AccessMedicine | Print: Chapter General Principles & Energy Productio of 44 http://www.accessmedicine.com/popup.aspx?aID=5242839&print=yes_c Print Close Window Note: Large images and tables on this page may necessitate printing in landscape mode Copyright © The McGraw-Hill Companies All rights reserved Ganong's Review of Medical Physiology > Chapter General Principles & Energy Production in Medical Physiology > OBJECTIVES After studying this chapter, you should be able to: Name the different fluid compartments in the human body Define moles, equivalents, and osmoles Define pH and buffering Understand electrolytes and define diffusion, osmosis, and tonicity Define and explain the resting membrane potential Understand in general terms the basic building blocks of the cell: nucleotides, amino acids, carbohydrates, and fatty acids Understand higher-order structures of the basic building blocks: DNA, RNA, proteins, and lipids Understand the basic contributions of these building blocks to cell structure, function, and energy balance GENERAL PRINCIPLES & ENERGY PRODUCTION IN MEDICAL PHYSIOLOGY: INTRODUCTION In unicellular organisms, all vital processes occur in a single cell As the evolution of multicellular organisms has progressed, various cell groups organized into tissues and organs have taken over particular functions In humans and other vertebrate animals, the specialized cell groups include a gastrointestinal system to digest and absorb food; a respiratory system to take up O2 and eliminate CO2; a urinary system to remove wastes; a cardiovascular system to distribute nutrients, O2, and the products of metabolism; a reproductive system to perpetuate the species; and nervous and endocrine systems to coordinate and integrate the functions of the other systems This book is concerned with the way these systems function and the way each contributes to the functions of the body as a whole In this section, general concepts and biophysical and biochemical principles that are basic to the function of all the systems are presented In the first chapter, the focus is on review of basic biophysical and biochemical principles and the introduction of the molecular building blocks that contribute to cellular physiology In the second chapter, a review of basic cellular morphology and physiology is presented In the third chapter, the process of immunity and inflammation, and their link to physiology, are considered GENERAL PRINCIPLES THE BODY AS AN ORGANIZED "SOLUTION" The cells that make up the bodies of all but the simplest multicellular animals, both aquatic and terrestrial, exist in an "internal sea" of extracellular fluid (ECF) enclosed within the integument of the animal From this fluid, the cells take up O2 and nutrients; into it, they discharge metabolic waste products The ECF is more dilute than present-day seawater, but its composition closely resembles that of the primordial oceans in which, presumably, all life originated In animals with a closed vascular system, the ECF is divided into two components: the interstitial fluid and the circulating blood plasma The plasma and the cellular elements of the blood, principally red blood cells, fill the vascular system, and together they constitute the total blood volume The interstitial fluid is that part of the ECF that is outside the vascular system, bathing the cells The special fluids considered together as transcellular fluids are discussed in the following text About a third of the total body water is extracellular; the remaining two thirds is intracellular (intracellular fluid) In the average young adult male, 18% of the body weight is protein and related 8/18/2009 3:04 AM AccessMedicine | Print: Chapter General Principles & Energy Productio of 44 http://www.accessmedicine.com/popup.aspx?aID=5242839&print=yes_c substances, 7% is mineral, and 15% is fat The remaining 60% is water The distribution of this water is shown in Figure 1–1A Figure 1–1 8/18/2009 3:04 AM AccessMedicine | Print: Chapter General Principles & Energy Productio of 44 http://www.accessmedicine.com/popup.aspx?aID=5242839&print=yes_c 8/18/2009 3:04 AM AccessMedicine | Print: Chapter General Principles & Energy Productio of 44 http://www.accessmedicine.com/popup.aspx?aID=5242839&print=yes_c Organization of body fluids and electrolytes into compartments A) Body fluids are divided into Intracellular and extracellular fluid compartments (ICF and ECF, respectively) Their contribution to percentage body weight (based on a healthy young adult male; slight variations exist with age and gender) emphasizes the dominance of fluid makeup of the body Transcellular fluids, which constitute a very small percentage of total body fluids, are not shown Arrows represent fluid movement between compartments B) Electrolytes and proteins are unequally distributed among the body fluids This uneven distribution is crucial to physiology Prot –, protein, which tends to have a negative charge at physiologic pH The intracellular component of the body water accounts for about 40% of body weight and the extracellular component for about 20% Approximately 25% of the extracellular component is in the vascular system (plasma = 5% of body weight) and 75% outside the blood vessels (interstitial fluid = 15% of body weight) The total blood volume is about 8% of body weight Flow between these compartments is tightly regulated UNITS FOR MEASURING CONCENTRATION OF SOLUTES In considering the effects of various physiologically important substances and the interactions between them, the number of molecules, electric charges, or particles of a substance per unit volume of a particular body fluid are often more meaningful than simply the weight of the substance per unit volume For this reason, physiological concentrations are frequently expressed in moles, equivalents, or osmoles Moles A mole is the gram-molecular weight of a substance, ie, the molecular weight of the substance in grams Each mole (mol) consists of x 1023 molecules The millimole (mmol) is 1/1000 of a mole, and the micromole ( mol) is 1/1,000,000 of a mole Thus, mol of NaCl = 23 g + 35.5 g = 58.5 g, and mmol = 58.5 mg The mole is the standard unit for expressing the amount of substances in the SI unit system The molecular weight of a substance is the ratio of the mass of one molecule of the substance to the mass of one twelfth the mass of an atom of carbon-12 Because molecular weight is a ratio, it is dimensionless The dalton (Da) is a unit of mass equal to one twelfth the mass of an atom of carbon-12 The kilodalton (kDa = 1000 Da) is a useful unit for expressing the molecular mass of proteins Thus, for example, one can speak of a 64-kDa protein or state that the molecular mass of the protein is 64,000 Da However, because molecular weight is a dimensionless ratio, it is incorrect to say that the molecular weight of the protein is 64 kDa Equivalents The concept of electrical equivalence is important in physiology because many of the solutes in the body are in the form of charged particles One equivalent (eq) is mol of an ionized substance divided by its valence One mole of NaCl dissociates into eq of Na+ and eq of Cl– One equivalent of Na+ = 23 g, but eq of Ca2+ = 40 g/2 = 20 g The milliequivalent (meq) is 1/1000 of eq Electrical equivalence is not necessarily the same as chemical equivalence A gram equivalent is the weight of a substance that is chemically equivalent to 8.000 g of oxygen The normality (N) of a solution is the number of gram equivalents in liter A N solution of hydrochloric acid contains both H + (1 g) and Cl– (35.5 g) equivalents, = (1 g + 35.5 g)/L = 36.5 g/L WATER, ELECTROLYTES, & ACID/BASE The water molecule (H O) is an ideal solvent for physiological reactions H 2O has a dipole moment where oxygen slightly pulls away electrons from the hydrogen atoms and creates a charge separation that makes the molecule polar This allows water to dissolve a variety of charged atoms and molecules It also allows the H2O molecule to interact with other H O molecules via hydrogen bonding The resultant hydrogen bond network in water allows for several key properties in physiology: (1) water has a high surface tension, (2) water has a high heat of vaporization and heat capacity, and (3) water has a high dielectric constant In layman's terms, H O is an excellent biological fluid that serves as a solute; it provides optimal heat transfer and conduction of current Electrolytes (eg, NaCl) are molecules that dissociate in water to their cation (Na +) and anion (Cl– ) equivalents Because of the net charge on water molecules, these electrolytes tend not to reassociate in water There are many important electrolytes in physiology, notably Na +, K+, Ca2+, Mg2+, Cl– , and HCO3 – It is important to note that electrolytes and other charged compounds (eg, proteins) are unevenly distributed in the body fluids (Figure 1–1B) 8/18/2009 3:04 AM AccessMedicine | Print: Chapter General Principles & Energy Productio of 44 http://www.accessmedicine.com/popup.aspx?aID=5242839&print=yes_c These separations play an important role in physiology PH AND BUFFERING The maintenance of a stable hydrogen ion concentration ([H +]) in body fluids is essential to life The pH of a solution is defined as the logarithm to the base 10 of the reciprocal of the H + concentration ([H +]), ie, the negative logarithm of the [H +] The pH of water at 25 °C, in which H + and OH – ions are present in equal numbers, is 7.0 (Figure 1–2) For each pH unit less than 7.0, the [H +] is increased tenfold; for each pH unit above 7.0, it is decreased tenfold In the plasma of healthy individuals, pH is slightly alkaline, maintained in the narrow range of 7.35 to 7.45 Conversely, gastric fluid pH can be quite acidic (on the order of 2.0) and pancreatic secretions can be quite alkaline (on the order of 8.0) Enzymatic activity and protein structure are frequently sensitive to pH; in any given body or cellular compartment, pH is maintained to allow for maximal enzyme/protein efficiency Figure 1–2 Proton concentration and pH Relative proton (H+) concentrations for solutions on a pH scale are shown (Redrawn from Alberts B et al: Molecular Biology of the Cell, 4th ed Garland Science, 2002.) Molecules that act as H + donors in solution are considered acids, while those that tend to remove H + from solutions are considered bases Strong acids (eg, HCl) or bases (eg, NaOH) dissociate completely in water and thus can most change the [H +] in solution In physiological compounds, most acids or bases are considered "weak," that is, they contribute relatively few H + or take away relatively few H + from solution Body pH is stabilized by the buffering capacity of the body fluids A buffer is a substance that has the ability to bind or release H + in solution, thus keeping the pH of the solution relatively constant despite the addition of considerable quantities of acid or base Of course there are a number of buffers at work in biological fluids at any given time All buffer pairs in a homogenous solution are in equilibrium with the same [H +]; this is known as the isohydric principle One outcome of this principle is that by assaying a single buffer system, we can understand a great deal about all of the biological buffers in that system When acids are placed into solution, there is a dissociation of some of the component acid (HA) into its proton (H +) and free acid (A– ) This is frequently written as an equation: According to the laws of mass action, a relationship for the dissociation can be defined mathematically as: where Ka is a constant, and the brackets represent concentrations of the individual species In layman's terms, the product of the proton concentration ([H +]) times the free acid concentration ([A– ]) divided by the bound acid 8/18/2009 3:04 AM AccessMedicine | Print: Chapter General Principles & Energy Productio of 44 http://www.accessmedicine.com/popup.aspx?aID=5242839&print=yes_c concentration ([HA]) is a defined constant (K) This can be rearranged to read: If the logarithm of each side is taken: Both sides can be multiplied by –1 to yield: This can be written in a more conventional form known as the Henderson Hasselbach equation: This relatively simple equation is quite powerful One thing that we can discern right away is that the buffering capacity of a particular weak acid is best when the pKa of that acid is equal to the pH of the solution, or when: Similar equations can be set up for weak bases An important buffer in the body is carbonic acid Carbonic acid is a weak acid, and thus is only partly dissociated into H + and bicarbonate: If H+ is added to a solution of carbonic acid, the equilibrium shifts to the left and most of the added H + is removed from solution If OH – is added, H+ and OH – combine, taking H + out of solution However, the decrease is countered by more dissociation of H 2CO3, and the decline in H+ concentration is minimized A unique feature of bicarbonate is the linkage between its buffering ability and the ability for the lungs to remove carbon dioxide from the body Other important biological buffers include phosphates and proteins DIFFUSION Diffusion is the process by which a gas or a substance in a solution expands, because of the motion of its particles, to fill all the available volume The particles (molecules or atoms) of a substance dissolved in a solvent are in continuous random movement A given particle is equally likely to move into or out of an area in which it is present in high concentration However, because there are more particles in the area of high concentration, the total number of particles moving to areas of lower concentration is greater; that is, there is a net flux of solute particles from areas of high to areas of low concentration The time required for equilibrium by diffusion is proportionate to the square of the diffusion distance The magnitude of the diffusing tendency from one region to another is directly proportionate to the cross-sectional area across which diffusion is taking place and the concentration gradient, or chemical gradient, which is the difference in concentration of the diffusing substance divided by the thickness of the boundary (Fick's law of diffusion) Thus, where J is the net rate of diffusion, D is the diffusion coefficient, A is the area, and c/ x is the concentration gradient The minus sign indicates the direction of diffusion When considering movement of molecules from a higher to a lower concentration, c/ x is negative, so multiplying by –DA gives a positive value The permeabilities of the boundaries across which diffusion occurs in the body vary, but diffusion is still a major force affecting the distribution of water and solutes OSMOSIS When a substance is dissolved in water, the concentration of water molecules in the solution is less than that in pure water, because the addition of solute to water results in a solution that occupies a greater volume than does the water alone If the solution is placed on one side of a membrane that is permeable to water but not to the solute, and an equal volume of water is placed on the other, water molecules diffuse down their concentration (chemical) gradient into the solution (Figure 1–3) This process—the diffusion of solvent molecules into a region in which there is a higher concentration of a solute to which the membrane is impermeable—is called osmosis It is an important factor in physiologic processes The tendency for movement of solvent molecules to a region of greater solute concentration can be prevented by applying pressure to the more concentrated solution The pressure necessary to prevent solvent migration is the osmotic pressure of the solution 8/18/2009 3:04 AM AccessMedicine | Print: Chapter General Principles & Energy Productio of 44 http://www.accessmedicine.com/popup.aspx?aID=5242839&print=yes_c Figure 1–3 Diagrammatic representation of osmosis Water molecules are represented by small open circles, solute molecules by large solid circles In the diagram on the left, water is placed on one side of a membrane permeable to water but not to solute, and an equal volume of a solution of the solute is placed on the other Water molecules move down their concentration (chemical) gradient into the solution, and, as shown in the diagram on the right, the volume of the solution increases As indicated by the arrow on the right, the osmotic pressure is the pressure that would have to be applied to prevent the movement of the water molecules Osmotic pressure—like vapor pressure lowering, freezing-point depression, and boiling-point elevation—depends on the number rather than the type of particles in a solution; that is, it is a fundamental colligative property of solutions In an ideal solution, osmotic pressure (P) is related to temperature and volume in the same way as the pressure of a gas: where n is the number of particles, R is the gas constant, T is the absolute temperature, and V is the volume If T is held constant, it is clear that the osmotic pressure is proportional to the number of particles in solution per unit volume of solution For this reason, the concentration of osmotically active particles is usually expressed in osmoles One osmole (Osm) equals the gram-molecular weight of a substance divided by the number of freely moving particles that each molecule liberates in solution For biological solutions, the milliosmole (mOsm; 1/1000 of Osm) is more commonly used If a solute is a nonionizing compound such as glucose, the osmotic pressure is a function of the number of glucose molecules present If the solute ionizes and forms an ideal solution, each ion is an osmotically active particle For example, NaCl would dissociate into Na+ and Cl– ions, so that each mole in solution would supply Osm One mole of Na2 SO4 would dissociate into Na+, Na+, and SO4 2– supplying Osm However, the body fluids are not ideal solutions, and although the dissociation of strong electrolytes is complete, the number of particles free to exert an osmotic effect is reduced owing to interactions between the ions Thus, it is actually the effective concentration (activity) in the body fluids rather than the number of equivalents of an electrolyte in solution that determines its osmotic capacity This is why, for example, mmol of NaCl per liter in the body fluids contributes somewhat less than mOsm of osmotically active particles per liter The more concentrated the solution, the greater the deviation from an ideal solution The osmolal concentration of a substance in a fluid is measured by the degree to which it depresses the freezing point, with mol of an ideal solution depressing the freezing point 1.86 °C The number of milliosmoles per liter in a solution equals the freezing point depression divided by 0.00186 The osmolarity is the number of osmoles per liter of solution (eg, plasma), whereas the osmolality is the number of osmoles per kilogram of solvent Therefore, osmolarity is affected by the volume of the various solutes in the solution and the temperature, while the osmolality is not Osmotically active substances in the body are dissolved in water, and the density of water is 1, so osmolal concentrations can be expressed as osmoles per liter (Osm/L) of water In this book, osmolal (rather than osmolar) concentrations are considered, and osmolality is expressed in milliosmoles per liter (of water) Note that although a homogeneous solution contains osmotically active particles and can be said to have an osmotic 8/18/2009 3:04 AM AccessMedicine | Print: Chapter General Principles & Energy Productio of 44 http://www.accessmedicine.com/popup.aspx?aID=5242839&print=yes_c pressure, it can exert an osmotic pressure only when it is in contact with another solution across a membrane permeable to the solvent but not to the solute OSMOLAL CONCENTRATION OF PLASMA: TONICITY The freezing point of normal human plasma averages –0.54 °C, which corresponds to an osmolal concentration in plasma of 290 mOsm/L This is equivalent to an osmotic pressure against pure water of 7.3 atm The osmolality might be expected to be higher than this, because the sum of all the cation and anion equivalents in plasma is over 300 It is not this high because plasma is not an ideal solution and ionic interactions reduce the number of particles free to exert an osmotic effect Except when there has been insufficient time after a sudden change in composition for equilibrium to occur, all fluid compartments of the body are in (or nearly in) osmotic equilibrium The term tonicity is used to describe the osmolality of a solution relative to plasma Solutions that have the same osmolality as plasma are said to be isotonic; those with greater osmolality are hypertonic; and those with lesser osmolality are hypotonic All solutions that are initially isosmotic with plasma (ie, that have the same actual osmotic pressure or freezing-point depression as plasma) would remain isotonic if it were not for the fact that some solutes diffuse into cells and others are metabolized Thus, a 0.9% saline solution remains isotonic because there is no net movement of the osmotically active particles in the solution into cells and the particles are not metabolized On the other hand, a 5% glucose solution is isotonic when initially infused intravenously, but glucose is metabolized, so the net effect is that of infusing a hypotonic solution It is important to note the relative contributions of the various plasma components to the total osmolal concentration of plasma All but about 20 of the 290 mOsm in each liter of normal plasma are contributed by Na+ and its accompanying anions, principally Cl– and HCO3– Other cations and anions make a relatively small contribution Although the concentration of the plasma proteins is large when expressed in grams per liter, they normally contribute less than mOsm/L because of their very high molecular weights The major nonelectrolytes of plasma are glucose and urea, which in the steady state are in equilibrium with cells Their contributions to osmolality are normally about mOsm/L each but can become quite large in hyperglycemia or uremia The total plasma osmolality is important in assessing dehydration, overhydration, and other fluid and electrolyte abnormalities (Clinical Box 1–1) Clinical Box 1–1 Plasma Osmolality & Disease Unlike plant cells, which have rigid walls, animal cell membranes are flexible Therefore, animal cells swell when exposed to extracellular hypotonicity and shrink when exposed to extracellular hypertonicity Cells contain ion channels and pumps that can be activated to offset moderate changes in osmolality; however, these can be overwhelmed under certain pathologies Hyperosmolality can cause coma (hyperosmolar coma) Because of the predominant role of the major solutes and the deviation of plasma from an ideal solution, one can ordinarily approximate the plasma osmolality within a few mosm/liter by using the following formula, in which the constants convert the clinical units to millimoles of solute per liter: Osmolality (mOsm/L) = 2[Na+] (mEq/L) + 0.055[Glucose] (mg/dL) + 0.36[BUN] (mg/dL) BUN is the blood urea nitrogen The formula is also useful in calling attention to abnormally high concentrations of other solutes An observed plasma osmolality (measured by freezing- point depression) that greatly exceeds the value predicted by this formula probably indicates the presence of a foreign substance such as ethanol, mannitol (sometimes injected to shrink swollen cells osmotically), or poisons such as ethylene glycol or methanol (components of antifreeze) NONIONIC DIFFUSION Some weak acids and bases are quite soluble in cell membranes in the undissociated form, whereas they cannot cross membranes in the charged (ie, dissociated) form Consequently, if molecules of the undissociated substance diffuse from one side of the membrane to the other and then dissociate, there is appreciable net movement of the undissociated substance from one side of the membrane to the other This phenomenon is called nonionic diffusion DONNAN EFFECT When an ion on one side of a membrane cannot diffuse through the membrane, the distribution of other ions to which 8/18/2009 3:04 AM AccessMedicine | Print: Chapter General Principles & Energy Productio of 44 http://www.accessmedicine.com/popup.aspx?aID=5242839&print=yes_c the membrane is permeable is affected in a predictable way For example, the negative charge of a nondiffusible anion hinders diffusion of the diffusible cations and favors diffusion of the diffusible anions Consider the following situation, in which the membrane (m) between compartments X and Y is impermeable to charged proteins (Prot– ) but freely permeable to K+ and Cl– Assume that the concentrations of the anions and of the cations on the two sides are initially equal Cl– diffuses down its concentration gradient from Y to X, and some K+ moves with the negatively charged Cl– because of its opposite charge Therefore Furthermore, that is, more osmotically active particles are on side X than on side Y Donnan and Gibbs showed that in the presence of a nondiffusible ion, the diffusible ions distribute themselves so that at equilibrium their concentration ratios are equal: Cross-multiplying, This is the Gibbs–Donnan equation It holds for any pair of cations and anions of the same valence The Donnan effect on the distribution of ions has three effects in the body introduced here and discussed below First, because of charged proteins (Prot–) in cells, there are more osmotically active particles in cells than in interstitial fluid, and because animal cells have flexible walls, osmosis would make them swell and eventually rupture if it were not for Na, K ATPase pumping ions back out of cells Thus, normal cell volume and pressure depend on Na, K ATPase Second, because at equilibrium the distribution of permeant ions across the membrane (m in the example used here) is asymmetric, an electrical difference exists across the membrane whose magnitude can be determined by the Nernst equation In the example used here, side X will be negative relative to side Y The charges line up along the membrane, with the concentration gradient for Cl – exactly balanced by the oppositely directed electrical gradient, and the same holds true for K+ Third, because there are more proteins in plasma than in interstitial fluid, there is a Donnan effect on ion movement across the capillary wall FORCES ACTING ON IONS The forces acting across the cell membrane on each ion can be analyzed mathematically Chloride ions (Cl– ) are present in higher concentration in the ECF than in the cell interior, and they tend to diffuse along this concentration gradient into the cell The interior of the cell is negative relative to the exterior, and chloride ions are pushed out of the cell along this electrical gradient An equilibrium is reached between Cl– influx and Cl– efflux The membrane potential at which this equilibrium exists is the equilibrium potential Its magnitude can be calculated from the Nernst equation, as follows: where 8/18/2009 3:04 AM AccessMedicine | Print: Chapter General Principles & Energy Productio 10 of 44 http://www.accessmedicine.com/popup.aspx?aID=5242839&print=yes_c ECl = equilibrium potential for Cl– R = gas constant T = absolute temperature F = the faraday (number of coulombs per mole of charge) ZCl = valence of Cl– (–1) [Clo – ] = Cl– concentration outside the cell [Cli–] = Cl– concentration inside the cell Converting from the natural log to the base 10 log and replacing some of the constants with numerical values, the equation becomes: Note that in converting to the simplified expression the concentration ratio is reversed because the –1 valence of Cl– has been removed from the expression The equilibrium potential for Cl– (ECl), calculated from the standard values listed in Table 1–1, is –70 mV, a value identical to the measured resting membrane potential of –70 mV Therefore, no forces other than those represented by the chemical and electrical gradients need be invoked to explain the distribution of Cl– across the membrane Table 1–1 Concentration of Some Ions Inside and Outside Mammaliam Spinal Motor Neurons Ion Concentration (mmol/L of H2 O) Equilibrium Potential (mV) Inside Cell Outside Cell Na+ 15.0 150.0 +60 K+ 150.0 5.5 –90 Cl– 9.0 125.0 –70 Resting membrane potential = –70 mV A similar equilibrium potential can be calculated for K+ (EK): where EK = equilibrium potential for K+ ZK = valence of K+ (+1) [Ko +] = K+ concentration outside the cell [Ki+] = K+ concentration inside the cell R, T, and F as above In this case, the concentration gradient is outward and the electrical gradient inward In mammalian spinal motor neurons, EK is –90 mV (Table 1–1) Because the resting membrane potential is –70 mV, there is somewhat more K+ in 8/18/2009 3:04 AM AccessMedicine | Print: Chapter 39 Regulation of Extracellular Fluid C 21 of 22 http://www.accessmedicine.com/popup.aspx?aID=5244208&print=yes_c maturation is a relatively slow process Loss of even a small portion of the sialic acid residues in the carbohydrate moieties that are part of the erythropoietin molecule shortens its half-life to min, making it biologically ineffective SOURCES In adults, about 85% of the erythropoietin comes from the kidneys and 15% from the liver Both these organs contain the mRNA for erythropoietin Erythropoietin can also be extracted from the spleen and salivary glands, but these tissues not contain the mRNA and consequently not appear to manufacture the hormone When renal mass is reduced in adults by renal disease or nephrectomy, the liver cannot compensate and anemia develops Erythropoietin is produced by interstitial cells in the peritubular capillary bed of the kidneys and by perivenous hepatocytes in the liver It is also produced in the brain, where it exerts a protective effect against excitotoxic damage triggered by hypoxia; and in the uterus and oviducts, where it is induced by estrogen and appears to mediate estrogen-dependent angiogenesis The gene for the hormone has been cloned, and recombinant erythropoietin produced in animal cells is available for clinical use as epoetin alfa The recombinant erythropoietin is of value in the treatment of the anemia associated with renal failure; 90% of the patients with end-stage renal failure who are on dialysis are anemic as a result of erythropoietin deficiency Erythropoietin is also used to stimulate red cell production in individuals who are banking a supply of their own blood in preparation for autologous transfusions during elective surgery (see Chapter 32) REGULATION OF SECRETION The usual stimulus for erythropoietin secretion is hypoxia, but secretion of the hormone can also be stimulated by cobalt salts and androgens Recent evidence suggests that the O sensor regulating erythropoietin secretion in the kidneys and the liver is a heme protein that in the deoxy form stimulates and in the oxy form inhibits transcription of the erythropoietin gene to form erythropoietin mRNA Secretion of the hormone is facilitated by the alkalosis that develops at high altitudes Like renin secretion, erythropoietin secretion is facilitated by catecholamines via a -adrenergic mechanism, although the renin–angiotensin system is totally separate from the erythropoietin system CHAPTER SUMMARY Total body osmolality is directly proportional to the total body sodium plus the total body potassium divided by the total body water Changes in the osmolality of the body fluids occur when a disproportion exists between the amount of these electrolytes and the amount of water ingested or lost from the body Vasopressin's main physiologic effect is the retention of water by the kidney by increasing the water permeability of the renal collecting ducts Water is absorbed from the urine, the urine becomes concentrated, and its volume decreases Vasopressin is stored in the posterior pituitary and released into the bloodstream in response to the stimulation of osmoreceptors or baroreceptors Increases in secretion occur when osmolality is changed as little as 1%, thus keeping the osmolality of the plasma very close to 285 mOsm/L The amount of Na + in the ECF is the most important determinant of ECF volume, and mechanisms that control Na+ balance are the major mechanisms defending ECF volume The main mechanism regulating sodium balance is the renin–angiotensin system, a hormone system that regulates blood pressure The kidneys secrete the enzymerenin and renin acts in concert with angiotensin-converting enzyme to form angiotensin II Angiotensin II acts directly on the adrenal cortex to increase the secretion of aldosterone Aldosterone increases the retention of sodium from the urine via action on the renal collecting duct CHAPTER RESOURCES Adrogue HJ, Madias NE: Hypernatremia N Engl J Med 2000;342:1493 [PMID: 10816188] Adrogue HJ, Madias NE: Hyponatremia N Engl J Med 2000;342:101 8/18/2009 4:25 AM AccessMedicine | Print: Chapter 39 Regulation of Extracellular Fluid C 22 of 22 http://www.accessmedicine.com/popup.aspx?aID=5244208&print=yes_c Corvol P, Jeunemaitre X: Molecular genetics of human hypertension: Role of angiotensinogen Endocr Rev 1997;18:662 [PMID: 9331547] Morel F: Sites of hormone action in the mammalian nephron Am J Physiol 1981;240:F159 McKinley MS, Johnson AK: The physiologic regulation of thirst and fluid intake News Physiol Sci 2004;19:1 [PMID: 14739394] Robinson AG, Verbalis JG: Diabetes insipidus Curr Ther Endocrinol Metab 1997;6:1 [PMID: 9174688] Verkman AS: Mammalian aquaporins: Diverse physiological roles and potential clinical significance Expert Rev Mol Med 2008;10:13 Zeidel ML: Hormonal regulation of inner medullary collecting duct sodium transport Am J Physiol 1993;265:F159 Copyright © The McGraw-Hill Companies All rights reserved Privacy Notice Any use is subject to the Terms of Use and Notice 8/18/2009 4:25 AM AccessMedicine | Print: Chapter 40 Acidification of the Urine & Bicarbo of 13 http://www.accessmedicine.com/popup.aspx?aID=5244357&print=yes_c Print Close Window Note: Large images and tables on this page may necessitate printing in landscape mode Copyright © The McGraw-Hill Companies All rights reserved Ganong's Review of Medical Physiology > Chapter 40 Acidification of the Urine & Bicarbonate Excretion > OBJECTIVES After reading this chapter, you should be able to: Outline the processes involved in the secretion of H + into the tubules and discuss the significance of these processes in the regulation of acid–base balance Define acidosis and alkalosis, and give (in mEq/L and pH) the normal mean and the range of H+ concentrations in blood that are compatible with health List the principal buffers in blood, interstitial fluid, and intracellular fluid, and, using the Henderson– Hasselbalch equation, describe what is unique about the bicarbonate buffer system Describe the changes in blood chemistry that occur during the development of metabolic acidosis and metabolic alkalosis, and the respiratory and renal compensations for these conditions Describe the changes in blood chemistry that occur during the development of respiratory acidosis and respiratory alkalosis, and the renal compensation for these conditions RENAL H+ SECRETION The cells of the proximal and distal tubules, like the cells of the gastric glands, secrete hydrogen ions (see Chapter 26) Acidification also occurs in the collecting ducts The reaction that is primarily responsible for H + secretion in the proximal tubules is Na–H exchange (Figure 40–1) This is an example of secondary active transport; extrusion of Na+ from the cells into the interstitium by Na, K ATPase lowers intracellular Na +, and this causes Na+ to enter the cell from the tubular lumen, with coupled extrusion of H + The H+ comes from intracellular dissociation of H CO3 , and the HCO3 – that is formed diffuses into the interstitial fluid Thus, for each H+ ion secreted, one Na+ ion and one HCO3– ion enter the interstitial fluid Figure 40–1 8/18/2009 4:27 AM AccessMedicine | Print: Chapter 40 Acidification of the Urine & Bicarbo of 13 http://www.accessmedicine.com/popup.aspx?aID=5244357&print=yes_c Secretion of acid by proximal tubular cells in the kidney H+ is transported into the tubular lumen by an antiport in exchange for Na+ Active transport by Na, K ATPase is indicated by arrows in the circle Dashed arrows indicate diffusion Carbonic anhydrase catalyzes the formation of H CO3 , and drugs that inhibit carbonic anhydrase depress both secretion of acid by the proximal tubules and the reactions which depend on it Some evidence suggests that H + is secreted in the proximal tubules by other types of pumps, but the evidence for these additional pumps is controversial, and in any case, their contribution is small relative to that of the Na–H exchange mechanism This is in contrast to what occurs in the distal tubules and collecting ducts, where H + secretion is relatively independent of Na+ in the tubular lumen In this part of the tubule, most H + is secreted by an ATP-driven proton pump Aldosterone acts on this pump to increase distal H + secretion The I cells in this part of the renal tubule secrete acid and, like the parietal cells in the stomach, contain abundant carbonic anhydrase and numerous tubulovesicular structures There is evidence that the H +-translocating ATPase that produces H + secretion is located in these vesicles as well as in the luminal cell membrane and that, in acidosis, the number of H+ pumps is increased by insertion of these tubulovesicles into the luminal cell membrane Some of the H + is also secreted by H–K+ ATPase The I cells contain Band 3, an anion exchange protein, in their basolateral cell membranes, and this protein may function as a Cl/HCO3 exchanger for the transport of HCO3 – to the interstitial fluid FATE OF H+ IN THE URINE The amount of acid secreted depends upon the subsequent events in the tubular urine The maximal H + gradient against which the transport mechanisms can secrete in humans corresponds to a urine pH of about 4.5; that is, an H+ concentration in the urine that is 1000 times the concentration in plasma pH 4.5 is thus the limiting pH This is normally reached in the collecting ducts If there were no buffers that "tied up" H+ in the urine, this pH would be reached rapidly, and H + secretion would stop However, three important reactions in the tubular fluid remove free H +, permitting more acid to be secreted (Figure 40–2) These are the reactions with HCO3 – to form CO2 and H2 O, with HPO4 2– to form H2 PO4 – , and with NH3 to form NH4 + Figure 40–2 8/18/2009 4:27 AM AccessMedicine | Print: Chapter 40 Acidification of the Urine & Bicarbo of 13 http://www.accessmedicine.com/popup.aspx?aID=5244357&print=yes_c Fate of H+ secreted into a tubule in exchange for Na+ Top: Reabsorption of filtered bicarbonate via CO2 Middle: Formation of monobasic phosphate Bottom: Ammonium formation Note that in each instance one Na+ ion and one HCO3– ion enter the bloodstream for each H + ion secreted A –, anion REACTION WITH BUFFERS The dynamics of buffering are discussed in Chapter and below The pK' of the bicarbonate system is 6.1, that of the dibasic phosphate system is 6.8, and that of the ammonia system is 9.0 The concentration of HCO3 – in the plasma, and consequently in the glomerular filtrate, is normally about 24 mEq/L, whereas that of phosphate is only 1.5 mEq/L Therefore, in the proximal tubule, most of the secreted H + reacts with HCO3 – to form H2 CO3 (Figure 40–2) The H CO3 breaks down to form CO2 and H2 O In the proximal (but not in the distal) tubule, there is carbonic anhydrase in the brush border of the cells; this facilitates the formation of CO2 and H 2O in the tubular fluid The CO2 , which diffuses readily across all biological membranes, enters the tubular cells, where it adds to the pool of CO2 available to form H CO3 Because most of the H + is removed from the tubule, the pH of the fluid is changed very little This is the mechanism by which HCO3 – is reabsorbed; for each mole of HCO3 – removed from the tubular fluid, mol of HCO3– diffuses from the tubular cells into the blood, even though it is not the same mole that disappeared from the tubular fluid Secreted H + also reacts with dibasic phosphate (HPO42– ) to form monobasic phosphate (H PO4 –) This happens to the greatest extent in the distal tubules and collecting ducts, because it is here that the phosphate that escapes proximal reabsorption is greatly concentrated by the reabsorption of water The reaction with NH occurs in the proximal and distal tubules H + also combines to a minor degree with other buffer anions Each H+ ion that reacts with the buffers contributes to the urinary titratable acidity, which is measured by determining the amount of alkali that must be added to the urine to return its pH to 7.4, the pH of the 8/18/2009 4:27 AM AccessMedicine | Print: Chapter 40 Acidification of the Urine & Bicarbo of 13 http://www.accessmedicine.com/popup.aspx?aID=5244357&print=yes_c glomerular filtrate However, the titratable acidity obviously measures only a fraction of the acid secreted, since it does not account for the H 2CO3 that has been converted to H O and CO2 In addition, the pK' of the ammonia system is 9.0, and the ammonia system is titrated only from the pH of the urine to pH 7.4, so it contributes very little to the titratable acidity AMMONIA SECRETION Reactions in the renal tubular cells produce NH + and HCO3 – NH4 + is in equilibrium with NH and H+ in the cells Because the pK' of this reaction is 9.0, the ratio of NH to NH4 + at pH 7.0 is 1:100 (Figure 40–3) However, NH3 is lipid-soluble and diffuses across the cell membranes down its concentration gradient into the interstitial fluid and tubular urine In the urine it reacts with H + to form NH4 +, and the NH4 + remains in the urine Figure 40–3 Major reactions involved in ammonia production in the kidneys The principal reaction producing NH + in cells is conversion of glutamine to glutamate This reaction is catalyzed by the enzyme glutaminase, which is abundant in renal tubular cells (Figure 40–3) Glutamic dehydrogenase catalyzes the conversion of glutamate to -ketoglutarate, with the production of more NH + Subsequent metabolism of -ketoglutarate utilizes 2H +, freeing 2HCO3 – In chronic acidosis, the amount of NH + excreted at any given urine pH also increases, because more NH enters the tubular urine The effect of this adaptation of NH3 secretion, the cause of which is unsettled, is a further removal of H + from the tubular fluid and consequently a further enhancement of H + secretion The process by which NH is secreted into the urine and then changed to NH 4+, maintaining the concentration gradient for diffusion of NH , is called nonionic diffusion (see Chapter 2) Salicylates and a number of other drugs that are weak bases or weak acids are also secreted by nonionic diffusion They diffuse into the tubular fluid at a rate that depends on the pH of the urine, so the amount of each drug excreted varies with the pH of the urine PH CHANGES ALONG THE NEPHRONS A moderate drop in pH occurs in the proximal tubular fluid, but, as noted above, most of the secreted H + has little effect on luminal pH because of the formation of CO2 and H2 O from H 2CO3 In contrast, the distal tubule has less capacity to secrete H +, but secretion in this segment has a greater effect on urinary pH FACTORS AFFECTING ACID SECRETION Renal acid secretion is altered by changes in the intracellular P CO , K+ concentration, carbonic anhydrase level, and adrenocortical hormone concentration When the P CO is high (respiratory acidosis), more intracellular 8/18/2009 4:27 AM AccessMedicine | Print: Chapter 40 Acidification of the Urine & Bicarbo of 13 http://www.accessmedicine.com/popup.aspx?aID=5244357&print=yes_c H2 CO3 is available to buffer the hydroxyl ions and acid secretion is enhanced, whereas the reverse is true when the PCO2 falls K+ depletion enhances acid secretion, apparently because the loss of K+ causes intracellular acidosis even though the plasma pH may be elevated Conversely, K+ excess in the cells inhibits acid secretion When carbonic anhydrase is inhibited, acid secretion is inhibited because the formation of H 2CO3 is decreased Aldosterone and the other adrenocortical steroids that enhance tubular reabsorption of Na+ also increase the secretion of H + and K+ BICARBONATE EXCRETION Although the process of HCO3 – reabsorption does not actually involve transport of this ion into the tubular cells, HCO3– reabsorption is proportional to the amount filtered over a relatively wide range There is no demonstrable Tm, but HCO3 – reabsorption is decreased by an unknown mechanism when the extracellular fluid (ECF) volume is expanded (Figure 40–4) When the plasma HCO3 – concentration is low, all the filtered HCO3 – is reabsorbed; but when the plasma HCO3– concentration is high; that is, above 26 to 28 mEq/L (the renal threshold for HCO3 –), HCO3– appears in the urine and the urine becomes alkaline Conversely, when the plasma HCO3– falls below about 26 mEq/L, the value at which all the secreted H + is being used to reabsorb HCO3– , more H+ becomes available to combine with other buffer anions Therefore, the lower the plasma HCO3 – concentration drops, the more acidic the urine becomes and the greater its NH + content (see Clinical Box 40–1) Figure 40–4 Effect of ECF volume on HCO3– filtration, reabsorption, and excretion in rats The pattern of HCO3– excretion is similar in humans The plasma HCO3– concentration is normally about 24 mEq/L (Reproduced with permission from Valtin H: Renal Function, 2nd ed Little, Brown, 1983.) Clinical Box 40–1 8/18/2009 4:27 AM AccessMedicine | Print: Chapter 40 Acidification of the Urine & Bicarbo of 13 http://www.accessmedicine.com/popup.aspx?aID=5244357&print=yes_c Implications of Urinary pH Changes Depending on the rates of the interrelated processes of acid secretion, NH + production, and HCO3 – excretion, the pH of the urine in humans varies from 4.5 to 8.0 Excretion of urine that is at a pH different from that of the body fluids has important implications for the body's electrolyte and acid–base economy Acids are buffered in the plasma and cells, the overall reaction being HA + NaH NaA + H2 CO3 The H2 CO3 forms CO2 and H2 O, and the CO2 is expired, while the NaA appears in the glomerular filtrate To the extent that the Na+ is replaced by H + in the urine, Na+ is conserved in the body Furthermore, for each H + ion excreted with phosphate or as NH4 +, there is a net gain of one HCO3 – ion in the blood, replenishing the supply of this important buffer anion Conversely, when base is added to the body fluids, the OH – ions are buffered, raising the plasma HCO3– When the plasma level exceeds 28 mEq/L, the urine becomes alkaline and the extra HCO 3– is excreted in the urine Because the rate of maximal H + secretion by the tubules varies directly with the arterial P CO2 , HCO3 – reabsorption also is affected by the PCO2 This relationship has been discussed in more detail in the text DEFENSE OF H+ CONCENTRATION The mystique that envelopes the subject of acid–base balance makes it necessary to point out that the core of the problem is not "buffer base" or "fixed cation" or the like, but simply the maintenance of the H + concentration of the ECF The mechanisms regulating the composition of the ECF are particularly important as far as this specific ion is concerned, because the machinery of the cells is very sensitive to changes in H + concentration Intracellular H + concentration, which can be measured by using microelectrodes, pH-sensitive fluorescent dyes, and phosphorus magnetic resonance, is different from extracellular pH and appears to be regulated by a variety of intracellular processes However, it is sensitive to changes in ECF H + concentration The pH notation is a useful means of expressing H + concentrations in the body, because the H + concentrations happen to be low relative to those of other cations Thus, the normal Na + concentration of arterial plasma that has been equilibrated with red blood cells is about 140 mEq/L, whereas the H + concentration is 0.00004 mEq/L (Table 40–1) The pH, the negative logarithm of 0.00004, is therefore 7.4 Of course, a decrease in pH of unit, for example, from 7.0 to 6.0, represents a 10-fold increase in H + concentration It is important to remember that the pH of blood is the pH of true plasma—plasma that has been in equilibrium with red cells—because the red cells contain hemoglobin, which is quantitatively one of the most important blood buffers (see Chapter 36) Table 40–1 H + Concentration and pH of Body Fluids H+ Concentration pH mEq/L mol/L Gastric HCI 150 0.15 0.8 Maximal urine acidity 0.03 x 10–5 4.5 Plasma Extreme acidosis 0.0001 x 10–7 7.0 Normal 0.00004 x 10–8 7.4 Extreme alkalosis 0.00002 x 10–8 7.7 0.00001 x 10–8 8.0 Pancreatic juice 8/18/2009 4:27 AM AccessMedicine | Print: Chapter 40 Acidification of the Urine & Bicarbo of 13 http://www.accessmedicine.com/popup.aspx?aID=5244357&print=yes_c H+ BALANCE The pH of the arterial plasma is normally 7.40 and that of venous plasma slightly lower Technically, acidosis is present whenever the arterial pH is below 7.40, and alkalosis is present whenever it is above 7.40, although variations of up to 0.05 pH unit occur without untoward effects The H + concentrations in the ECF that are compatible with life cover an approximately fivefold range, from 0.00002 mEq/L (pH 7.70) to 0.0001 mEq/L (pH 7.00) Amino acids are utilized in the liver for gluconeogenesis, leaving NH + and HCO3 – as products from their amino and carboxyl groups (Figure 40–5) The NH + is incorporated into urea and the protons that are formed are buffered intracellularly by HCO3 – , so little NH4 + and HCO3 – escape into the circulation However, metabolism of sulfur-containing amino acids produces H 2SO4, and metabolism of phosphorylated amino acids such as phosphoserine produces H PO4 These strong acids enter the circulation and present a major H + load to the buffers in the ECF The H + load from amino acid metabolism is normally about 50 mEq/d The CO formed by metabolism in the tissues is in large part hydrated to H CO3 (see Chapter 36), and the total H + load from this source is over 12,500 mEq/d However, most of the CO is excreted in the lungs, and only small quantities of the H+ remain to be excreted by the kidneys Common sources of extra acid loads are strenuous exercise (lactic acid), diabetic ketosis (acetoacetic acid and -hydroxybutyric acid), and ingestion of acidifying salts such as NH4 Cl and CaCl2, which in effect add HCl to the body Failure of diseased kidneys to excrete normal amounts of acid is also a cause of acidosis Fruits are the main dietary source of alkali They contain Na+ and K+ salts of weak organic acids, and the anions of these salts are metabolized to CO2 , leaving NaHCO3 and KHCO3 in the body NaHCO3 and other alkalinizing salts are sometimes ingested in large amounts, but a more common cause of alkalosis is loss of acid from the body as a result of vomiting of gastric juice rich in HCl This is, of course, equivalent to adding alkali to the body Figure 40–5 Role of the liver and kidneys in the handling of metabolically produced acid loads Sites where regulation occurs are indicated by asterisks (Modified and reproduced with permission from Knepper MA, et al: Ammonium, urea, and systemic pH regulation Am J Physiol 1987;235:F199.) 8/18/2009 4:27 AM AccessMedicine | Print: Chapter 40 Acidification of the Urine & Bicarbo of 13 http://www.accessmedicine.com/popup.aspx?aID=5244357&print=yes_c BUFFERING Buffering is of key importance in maintaining H + homeostasis It is defined in Chapter and discussed in Chapter 36 in the context of gas transport, with an emphasis on roles for proteins, hemoglobin and the carbonic anhydrase system in the blood Carbonic anhydrase is also found in high concentration in gastric acid-secreting cells (see Chapter 26) and in renal tubular cells (see Chapter 38) Carbonic anhydrase is a protein with a molecular weight of 30,000 that contains an atom of zinc in each molecule It is inhibited by cyanide, azide, and sulfide The sulfonamides also inhibit this enzyme, and sulfonamide derivatives have been used clinically as diuretics because of their inhibitory effects on carbonic anhydrase in the kidney (see Chapter 38) Buffering in vivo is, of course, not limited to the blood The principal buffers in the blood, interstitial fluid, and intracellular fluid are listed in Table 40–2 The principal buffers in cerebrospinal fluid (CSF) and urine are the bicarbonate and phosphate systems In metabolic acidosis, only 15–20% of the acid load is buffered by the H2 CO3 –HCO3– system in the ECF, and most of the remainder is buffered in cells In metabolic alkalosis, about 30–35% of the OH – load is buffered in cells, whereas in respiratory acidosis and alkalosis, almost all the buffering is intracellular Table 40–2 Principal Buffers in Body Fluids Blood H 2CO3 ⇆ H + + HCO3 – HProt ⇆ H+ + Prot– HHb ⇆ H+ + Hb– Interstitial fluid H 2CO3 ⇆ H + + HCO3 – Intracellular fluid HProt ⇆ H+ + Prot– H 2PO4 – ⇆ H+ + HPO4 2– In animal cells, the principal regulators of intracellular pH are HCO3 – transporters Those characterized to date include the Cl– HCO3– exchanger AE1 (formerly band 3), three Na+–HCO3 – cotransporters, and a K+–HCO3 – cotransporter SUMMARY When a strong acid is added to the blood, the major buffer reactions are driven to the left The blood levels of the three "buffer anions" Hb– (hemoglobin), Prot– (protein), and HCO3– consequently drop The anions of the added acid are filtered into the renal tubules They are accompanied ("covered") by cations, particularly Na+, because electrochemical neutrality is maintained By processes that have been discussed above, the tubules replace the Na+ with H+ and in so doing reabsorb equimolar amounts of Na+ and HCO3– , thus conserving the cations, eliminating the acid, and restoring the supply of buffer anions to normal When CO2 is added to the blood, similar reactions occur, except that since it is H CO3 that is formed, the plasma HCO3 – rises rather than falls RENAL COMPENSATION TO RESPIRATORY ACIDOSIS AND ALKALOSIS As noted in Chapter 36, a rise in arterial P CO due to decreased ventilation causes respiratory acidosis and conversely, a decline in PCO causes respiratory alkalosis The initial changes shown in Figure 40–6 are those that occur independently of any compensatory mechanism; that is, they are those of uncompensated 8/18/2009 4:27 AM AccessMedicine | Print: Chapter 40 Acidification of the Urine & Bicarbo of 13 http://www.accessmedicine.com/popup.aspx?aID=5244357&print=yes_c respiratory acidosis or alkalosis In either situation, changes are produced in the kidneys, which then tend to compensate for the acidosis or alkalosis, adjusting the pH toward normal Figure 40–6 Acid–base nomogram showing changes in the CO2 (curved lines), plasma HCO3–, and pH of arterial blood in respiratory and metabolic acidosis Note the shifts in HCO3– and pH as acute respiratory acidosis and alkalosis are compensated, producing their chronic counterparts (Reproduced with permission from Cogan MG, Rector FC Jr: Acid–base disorders In: The Kidney, 4th ed Brenner BM, Rector FC Jr [editors] Saunders, 1991.) HCO3– reabsorption in the renal tubules depends not only on the filtered load of HCO3 –, which is the product of the glomerular filtration rate (GFR) and the plasma HCO3 – level, but also on the rate of H + secretion by the renal tubular cells, since HCO3 – is reabsorbed by exchange for H + The rate of H + secretion—and hence the rate of HCO3– reabsorption—is proportional to the arterial P CO2 , probably because the more CO2 that is available to form H2 CO3 in the cells, the more H + can be secreted Furthermore, when the P CO2 is high, the interior of most cells becomes more acidic In respiratory acidosis, renal tubular H + secretion is therefore increased, removing H+ from the body; and even though the plasma HCO3– is elevated, HCO3 – reabsorption is increased, further raising the plasma HCO3 – This renal compensation for respiratory acidosis is shown graphically in the shift from acute to chronic respiratory acidosis in Figure 40–6 Cl – excretion is increased, and plasma Cl– falls as plasma HCO3– is increased Conversely, in respiratory alkalosis, the low P CO2 hinders renal H + secretion, HCO3 – reabsorption is depressed, and HCO3 – is excreted, further reducing the already low plasma HCO3 – and lowering the pH toward normal METABOLIC ACIDOSIS When acids stronger than HHb and the other buffer acids are added to blood, metabolic acidosis is produced; and when the free H + level falls as a result of addition of alkali or removal of acid, metabolic alkalosis results Following the example from Chapter 36, if H SO4 is added, the H+ is buffered and the Hb–, Prot–, and HCO3 – 8/18/2009 4:27 AM AccessMedicine | Print: Chapter 40 Acidification of the Urine & Bicarbo 10 of 13 http://www.accessmedicine.com/popup.aspx?aID=5244357&print=yes_c levels in plasma drop The H CO3 formed is converted to H O and CO2 , and the CO2 is rapidly excreted via the lungs This is the situation in uncompensated metabolic acidosis Actually, the rise in plasma H + stimulates respiration, so that the PCO , instead of rising or remaining constant, is reduced This respiratory compensation raises the pH even further The renal compensatory mechanisms then bring about the excretion of the extra H + and return the buffer systems to normal RENAL COMPENSATION The anions that replace HCO3 – in the plasma in metabolic acidosis are filtered, each with a cation (principally Na+), thus maintaining electrical neutrality The renal tubular cells secrete H + into the tubular fluid in exchange for Na+; and for each H + secreted, one Na+ and one HCO3– are added to the blood The limiting urinary pH of 4.5 would be reached rapidly and the total amount of H + secreted would be small if no buffers were present in the urine to "tie up" H + However, secreted H + reacts with HCO3 – to form CO2 and H 2O (bicarbonate reabsorption); with HPO4 2– to form H2 PO4– ; and with NH to form NH4 + In this way, large amounts of H + can be secreted, permitting correspondingly large amounts of HCO3 – to be returned to (in the case of bicarbonate reabsorption) or added to the depleted body stores and large numbers of the cations to be reabsorbed It is only when the acid load is very large that cations are lost with the anions, producing diuresis and depletion of body cation stores In chronic acidosis, glutamine synthesis in the liver is increased, using some of the NH + that usually is converted to urea (Figure 40–5), and the glutamine provides the kidneys with an additional source of NH4 + NH secretion increases over a period of days (adaptation of NH secretion), further improving the renal compensation for acidosis In addition, the metabolism of glutamine in the kidneys produces -ketoglutarate, and this in turn is decarboxylated, producing HCO3– , which enters the bloodstream and helps buffer the acid load (Figure 40–5) The overall reaction in blood when a strong acid such as H SO4 is added is: For each mole of H + added, mole of NaHCO3 is lost The kidney in effect reverses the reaction: and the H + and SO4 2– are excreted Of course, H SO4 is not excreted as such, the H + appearing in the urine as titratable acidity and NH 4+ In metabolic acidosis, the respiratory compensation tends to inhibit the renal response in the sense that the induced drop in PCO2 hinders acid secretion, but it also decreases the filtered load of HCO3 – and so its net inhibitory effect is not great METABOLIC ALKALOSIS In metabolic alkalosis, the plasma HCO3 – level and pH rise (Figure 40–7) The respiratory compensation is a decrease in ventilation produced by the decline in H + concentration, and this elevates the PCO2 This brings the pH back toward normal while elevating the plasma HCO3 – level still further The magnitude of this compensation is limited by the carotid and aortic chemoreceptor mechanisms, which drive the respiratory center if any appreciable fall occurs in the arterial PO2 In metabolic alkalosis, more renal H + secretion is expended in reabsorbing the increased filtered load of HCO3– ; and if the HCO3 – level in plasma exceeds 26–28 mEq/L, HCO3– appears in the urine The rise in PCO2 inhibits the renal compensation by facilitating acid secretion, but its effect is relatively slight Figure 40–7 8/18/2009 4:27 AM AccessMedicine | Print: Chapter 40 Acidification of the Urine & Bicarbo 11 of 13 http://www.accessmedicine.com/popup.aspx?aID=5244357&print=yes_c Siggaard–Andersen curve nomogram (Courtesy of O Siggaard–Andersen and Radiometer, Copenhagen, Denmark.) THE SIGGAARD–ANDERSEN CURVE NOMOGRAM Use of the Siggaard–Andersen curve nomogram (Figure 40–7) to plot the acid–base characteristics of arterial blood is helpful in clinical situations This nomogram has P CO2 plotted on a log scale on the vertical axis and pH on the horizontal axis Thus, any point to the left of a vertical line through pH 7.40 indicates acidosis, and any point to the right indicates alkalosis The position of the point above or below the horizontal line through a PCO2 of 40 mm Hg defines the effective degree of hypoventilation or hyperventilation If a solution containing NaHCO3 and no buffers were equilibrated with gas mixtures containing various amounts of CO2 , the pH and PCO values at equilibrium would fall along the dashed line on the left in Figure 40–7 or a line parallel to it If buffers were present, the slope of the line would be greater; and the greater the buffering capacity of the solution, the steeper the line For normal blood containing 15 g of hemoglobin/dL, the CO2 8/18/2009 4:27 AM AccessMedicine | Print: Chapter 40 Acidification of the Urine & Bicarbo 12 of 13 http://www.accessmedicine.com/popup.aspx?aID=5244357&print=yes_c titration line passes through the 15-g/dL mark on the hemoglobin scale (on the underside of the upper curved scale) and the point where the PCO2 = 40 mm Hg and pH = 7.40 lines intersect, as shown in Figure 40–7 When the hemoglobin content of the blood is low, there is significant loss of buffering capacity, and the slope of the CO2 titration line diminishes However, blood of course contains buffers in addition to hemoglobin, so that even the line drawn from the zero point on the hemoglobin scale through the normal P CO2–pH intercept is steeper than the curve for a solution containing no buffers For clinical use, arterial blood or arterialized capillary blood is drawn anaerobically and its pH measured The pHs of the same blood after equilibration with each of two gas mixtures containing different known amounts of CO2 are also determined The pH values at the known PCO levels are plotted and connected to provide the CO2 titration line for the blood sample The pH of the blood sample before equilibration is plotted on this line, and the PCO of the sample is read off the vertical scale The standard bicarbonate content of the sample is indicated by the point at which the CO2 titration line intersects the bicarbonate scale on the P CO2 = 40 mm Hg line The standard bicarbonate is not the actual bicarbonate concentration of the sample but, rather, what the bicarbonate concentration would be after elimination of any respiratory component It is a measure of the alkali reserve of the blood, except that it is measured by determining the pH rather than the total CO2 content of the sample after equilibration Like the alkali reserve, it is an index of the degree of metabolic acidosis or alkalosis present Additional graduations on the upper curved scale of the nomogram (Figure 40–7) are provided for measuring buffer base content; the point where the CO2 calibration line of the arterial blood sample intersects this scale shows the mEq/L of buffer base in the sample The buffer base is equal to the total number of buffer anions (principally Prot–, HCO3 – , and Hb–) that can accept hydrogen ions in the blood The normal value in an individual with 15 g of hemoglobin per deciliter of blood is 48 mEq/L The point at which the CO2 calibration line intersects the lower curved scale on the nomogram indicates the base excess This value, which is positive in alkalosis and negative in acidosis, is the amount of acid or base that would restore L of blood to normal acid–base composition at a P CO2 of 40 mm Hg It should be noted that a base deficiency cannot be completely corrected simply by calculating the difference between the normal standard bicarbonate (24 mEq/L) and the actual standard bicarbonate and administering this amount of NaHCO3 per liter of blood; some of the added HCO3 – is converted to CO2 and H 2O, and the CO2 is lost in the lungs The actual amount that must be added is roughly 1.2 times the standard bicarbonate deficit, but the lower curved scale on the nomogram, which has been developed empirically by analyzing many blood samples, is more accurate In treating acid–base disturbances, one must, of course, consider not only the blood but also all the body fluid compartments The other fluid compartments have markedly different concentrations of buffers It has been determined empirically that administration of an amount of acid (in alkalosis) or base (in acidosis) equal to 50% of the body weight in kilograms times the blood base excess per liter will correct the acid–base disturbance in the whole body At least when the abnormality is severe, however, it is unwise to attempt such a large correction in a single step; instead, about half the indicated amount should be given and the arterial blood acid–base values determined again The amount required for final correction can then be calculated and administered It is also worth noting that, at least in lactic acidosis, NaHCO3 decreases cardiac output and lowers blood pressure, so it should be used with caution CHAPTER SUMMARY The cells of the proximal and distal tubules secrete hydrogen ions Acidification also occurs in the collecting ducts The reaction that is primarily responsible for H + secretion in the proximal tubules is Na+–H + exchange Na is absorbed from the lumen of the tubule and H is excreted The maximal H + gradient against which the transport mechanisms can secrete in humans corresponds to a urine pH of about 4.5 However, three important reactions in the tubular fluid remove free H +, 8/18/2009 4:27 AM AccessMedicine | Print: Chapter 40 Acidification of the Urine & Bicarbo 13 of 13 http://www.accessmedicine.com/popup.aspx?aID=5244357&print=yes_c permitting more acid to be secreted These are the reactions with HCO3 – to form CO2 and H2 O, with HPO4 2– to form H 2PO4 – , and with NH3 to form NH 4+ Carbonic anhydrase catalyzes the formation of H CO3 , and drugs that inhibit carbonic anhydrase depress secretion of acid by the proximal tubules Renal acid secretion is altered by changes in the intracellular P CO2, K+ concentration, carbonic anhydrase level, and adrenocortical hormone concentration CHAPTER RESOURCES Adrogué HJ, Madius NE: Management of life-threatening acid–base disorders N Engl J Med 1998;338:26 Brenner BM, Rector FC Jr (editors): The Kidney, 6th ed vols Saunders, 1999 Davenport HW: The ABC of Acid–Base Chemistry, 6th ed University of Chicago Press, 1974 Halperin ML: Fluid, Electrolyte, and Acid–Base Physiology, 3rd ed Saunders, 1998 Lemann J Jr., Bushinsky DA, Hamm LL: Bone buffering of acid and base in humans Am J Physiol Renal Physiol 2003;285:F811 Review Vize PD, Wolff AS, Bard JBL (editors): The Kidney: From Normal Development to Congenital Disease Academic Press, 2003 Copyright © The McGraw-Hill Companies All rights reserved Privacy Notice Any use is subject to the Terms of Use and Notice 8/18/2009 4:27 AM ... 18 of 44 http://www.accessmedicine.com/popup.aspx?aID=5242839&print=yes_c 8/18/2009 3:04 AM AccessMedicine | Print: Chapter General Principles & Energy Productio 19 of 44 http://www.accessmedicine.com/popup.aspx?aID=5242839&print=yes_c... distribution of water and solutes OSMOSIS When a substance is dissolved in water, the concentration of water molecules in the solution is less than that in pure water, because the addition of solute to water... readily with substances in reactions that would otherwise require outside energy Acetyl-CoA is therefore often called "active acetate." From the point of view of energetics, formation of mol of any