4 + and two HCO 3 −. The NH 4 + is secreted into the tubular lumen by a counter-transport mechanism in exchange for sodium, which is reabsorbed. The HCO 3 − is transported across the basolateral membrane, along with the reabsorbed Na + , into the interstitial fluid and is taken up by the peritubular capillaries. For each molecule of glutamine metabolized in the proximal tubules, two NH 4 + are secreted into the urine and two HCO 3 − are reabsorbed into the blood. The HCO 3 − generated by this process constitutes new HCO 3 −. Figure: Production and secretion of ammonium ion (NH 4 + ) by proximal tubular cells. Glutamine is metabolized in the cell, yielding NH 4 + and HCO 3 −. The NH 4 + is secreted into the lumen by a Na + -NH 4 + exchanger. For each glutamine molecule metabolized, two NH 4 + are produced and secreted, and two HCO 3 − are returned to the blood. In the collecting tubules, the addition of NH 4 + to the tubular fluids occurs through a different mechanism. Here, H + is actively secreted by the tubular membrane into the lumen, where it combines with NH 3 to form NH 4 + , which is then excreted. The collecting ducts are permeable to NH 3 , which can easily diffuse into the tubular lumen. However, the luminal membrane of this part of the tubules is much less permeable to NH 4 + ; therefore, once the H + has reacted with NH 3 to form NH 4 + , the NH 4 + is trapped in the tubular lumen and eliminated in the urine. For each NH 4 + excreted, a new HCO 3 − is generated and added to the blood. Buffering of H + secretion by ammonia (NH 3 ) in the collecting tubules. NH 3 diffuses into the tubular lumen, where it reacts with secreted H + to form NH 4 + , which is then excreted. For each NH 4 + excreted, a new HCO 3 − is formed in the tubular cells and returned to the blood. Chronic acidosis increases NH4+ excretion One of the most important features of the renal ammonium-ammonia buffer system is that it is subject to physiological control. An increase in extracellular fluid H + concentration stimulates renal glutamine metabolism and, therefore, increases formation of NH 4 + and new HCO 3 − to be used in H + buffering; a decrease in H + concentration has the opposite effect. Under normal conditions , the amount of H + eliminated by the ammonia buffer system accounts for about 50% of the acid excreted and 50% of the new HCO 3 − generated by the kidneys. However, with chronic acidosis , the rate of NH 4 + excretion can increase to as much as 500 mEq/day. Therefore, with chronic acidosis, the dominant mechanism for acid elimination is excretion of NH 4 +. This process also provides the most important mechanism for generating new bicarbonate during chronic acidosis.