Chapter 13 Respiratory Student Fall 2024 PDF

Pulmonary Physiology 0  Respiration: The sum of the processes that accomplish ongoing passive movement of O2 from the atmosphere to the tissues to support cell metabolism and the continual passive movement of metabolically...

Pulmonary Physiology 0  Respiration: The sum of the processes that accomplish ongoing passive movement of O2 from the atmosphere to the tissues to support cell metabolism and the continual passive movement of metabolically produced CO2 from the tissues to the atmosphere. Kreb's Cycle, ETC , glycolysis M Cellular Respiration: External Respiration: The intracellular metabolic processes The entire sequence of events in the carried out within the mitochondria, exchange of O2 and CO2 between which use O2 and produce CO2 the external environment and the while delivering energy form tissue cells. nutrient molecules. 0  External Respiration Refers to sequence of events involved in the exchange of O2 and CO2 between the external environment and the cells of the body outside Four steps get the air from into our lungs body and 1. Ventilation – movement of Loading… air into and out of the lungs. 2. Diffusion of O2 and CO2 between air in alveoli and blood within the pulmonary capillaries. 3. Blood transports O2 and CO2 between lungs and tissues. 4. Diffusion of O2 and CO2 between tissues and blood across systemic (tissue) capillaries. 0  P82 · Partial Pressures ↳ partial pressure of ↳ flow down how much oxygen pressure oxygen Wherever it is in the body gradients is in our blood function of Pulmonary system - readily - Store availible > - to move 98 5 % of all the oxygen. gases in the blood is bound to Hb 1. 5 % of all the oxygen is dissolved in the blood oxygen doesn't - go into the like to Plasma due to solubility from ↓ - easier to pull mechanical plasma than Hb events of - use Ab due to bound the oxygen store to replenish being long to what is being pulled out in the hemoglobin gastexchange plasma ↑ earth atmosphere ; sea level Normal air composition is 21% O2 with an atmospheric pressure of 760 mm Hg at sea level. When we breath this air, normal arterial blood leaving the lungs has a PO2 of 100 mm Hg and Hb saturation of 98%. * used predict one can be to the otherA – Normal PO2 (80-100 mm Hg) normal Hb saturation (95-100%) Assuming normal Hb levels, total oxygen content is 20 ml oxygen/100 ml of blood (20 volume percent). side Arterial blood gases reflect lung function. ovenous reflection of ↳ tissues ↳ blood has not 0 gone to any tissues yet ; direct reflection of the lungs  Lungs-basic structure · tissue of the lungs airways · within the Occupy much of thoracic cavity longs along with heart, vessels, esophagus, thymus. Two lungs: – Divided into lobes, lobes – divided into segments Loading… Consists of highly branched airways, alveoli, pulmonary blood vessels, elastic connective tissue Outer chest wall – Formed by 12 pairs of ribs and variety of skeletal muscle 0  Crings) Conducting Zone very stiff W No gas exchange had Trachea and Bronchi if we only cartilage not we have wouldn't good contain cartilage highly flexibility in flexible our neck Bronchioles-smooth muscle, regulate resistance *Anatomic dead space simply getting * 150 MLA air in ↳ marks resp Zone. Respiratory Zone Respiratory bronchioles to alveolar sacs Involved in gas exchange High surface area for capillary exchange normal breath Dead Space: regions of the respiratory system - soo ml tidal volume that contain air but are not exchanging O2 and CO2 with blood are considered dead space. short shallow breaths Conducting zone is anatomic dead space (150 ml why do we hyperventilate ? - less gas exchange of air) pushing air into conducting zone - and back out 0  A air we breathe isn't always clean A > produce mucous to trap particles and use cillia to get it back out Conducting zone –Host defense involves mucociliary escalator. - Cillia beat upwards in trached Under healthy conditions, few mucous cells reside within the airway epithelium. However, in humans with asthma, cystic fibrosis (CF), or chronic obstructive pulmonary disease (COPD) the production and secretion of mucus are markedly upregulated. 0  Alveoli – 500 million= 75 m2 Thin-walled inflatable sacs. Function in gas exchange. Walls consist of a single layer of flattened Type I alveolar cells. Pulmonary capillaries encircle each alveolus. Type II alveolar cells secrete pulmonary surfactant. ↳ a chemical that helps keep alveoli from your collapsing 0 Pleural Sac 0 Pressures Important in Ventilation 0 A patient with a was found to have an alveolar PO2 measured at 75 mm Hg (normal is 100 mm Hg). Which of the following might be consistent with his condition? a)Arterial PO2 would be higher than normal b)The amount of oxygen dissolved in the arterial blood is normal, but Hb saturation is low Loading… c)Hb saturation is 75% d)Total oxygen content would remain normal 0  Respiratory System: Static Respiratory Mechanics 0 Lung Volumes and Capacities 0 Lung volumes are direct measurements from the tracing, lung capacities are calculated using measured volumes.  Respiratory System: Static Respiratory Mechanics 0  Isolated Lung recoil represents the Recoil Forces inward force created by the elastic recoil properties of lung - tissue and the alveoli. – Recoil as a force, always acts to collapse lung. – As the lung expands, recoil increases; as the lung gets smaller, recoil decreases. FRC represents the point where the outward recoil of the chest Chest wall recoil is the outward wall is counterbalanced by the force. inward recoil of the lung. These forces moving in the opposite – Chest wall wants to expand direction create the negative IPP. 0 The figure shows lung volumes during pulmonary function testing. What is the inspiratory capacity of this patient? a.0.5 L b.2.0 L c.2.5 L d.3.0 L e.6.0 L You are asked to use the spirometry tracing to calculate functional residual capacity of a patient with restrictive airway disease. You are given ERV. In order to calculate FRC you would: a)add the volume of the value indicated by “F” b)subtract the volume of the value indicated by “F” c)add the volume of the value indicated by “E” d)subtract the volume of the value indicated by “E” e)add the volume of the value indicated by “B” f)subtract the volume of the value indicated by “B”  Intrapleural Pressure (IPP) This represents the pressure inside the thin film of fluid between the visceral pleura, which is attached to the lung, and the partial pleura, which is attached to the chest wall. The outward recoil of the chest and inward recoil of the lung create a negative (subatmospheric) IPP. 0  Transpulmonary (Transmural) Pressure Gradient Ptm Ptm= Pinside-Poutside At FRC, IPP is sub-atmospheric, so Ptm is positive. Ptm= 760-756= 4 This positive outward force counters the lung elastic recoil and prevents alveolar collapse 0  TMP Gradient Pathology Traumatic pneumothorax; perforation of Tension pneumothorax; air enters PP chest wall; air into PP space; IPP rises, space from damaged alveoli; cause IPP produces negative TMP; lung collapse and rises, produces negative TMP; tracheal chest wall expands on side of collapse. deviation; can occur in patients on positive-pressure ventilator. 0  Compliance Vs. Elasticity Compliance refers to how much effort is required to stretch or distend the lungs. – The less compliant (stiffer), the lungs are the more work is required to produce a given degree of inflation. Elasticity is the driving force that is going to make it come back to its original shape. Compliance is important for inspiration where elasticity is important for expiration Compliance of lung varies with volume; easy to inflate at small volumes; harder to inflate at large volumes. So, imagine a balloon that is being inflated, easy to put air in at the beginning, harder as the balloon enlarges because the compliance decreases as the balloon inflates. High Elasticity Low Elasticity High Compliance Low Compliance 0  Components of Lung Recoil Elastic recoil causes the lungs to collapse. Elastic recoil comes from: 1. The tissue itself; collagen and elastic fibers of the lung. 2. The surface tension forces in the fluid lining the alveoli where liquid-air interface; greatest component of recoil. 3. These collapsing forces are necessary to exhale but must be countered at the end of expiration to prevent the alveoli from collapsing completely during expiration. 0  Pulmonary Surfactant lowers alveolar Surfactant surface tension forces by separating water molecules. This prevents alveoli from collapsing during expiration and maintains lung volumes. 0  Surfactant Deficiency If ↓ activity of pulmonary Infant Respiratory Distress surfactant: Syndrome (IRDS) when surface tension babies are born lung compliance prematurely and have not lung elasticity produced sufficient lung volume surfactant. risk of edema ARDS is same for adults; airway resistance caused by airway gastric Impaired gas exchange aspirations, infections that interfere with surfactant production. 0 A child born 12 weeks premature, unexpectedly. You remember that children born at this stage usually suffer from a lack of surfactant production. Which of the following is likely to be observed in this newborn? a)decreased alveolar surface tension b)decreased lung compliance c)stabilization of alveolar volume d)decreased pulmonary vascular resistance e)increased residual volume  Lung at Rest At FRC muscles relaxed. Tendency of the isolated lungs is to collapse. Tendency of the isolated chest wall is to expand. Chest wall and lungs cannot assume these natural positions because forces are balanced due to action of intrapleural space. 0  Respiratory System: Dynamic Respiratory Mechanics 0  Dynamic Forces To actively inflate lungs the muscles of the chest wall must exert energy to: 1. overcome the elastic recoil of the pulmonary system 2. overcome the friction caused by the moving tissue (lungs and chest) rubbing against tissues (tissue resistance) 3. Loading… overcome the friction caused by the moving air rubbing against the conducting airways (flow resistance) 4. overcome the forces of inertia associated with the moving tissues and the flowing air 0  Inspiration The diaphragm via phrenic nerve and external intercostal muscles contract. Diaphragm moves down, ribs are elevated. IPP falls (756 to 752) because more stretch and recoil from the contracting muscles. The lungs then expand. Intrapulmonary pressure then drops below atmospheric pressure (759), and air enters lungs. 0  Resting Expiration Onset of resting expiration begins with relaxation of inspiratory muscles. Relaxation of diaphragm and muscles of chest wall, plus the elastic recoil of the alveoli: 1. decrease the volume of the chest cavity 2. intrapulmonary pressure increases leading to pressure increases above atmospheric pressure (761); air is driven out 0  Review - Inspiration What is FRC? What causes the lungs to maintain FRC? What are the pressures at FRC? (3) What two muscles are involved with inspiration? Contraction of these two muscles has what effect on the IPP? What happens to the transmural pressure gradient when the lungs inflate? Boyle’s law examines the relationship between pressure and volume. How is Boyle’s law relevant during inspiration? 0  Review - Expiration What causes resting expiration? Relaxation of these two muscles allows what to natural tendency to kick in? What happens to the pressure inside the lungs following relaxation of inspiratory muscles? What is the pressure inside the lungs following relaxation of inspiratory muscles? What marks the end of expiration? What do we call this point on spirometry tracing? 0  Forced Expiration 1. Muscles of anterior abdominal wall (increase intra- abdominal pressure). 2. Internal intercostals (depress rib cage). 3. Accessory neck muscles. 4. Active at high ventilation rates, compensation for COPD. Also essential for coughing, sneezing, straining. 0 0  Work of Breathing Normally requires 3% of total energy expenditure for quiet breathing. Three factors must be overcome during ventilation: – the elastic recoil of the chest and lung – frictional resistance to gas flow in the airways – tissue frictional resistance Pathologies can change these forces and can increase total energy expenditure during quiet breathing. 0 Which of the following is true during inspiration when air is moving? a)Pleural pressure is positive relative to atmospheric b)The volume in the lungs is less than FRC c)Alveolar pressure equals atmospheric pressure d)Alveolar pressure is higher than atmospheric pressure e)Pleural pressure is more negative than it is at FRC During a portion of the respiratory cycle the intrapleural pressure was measured at 760 mm Hg. Which of the following is true for this portion of the ventilation cycle? (assume breathing at sea level) a)Intra-alveolar pressure is less than 760 mm Hg; air is flowing out of the lung b)Intra-alveolar pressure is less than 760 mm Hg; air is flowing out of the lung c)Intra-alveolar pressure is greater than 760 mm Hg; air is flowing out of the lung d)Intra-alveolar pressure is less than 760 mm Hg; air is flowing into the lung e)Intra-alveolar pressure is equal to 760 mm Hg; air is not moving into or out of the lung 0 Respiratory System: Oxygen Transport 0  Alveolar Ventilation The process of exchanging O2 and CO2 between the alveoli of the lungs and the outside environment PAO2 = 100 mm Hg PACO2 = 40 mm Hg PO2 = 40 mm Hg PCO2 = 46 mm Hg 0  Gas Partial Pressure Gas exchange involves simple diffusion of O2 and CO2 down partial pressure gradients. Partial pressure= pressure exerted on gas x percentage of gas in the mixture PO2 atm = 760 mm Hg x (0.21) = 160 mm Hg Atmospheric 21% pressure exerted oxygen 0 on gas  PO2: Atmospheric and Inspired Air PatmO2= 0.21(760)= 160 mm Hg Inspired air warmed to 37°C, and completely humidified. Humidifying the air reduces the partial pressure of the other gases. The -47 below is a correction factor for water vapor. PinspO2= 0.21(760 – 47) = 150 mm Hg 0  PO2: Alveolar Air Alveolar air under normal conditions, PAO2 is 100 mm Hg, determined by: – other gases in alveoli (CO2) – rate of oxygen delivery to the alveoli – rate of oxygen removal from the alveoli 0  Alveolar PCO2 (PACO2) Normal Values When PACO2 is lower than PO2 = 100 mm Hg PCO2 = 40 mm Hg normal associated condition is hyperventilation. If Determined by: alveolar ventilation is rate CO2 production (VCO2) doubled, PACO2 is cut in rate CO2 removal from lungs, half. alveolar ventilation When PACO2 is higher than (VA) normal associated condition PACO2 = VCO2 / VA is hypoventilation. If Assuming no CO2 in the alveolar ventilation is cut in inhaled air or increased half, PACO2 is doubled. production, PACO2 can be (shallow breathing). used to evaluate alveolar ventilation 0  Abnormal Breathing Patterns Hypoventilation Hyperventilation – Breathing is too shallow or – Breathing is too fast or deep slow – The body removes too much – Prevents the body from CO2 removing enough CO – CO2 levels are low in the – CO2 builds up in the body body Low O2 levels in body Minimal effect on O2 levels – Acidosis – Alkalosis Blood pH < 7.35 Blood pH > 7.45 0  Exchange of oxygen between blood and tissue: 1. Oxygen dissolved in plasma Reflection of lung moves into tissue by function diffusion. 2. As oxygen leaves plasma to enter the tissue it is replaced by oxygen from Hb. 3. Process is repeated until equilibrium between blood and tissue is reached. 4. Once blood leaves the capillary, process stops. 5. Blood enters venous system; partial pressure of gas in venous blood is Reflection of tissue function reflection of gas exchange at tissue. 0  Hemoglobin Oxygen Transport Hb major role is to store O2 and influences the total amount of O2 carried in the blood. One Hb has 4 iron-containing Heme groups, each can bind one oxygen. Normal Hb concentrations increase oxygen carrying capacity of the blood 70-fold. Blood leaving the lungs has a PaO2 of 100 mm Hg and Hb saturation of 98%. 0  Oxygen Transport on Hb PO2 is main factor determining hemoglobin saturation. PO2 100 mm Hg, lungs; site 4 – 98% saturated PO2 40 mm Hg, tissue, oxygen dissociates; site 3-75% saturated P50 , PO2 required for 50% 26 40 100 saturation; site 2 (normal PO2 ≅ 26 mm Hg); minimum de- saturation under normal conditions 0 Oxygen Transport on Hb 26 40 100 0  Oxygen Dissociation Curve PO2 of venous blood at rest; PO2 = PO2 of arterial blood; PO2 = 40 mmHg Saturation = 75% 100 mmHg Saturation = 98% P50 = is PO2 when Hb is 50% saturated = 26 mm Hg 0 Enhanced Oxygen Release from Hb Right shift is a reflection of the decreased affinity of Hb for O2 This represents enhanced oxygen release from Hb to tissues under metabolic demand. 0  Enhanced Oxygen Release from Hb Hb-75% saturated which means 25% was offloaded to tissue; this represents normal oxygen release Hb-55% saturated which means 45% was offloaded to tissue; this represents enhanced oxygen release 0 A 22-year-old man participates in a clinical study. He begins to hyperventilate voluntarily. His alveolar ventilation doubles and his CO2 production remains constant. After the study, his PCO2 level is 25 mm Hg. What was his alveolar PCO2 before the experiment was started? a) 10 mm Hg b) 25 mm Hg c) 50 mm Hg d) 75 mm Hg e) 100 mm Hg Which of the following described Hb-oxygen association as blood passes through exercising muscle? a)Hb affinity for O2 increases and the dissociation curves shifts to the left b)Hb affinity for O2 decreases and the dissociation curves shifts to the right c)Hb affinity for O2 increases and the dissociation curves shifts to the right d)Hb affinity for O2 decreases and the dissociation curves shifts to the left e)neither Hb affinity for O2 nor the Hb-O2 dissociation curve change 0  Respiratory System: Carbon Dioxide Transport and Neural Regulation of Breathing 0  CO2 and Blood 1. Dissolved in plasma-5%, PaCO2 2. Carbamino compounds-5% 3. Bicarbonate: 90% of the CO2 is carried as plasma bicarbonate. 0 Review: Modifying Oxygen Release from Hb More CO2 means more H+, curve right shifts, to enhance oxygen release; binding of H+ to Hb is known as the Bohr effect 0 Bohr Effect-step #5 0  Haldane Effect The ability of deoxygenated blood to carry more CO2 than oxygenated blood. Binding of oxygen with Hb in the lungs promotes dissociation of CO2 from blood. 0  Neural Control Respiration Blood Brain Cerebral Cortex Pre Botzinger-Complex: Pacemaker cells Dyspnea is the feeling of being short of breath, or the unpleasant conscious awareness of difficulty in breathing. 0  Central Chemoreceptors Activity increases ventilation. Monitor and are stimulated by changes in CSF pH via CO2. Main drive for ventilation is CO2 (H+) on the central chemoreceptors. The system does adapt usually within 12 to 24 hours. Produce significant increases in ventilation with hypercapnia (elevated CO2). There are no central PO2 receptors. 0  Peripheral Chemoreceptors Carotid bodies: near carotid sinus, afferents to CNS in glossopharyngeal nerve, IX. Aortic bodies: near aortic arch, afferents to CNS in vagus nerve, X. Monitor CO2 and pH of arterial blood: – Less sensitive than central receptors, small contribution to normal drive. – Respond first to changes in arterial CO2 levels. PO2 receptors: – Increase firing as PaO2 falls below 80 mmHg and becomes marked and progressive when PaO2 is less than 60 mmHg 0 0 Fine Control of Respiration 0 An anesthetized patient is breathing without assistance. She is then artificially ventilated for 10 minutes at a normal tidal volume but at twice her normal breathing rate. She is being ventilated on a mixture of 40% oxygen and 60% nitrogen. After the artificial ventilation is stopped, she fails to breath for several minutes. This period of apnea (not breathing) is due to which of the following conditions? a) High arterial PO2 suppressing the activity of the peripheral chemoreceptors b) Decrease in arterial pH suppressing the activity of the peripheral chemoreceptors c) Low arterial PCO2 suppressing the activity of the medullary central chemoreceptors d) High arterial PCO2 suppressing the activity of the medullary central chemoreceptors e) Low arterial PO2 suppressing overall neuronal activity 0 A young child in your office holds her breath for over 30 seconds while throwing a temper tantrum because they don’t want to receive their vaccination. Mom is worried about the child passing out, but you know she will eventually start breathing because: a) Her arterial PO2 will fall to a value that will trigger increased ventilation b) Her central respiratory chemoreceptors will trigger breathing related to H+ crossing from the plasma into the CSF c) Her blood pH will rise, triggering the peripheral respiratory chemoreceptors to stimulate ventilation d) Her peripheral respiratory chemoreceptors will respond first to the elevated CO2 and trigger increased ventilation 0 Respiratory Response to Stress Hypoxia is defined as a deficiency in the amount, delivery or utilization of oxygen at the tissue level, which can lead to changes in function, metabolism and even structure of the body. 0  Classification of Hypoxia Type Definition Typical Causes Hypoxic hypoxia High altitude; alveolar hypoventilation; decreased lung diffusion Low arterial PO2 (Hypoxemia) capacity; abnormal ventilation-perfusion ratio Decreased total amount of O2Blood loss; anemia (low [Hb] or altered HbO2 binding); carbon Anemic hypoxia bound to hemoglobin monoxide poisoning Heart failure (whole-body hypoxia); shock (peripheral hypoxia); Ischemic hypoxia Reduced blood flow thrombosis (hypoxia in a single organ) Failure of cells to use O2 Histotoxic hypoxia because cells have been Cyanide and other metabolic poisons poisoned Remember tissue status is reflected in venous gas values, lung functions are reflected in arterial gas values. 0  Altitude Stress Abnormal air composition: symptoms occur when atmospheric pressure falls to around 520 mmHg (10,000 feet) – Summit of Mount Everest calculated PAO2 is 35 mm Hg; PaO2 is 28 mm Hg – acclimatization (physiological adjustments): increased ventilation- peripheral chemoreceptors due to low arterial oxygen (fell below 60 mm Hg) increased hematocrit-due to EPO, increases oxygen carrying capacity of the blood 0  Hb Concentration Effects Total O2 content changes Anemia-reduction in Hb concentration Polycythemia- higher than normal Hb concentration P50 doesn’t change Hb saturation and PaO2 normal 0  Carbon Monoxide Poisoning Carbon monoxide (CO) binds with Hb to form carboxyhemoglobin (COHb). Hb affinity for CO is 200-times more than for O2 so small amounts of CO tie up large amounts of Hb. PCO of 0.5 mm Hg inactivates 50% of Hb. CO decreases functional concentration of Hb; form of acute- onset anemia. Defect is due to reduced arterial O2 content, not change in arterial PO2 Condition worsens because Hb-O2 dissociation curve shifts to left, P50 is decreased, unloading of O2 is hindered. 0  Carbon Monoxide Poisoning Decreased functional Hb Carrying capacity for Hb decreased due Hb-O2 dissociation curve to decreased O2-Hb saturation shifts to left, so unloading of O2 is decreases Normal The most common CO symptoms are headache, nausea and vomiting, dizziness, lethargy and a feeling of weakness. 0  Mammalian Diving Reflex A series of physiological changes that takes place in the body in response to a mammal holding its breath while submerged in water. It consists of Breathing cessation (apnea) A dramatic slowing of heart rate (bradycardia) An increase in peripheral vasoconstriction *This reflex doesn’t mean that babies can be Thought to conserve vital oxygen stores suddenly submerged without warning and thus maintain life by directing perfusion to the two organs most *Babies still are not able to swim and need an essential for life adult to bring them to the surface – the heart and brain. *This is a technique of using a baby’s natural reflexes from an early age to teach a child how The preservation of life by physiologic to swim and be comfortable in the water adaptation in response to the current environment. https://www.deeperblue.com/the-science-behind-the-freediving-breath-hold/ 0 Transmural Pressure Gradients The difference in pressure between the inside and outside of a compartment. Pinside – Poutside A = Intra-alveolar Pressure 760 mm Hg B = Intra-pleural Pressure 756 mm Hg C = Atmospheric Pressure 760 mm Hg Transpulmonary Pressure (Intra-alveolar – intra-pleural) Transthoracic Pressure (Intra-pleural – Atmospheric) Transrespiratory Pressure (Intra-alveolar – Atmospheric) 0 Transmural Pressure Gradients The difference in pressure between the inside and outside of a compartment. Pinside – Poutside A = Intra-alveolar Pressure 760 mm Hg B = Intra-pleural Pressure 756 mm Hg C = Atmospheric Pressure 760 mm Hg Transpulmonary Pressure (Intra-alveolar – intra-pleural) At FRC ~Muscles contract~ ↑ vol ~Muscles relax ~ ↓ vol At the end of breath [FRC] Transthoracic Pressure (Intra-pleural – Atmospheric) At FRC ~Muscles contract~ ↑ vol ~Muscles relax ~ ↓ vol At the end of breath [FRC] Transrespiratory Pressure (Intra-alveolar – Atmospheric) At FRC ~Muscles contract~ ↑ vol 0 ~Muscles relax ~ ↓ vol At the end of breath [FRC] Respiratory System: Oxygen Transport 1  Alveolar Ventilation The process of exchanging O2 and CO2 between the alveoli of the lungs and the outside environment PAO2 = 100 mm Hg PACO2 = 40 mm Hg PO2 = 40 mm Hg PCO2 = 46 mm Hg 2  Gas Partial Pressure Gas exchange involves simple diffusion of O2 and CO2 down partial pressure gradients. Partial pressure= Loading… pressure exerted on gas x percentage of gas in the mixture PO2 atm = 760 mm Hg x (0.21) = 160 mm Hg Atmospheric 21% pressure exerted oxygen 3 on gas PO2: Atmospheric and Inspired Air PatmO2= 0.21(760)= 160 mm Hg Inspired air warmed to 37°C, and completely humidified. Humidifying the air reduces the partial pressure of the other gases. The -47 below is a correction factor for water vapor. PinspO2= 0.21(760 – 47) = 150 mm Hg 4  PO2: Alveolar Air Alveolar air under normal conditions, PAO2 is 100 mm Hg, determined by: – other gases in alveoli (CO2) Loading… – rate of oxygen delivery to the alveoli – rate of oxygen removal from the alveoli 5  Alveolar PCO2 (PACO2) Normal Values When PACO2 is lower than PO2 = 100 mm Hg PCO2 = 40 mm Hg normal associated condition is hyperventilation. If Determined by: alveolar ventilation is rate CO2 production (VCO2) doubled, PACO2 is cut in rate CO2 removal from half. lungs, alveolar ventilation When PACO2 is higher than (VA) normal associated condition is hypoventilation. If PACO2 = VCO2 / VA Assuming no CO2 in the alveolar ventilation is cut in inhaled air or increased half, PACO2 is doubled. production, PACO2 can be (shallow breathing). used to evaluate alveolar ventilation 6  Abnormal Breathing Patterns Hypoventilation Hyperventilation – Breathing is too shallow – Breathing is too fast or or slow deep – Prevents the body from – The body removes too removing enough CO2 much CO2 – CO2 builds up in the – CO2 levels are low in the body body Low O2 levels in body Minimal effect on O2 levels – Acidosis – Alkalosis Blood pH < 7 Blood pH > 7.45 7  Exchange of oxygen between blood and tissue: 1. Oxygen dissolved in Reflection of plasma moves into tissue by lung function diffusion. 2. As oxygen leaves plasma to enter the tissue it is replaced by oxygen from Hb. 3. Process is repeated until equilibrium between blood and tissue is reached. 4. Once blood leaves the capillary, process stops. 5. Blood enters venous Reflection of system; partial pressure of tissue function gas in venous blood is reflection of gas exchange at tissue. 8  Hemoglobin Oxygen Transport Hb major role is to store O2 and influences the total amount of O2 carried in the blood. One Hb has 4 iron-containing Heme groups, each can bind one oxygen. Normal Hb concentrations increase oxygen carrying capacity of the blood 70-fold. Blood leaving the lungs has a PaO2 of 100 mm Hg and Hb saturation of 98%. 9  Oxygen Transport on Hb PO2 is main factor determining hemoglobin saturation. PO2 100 mm Hg, lungs; site 4 – 98% saturated PO2 40 mm Hg, tissue, oxygen dissociates; site 3-75% saturated P50 , PO2 required for 50% 26 40 100 saturation; site 2 (normal PO2 ≅ 26 mm Hg); minimum de- saturation under normal conditions 10 Oxygen Transport on Hb Loading… 26 40 100 11  Oxygen Dissociation Curve PO2 of venous blood at rest; PO2 PO2 of arterial blood; PO2 = = 100 mmHg Saturation = 40 mmHg Saturation = 75% 98% P50 = is PO2 when Hb is 50% saturated = 26 mm Hg 12 Enhanced Oxygen Release from Hb Right shift is a reflection of the decreased affinity of Hb for O2 This represents enhanced oxygen release from Hb to tissues under metabolic demand. 13 Enhanced Oxygen Release from Hb Hb-75% saturated which means 25% was offloaded to tissue; this represents normal oxygen release Hb-55% saturated which means 45% was offloaded to tissue; this represents enhanced oxygen release 14 A 22-year-old man participates in a clinical study. He begins to hyperventilate voluntarily. His alveolar ventilation doubles and his CO2 production remains constant. After the study, his PCO2 level is 25 mm Hg. What was his alveolar PCO2 before the experiment was started? a) 10 mm Hg b) 25 mm Hg c) 50 mm Hg d) 75 mm Hg e) 100 mm Hg  Which of the following described Hb-oxygen association as blood passes through exercising muscle? a) Hb affinity for O2 increases and the dissociation curves shifts to the left b) Hb affinity for O2 decreases and the dissociation curves shifts to the right c) Hb affinity for O2 increases and the dissociation curves shifts to the right d) Hb affinity for O2 decreases and the dissociation curves shifts to the left e) neither Hb affinity for O2 nor the Hb-O2 dissociation curve change 16  Respiratory System: Carbon Dioxide Transport and Neural Regulation of Breathing 17  CO2 and Blood 1. Dissolved in plasma-5%, PaCO2 2. Carbamino compounds-5% 3. Bicarbonate: 90% of the CO2 is carried as plasma bicarbonate. 18 Review: Modifying Oxygen Release from Hb More CO2 means more H+, curve right shifts, to enhance oxygen release; binding of H+ to Hb is known as the Bohr effect 19 Bohr Effect-step #5 20  Haldane Effect The ability of deoxygenated blood to carry more CO2 than oxygenated blood. Binding of oxygen with Hb in the lungs promotes dissociation of CO2 from blood. 21  The Urinary System: Introduction and Micturition  Overview of Kidney Maintain H2O balance in the body. Functions Maintain proper osmolarity of body fluids Regulate the quantity and concentration of most ECF ions. Maintain proper plasma volume. Help maintain proper acid-base balance. Eliminating wastes of bodily metabolism, especially urea. Excreting foreign compounds. Producing erythropoietin. Producing renin. Converting vitamin D into its active form.  General Renal Structures 1. Kidneys supplied by single renal artery & vein. 2. Body roughly divided into cortex and medulla. 3. Human kidneys are partially segmented with Loading… the medulla consisting of pyramids. 4. The urine is collected by minor and major calices; drains into pelvis and to ureter. 5. Abundant sympathetic innervation of vasculature and tubules.  Particle X is a waste product produced via cellular metabolism in the body. Particle X is measured in the renal artery. Would you expect the amount of particle X to increase, stay the same, or decrease in the renal vein? (Assuming normal kidney function) A. Increase B. Stay the Same Loading… C. Decrease  Nephron - functional unit of kidney consists of filtering glomerulus and tubule system surrounded by capillaries Vascular system – afferent arteriole, glomerulus capillary, efferent arteriole – peritubular capillaries, vasa recta Tubular component – Bowman’s Capsule – Proximal Tubules – Loop of Henle – Distal Tubules – Collecting ducts  The Nephron Vascular Steps Step 1. Blood enters the glomerulus via the afferent arteriole Step 2. The glomerulus filters the blood allowing small molecules, wastes and fluid [H2O] to pass into the tubule. Larger molecules, such as proteins and blood cells stay in the blood vessel. Step 3. Blood exits the glomerulus and enters into the efferent arteriole and then peritubular capillary/Vasa recta. The peritubular capillary feeds the cortical nephron and plays a role in reabsorption and secretion. The Vasa recta feeds the juxtamedullary nephron, plays a role in reabsorption and secretion and aids in the maintenance of vertical osmotic gradient. Tubular Steps Step 1. The glomerulus filters out small molecules, waste products, and fluid [mostly H2O]. Step 2. The filtrate leaves the glomerulus and enters into the proximal convoluted tubule Step 3. Within the proximal convoluted tubule, various molecules are both reabsorbed and secreted through both passive and active transport mechanisms. Step 4. The filtrate travels the Loop of Henle (descending limb – ascending limb). The main function of the loop of Henle is to reabsorb H2O and NaCl from the filtrate producing highly concentrated urine. Step 5. The filtrate enters into the Distal Convoluted Tubule where we see further reabsorption (active) and secretion of various molecules. The main function of the DCT is regulating extracellular fluid volume and electrolyte homeostasis. Step 6. The filtrate (urine) from all the nephrons dumps into the collecting duct and moves into the renal pelvis and ureters. The collecting duct contains aquaporins to regulate volume/concentration of urine. The Nephron  Nephron Subtypes Vertical osmotic About 1 million nephrons per gradient kidney (±200,000) 300 Superficial (cortical) nephrons mOSm have short Loops of Henle, surrounded by peritubular capillaries Juxtamedullary nephrons have long Loops of Henle, surrounded by vasa recta and contribute electrolytes to the vertical osmotic gradient which we will see later, is important for water conservation. 1200 mOSm Both types of nephrons drain into common collecting ducts.  Nephron Subtypes- Vasculature Loading… Afferent arteriole, glomerulus and efferent arteriole-function is filtration of blood. Cortical nephrons are surrounded by peritubular capillaries, function is reabsorption and secretion. Juxtamedullary nephrons give are surrounded by peritubular capillaries AND vasa recta that surround their Loops of Henle, function is reabsorption and secretion.  In cortical nephrons, blood passes into what structure after leaving the efferent arteriole? a) Afferent arteriole b) Glomerulus c) Renal artery d) Renal vein e) Peritubular capillaries f) Vasa recta  After passing though the loop of Henle, filtrate next moves into the _____. a) Vasa recta b) Peritubular capillaries c) Distal tubules d) Collecting ducts e) Bowman’s space  What are the blood vessels surrounding nephron A called? A. Efferent Arteriole B B. Afferent Arteriole C. Peritubular Capillaries D. Vasa Recta E. Glomerulus A  Pathway of Blood through the Kidney Lobar Artery Segmental Artery Arcuate Artery Renal Artery Interlobular Artery Aorta Afferent Arteriole Glomerulus (capillaries) Inferior Vena Cava Efferent Arteriole Renal Vein Peritubular Capillaries Interlobar vein Interlobular vein Arcuate Vein Renal Blood Flow  Nephron Subtypes Vertical osmotic About 1 million nephrons per gradient kidney (±200,000) 300 Superficial (cortical) nephrons mOSm have short Loops of Henle, surrounded by peritubular capillaries Juxtamedullary nephrons have long Loops of Henle, surrounded by vasa recta and contribute electrolytes to the vertical osmotic gradient which we will see later, is important for water conservation. 1200 mOSm Both types of nephrons drain into common collecting ducts.  Nephron Subtypes- Vasculature Afferent arteriole, glomerulus and efferent arteriole-function is filtration of blood. Cortical nephrons are surrounded by peritubular capillaries, function is reabsorption and secretion. Juxtamedullary nephrons give are surrounded by peritubular capillaries AND vasa recta that surround their Loops of Henle, function is reabsorption and secretion. Loading…  In cortical nephrons, blood passes into what structure after leaving the efferent arteriole? a) Afferent arteriole b) Glomerulus c) Renal artery d) Renal vein e) Peritubular capillaries f) Vasa recta  After passing though the loop of Henle, filtrate next moves into the _____. a) Vasa recta b) Peritubular capillaries c) Distal tubules d) Collecting ducts e) Bowman’s space Loading…  What are the blood vessels surrounding nephron A called? A. Efferent Arteriole B B. Afferent Arteriole C. Peritubular Capillaries D. Vasa Recta E. Glomerulus A  Pathway of Blood through the Kidney Lobar Artery Segmental Artery Arcuate Artery Renal Artery Interlobular Artery Aorta Afferent Arteriole Glomerulus (capillaries) Inferior Vena Cava Efferent Arteriole Renal Vein Peritubular Capillaries Interlobar vein Interlobular vein Arcuate Vein Renal Blood Flow  Renal Blood/Fluid Flow Renal Blood Flow: 20-25% of cardiac output; – approx. 1,200 ml/min Glomerular Filtration Rate (GFR); approx. 100-120 ml/min – How much fluid Bowman’s Capsule collects in a minute – Primary way we’re going to measure kidney function Urine flow rate; approx. 1 ml/min Urine production; 1.0-1.5 L/day; range 0.5-15 L/day Normal human physiology tends to favor water conservation by producing relatively concentrated urine. – Body prioritizes reabsorbing water from the filtrate rather than excreting large volumes of dilute urine.  Urine Formation-Basic Steps Blood is filtered creating a fluid known as renal filtrate. Filtration occurs at specialized capillary beds in the kidney called the glomerulus. GFR is the glomerular filtration rate (ml/min) The filtrate passes through various regions of the tubule. Filtrate is modified by reabsorption and secretion and what’s left behind in the tubules is excreted as urine.  Tubular Reabsorption Tubular reabsorption is the selective transfer of specific substances in the filtrate back into the blood of the peritubular capillaries. Loading… Reabsorption rates vary for different substances. On average, of the 180 liters of plasma filtered per day, 178.5 liters are reabsorbed. – The remaining 1.5 liters left is excreted as urine.  Tubular Secretion and Excretion Tubular secretion is the selective transfer of substances from the peritubular capillary blood into the tubular lumen. Process is opposite of reabsorption. Provides additional route for substances to enter the renal tubules from the blood. Urine excretion is the elimination of substances from the body in the urine.  Micturition Reflex Urine moves from ureters to the urinary bladder by peristalsis. Urine is temporarily stored in the bladder and emptied by micturition. The bladder can accommodate up to 250 to 400 ml of urine before stretch receptors initiate the micturition reflex. This reflex causes involuntary emptying of the bladder. Involves bladder contraction and opening of both the internal and external urethral sphincters. Micturition can be voluntarily prevented by deliberately tightening the external sphincter and pelvic diaphragm. Bladder Anatomy Ureter-carries urine into bladder from kidney Bladder wall-detrusor muscle-smooth muscle Internal sphincter- smooth muscle External sphincter- skeletal muscle  Micturition Reflex Sympathetic activity relaxes the 1 bladder allowing it to fill. Urine accumulation in bladder 2 4 stimulates stretch receptors Stretch receptors trigger 3 parasympathetic reflex that causes the smooth muscle in bladder wall to contract and internal sphincter opens Stretch receptors send input to the cortex signaling that voiding is 5 needed. However, urine is only expelled if we voluntarily relax the external sphincter via activity of somatic 6 motor system. We can choose to keep the sphincter closed.  Which of the following renal measurements is the smallest? a) Renal blood flow per minute b) GFR per minute c) GFR per day d) Urine formation per minute e) Urine formation per day  A patient is taking blood pressure medication that inhibits sympathetic activity. Which of the following urinary functions might also be affected by this drug? a) Relaxation of the external urethral sphincter b) Relaxation of the detrusor muscle c) Contraction of the detrusor muscle d) Contraction of the external urethral sphincter  The Urinary System: GFR and GFR Regulation  Glomerular Filtration: GFR Glomerular filtration is the formation of protein-free plasma as blood flows through the glomerulus. 20-25% of the plasma that enters the glomerulus is filtered. On average, 100-120 ml of glomerular filtrate is formed each minute; this is known as glomerular filtration rate or GFR. This amounts to 180 liters each day.  Glomerular Filtration First step in the process of making urine. Specialized capillary exchange, but general rules of bulk flow across capillary bed apply. – Hydrostatic pressure > colloid osmotic pressure Greater rate of exchange compared to other capillaries because: 1. Higher permeability 2. Higher capillary hydrostatic pressure 3. BP constant across glomerulus Normal Capillary Bed Glomerulus Hydrostatic Pressure Hydrostatic Pressure = ~17 mm Hg = ~55 mm Hg  Glomerular Filtration 1. High Permeability Fenestrations – pores in capillary wall, allow materials to be filtered. 2. Glomerular hydrostatic pressure is higher than that found in other beds. 2 arterioles: Afferent and Efferent dilate and constrict to very tightly regulate the pressure in the glomerulus. 3. Blood pressure does not fall across the glomerulus. Renal autoregulation: regulating the afferent and efferent arteriole  Glomerular Filtration Three physical forces involved in filtration; first two are same forces we discussed in terms of bulk flow across any capillary bed: 1. glomerular capillary blood pressure 2. plasma-colloid osmotic pressure 3. Bowman’s capsule hydrostatic pressure is an additional force to consider Net filtration pressure is the net difference in these forces favoring filtration.  Filtration Forces 1. Glomerular Blood Pressure= 55 mm Hg 2. Plasma Colloid Osmotic Pressure= 30 mm Hg; exists because of plasma proteins 3. Bowman’s Capsule Hydrostatic Pressure= 15 mm Hg; fluid accumulates in capsule and forces fluid back into glomerulus 4. Net filtration pressure (NFP) differences in the forces 5. NFP= 55-30-15= 10 mm Hg  Forces acting on Filtration What happens if I constrict the afferent arteriole?  Forces acting on Filtration How does the Bowman’s Capsule Hydrostatic Pressure go up? What happens if Bowman’s Capsule Hydrostatic Pressure goes up? GFR?  Pressure Profile across Renal Vasculature 120 Glo Peri In Affe Effe R mer tubu tr Dilating afferent and/or ret ret e ular lar ar Arte n constricting efferent Pr 100 capi Arte capi e al e riole llary riole llary n arteriole will lead to V s 80 R al ei s V elevated GFR due to e n ur n ei elevated glomerular e 60 al n ( pressure. A m 40 rt Colloid osmotic pressure m er H y g) 20 Hydrostatic pressure 0 In glomerulus hydrostatic pressure > osmotic pressure= filtration In peritubular capillaries osmotic pressure > hydrostatic pressure= reabsorption Why does hydrostatic pressure drop in the peritubular capillaries?  What’s the main event taking place in the glomerulus? What’s the main event taking place in the peritubular capillaries?  Micturition Reflex Urine moves from ureters to the urinary bladder by peristalsis. Urine is temporarily stored in the bladder and emptied by micturition. The bladder can accommodate up to 250 to 400 ml of urine before stretch receptors initiate the micturition reflex. This reflex causes involuntary emptying of the bladder. Involves bladder contraction and opening of both the internal and external urethral sphincters. Micturition can be voluntarily prevented by deliberately tightening the external sphincter and pelvic diaphragm. Bladder Anatomy Ureter-carries urine into bladder from kidney Bladder wall-detrusor muscle-smooth muscle Internal sphincter- smooth muscle External sphincter- skeletal muscle  Micturition Reflex Sympathetic activity relaxes the 1 bladder allowing it to fill. Urine accumulation in bladder 2 4 stimulates stretch receptors Stretch receptors trigger 3 parasympathetic reflex that causes the smooth muscle in bladder wall to Loading… contract and internal sphincter opens Stretch receptors send input to the cortex signaling that voiding is 5 needed. However, urine is only expelled if we voluntarily relax the external sphincter via activity of somatic 6 motor system. We can choose to keep the sphincter closed.  Which of the following renal measurements is the smallest? a) Renal blood flow per minute b) GFR per minute c) GFR per day d) Urine formation per minute e) Urine formation per day  A patient is taking blood pressure medication that inhibits sympathetic activity. Which of the following urinary functions might also be affected by this drug? a) Relaxation of the external urethral sphincter b) Relaxation of the detrusor muscle c) Contraction of the detrusor muscle d) Contraction of the external urethral sphincter Loading…  The Urinary System: GFR and GFR Regulation  Glomerular Filtration: GFR Glomerular filtration is the formation of protein-free plasma as blood flows through the glomerulus. 20-25% of the plasma that enters the glomerulus is filtered. On average, 100-120 ml of glomerular filtrate is formed each minute; this is known as glomerular filtration rate or GFR. This amounts to 180 liters each day.  Glomerular Filtration First step in the process of making urine. Specialized capillary exchange, but general rules of bulk flow across capillary bed apply. – Hydrostatic pressure > colloid osmotic pressure Greater rate of exchange compared to other capillaries because: 1. Higher permeability 2. Higher capillary hydrostatic pressure 3. BP constant across glomerulus Normal Capillary Bed Glomerulus Hydrostatic Pressure Hydrostatic Pressure = ~17 mm Hg = ~55 mm Hg  Glomerular Filtration 1. High Permeability Fenestrations – pores in capillary wall, allow materials to be filtered. 2. Glomerular hydrostatic pressure is higher than that found in other beds. 2 arterioles: Afferent and Efferent dilate and constrict to very tightly regulate the pressure in the glomerulus. 3. Blood pressure does not fall across the glomerulus. Renal autoregulation: regulating the afferent and efferent arteriole  Glomerular Filtration Three physical forces involved in filtration; first two are same forces we discussed in terms of bulk flow across any capillary bed: 1. Loading… glomerular capillary blood pressure 2. plasma-colloid osmotic pressure 3. Bowman’s capsule hydrostatic pressure is an additional force to consider Net filtration pressure is the net difference in these forces favoring filtration.  Filtration Forces 1. Glomerular Blood Pressure= 55 mm Hg 2. Plasma Colloid Osmotic Pressure= 30 mm Hg; exists because of plasma proteins 3. Bowman’s Capsule Hydrostatic Pressure= 15 mm Hg; fluid accumulates in capsule and forces fluid back into glomerulus 4. Net filtration pressure (NFP) differences in the forces 5. NFP= 55-30-15= 10 mm Hg  Forces acting on Filtration What happens if I constrict the afferent arteriole?  Forces acting on Filtration How does the Bowman’s Capsule Hydrostatic Pressure go up? What happens if Bowman’s Capsule Hydrostatic Pressure goes up? GFR?  Pressure Profile across Renal Vasculature 120 Glo Peri In Affe Effe R mer tubu tr Dilating afferent and/or ret ret e ular lar ar Arte n constricting efferent Pr 100 capi Arte capi e al e riole llary riole llary n arteriole will lead to V s 80 R al ei s V elevated GFR due to e n ur n ei elevated glomerular e 60 al n ( pressure. A m 40 rt Colloid osmotic pressure m er H y g) 20 Hydrostatic pressure 0 In glomerulus hydrostatic pressure > osmotic pressure= filtration In peritubular capillaries osmotic pressure > hydrostatic pressure= reabsorption Why does hydrostatic pressure drop in the peritubular capillaries?  What’s the main event taking place in the glomerulus? What’s the main event taking place in the peritubular capillaries?  Filtering Membrane The membrane of the glomerulus consists of 3 main structures: 1. Capillary endothelial wall with fenestrations (pores)- fenestrations in the capillary wall to promote filtration, but the pores are just large enough to allow small proteins (albumin) to pass through. To prevent the proteins from moving into the filtrate of the Bowman’s space, the glomerulus is surrounded two additional structures. 2. Glomerular basement membrane made up of a matrix of extracellular negatively charged proteins and other compounds. 3. Epithelial cell layer of podocytes next to Bowman’s space; the podocytes have foot processes that create filtration slits, or openings for particles to move into the filtrate. A particle must be able to pass through all three of these pathways to make its way into the filtrate.  Levels of filtration 1. Fenestrations in epithelial lining of capillaries 2. Glomerular Basement membrane 3. Filtration slits formed by podocytes Glomerular Exchange Pathway: results in protein-free filtrate containing water, electrolytes, nutrients and wastes.  Pathology – Nephrotic Syndrome In nephrotic syndrome, there is marked disruption of the filtering membrane; results in loss of negative charges from filtration barrier Plasma proteins now pass through the membrane and are eliminated in urine Associated with a non-inflammatory injury to glomerular membrane system Called minimal change disease in children  Nephrotic Syndrome: Signs Most common clinical signs are: Marked proteinuria > 3.5 gm/day Edema (loss of plasma oncotic pressure) Hypoalbuminemia (albumin lost in urine)  GFR Fluctuations GFR is held constant over time (autoregulation), but can change depending on body needs Renal plasma flow is most important factor affecting GFR Important concepts: Changes in GFR affect sodium excretion and total body sodium content; this affects ECF volume and MAP Changes in urine output (volume) controlled at tubules by the hormone ADH; this affects ECF osmolarity and ICF volume GFR does not really affect how much urine we produce, but affects what’s in the urine (electrolytes and wastes)  Control of GFR Autoregulation prevents spontaneous GFR changes; kidney regulates itself via intrinsic controls that keeps GFR constant. Sympathetic control of GFR is involved in long-term regulation of arterial blood pressure. In cases of dehydration, sympathetic control would override autoregulation and decrease GFR to conserve salts and water. Both mechanisms control glomerular blood flow by regulating the radius of the afferent arteriole.  Autoregulation- Myogenic Control Smooth muscle of afferent arteriole responds to changes in pressure. When stretched (increased pressure) vessel constricts to decrease flow and maintain GFR. Opposite occurs when pressure falls, muscle relaxes to increase flow. This itself is not enough to maintain GFR, so the kidney also uses tubuloglomerular feedback (TGF) to further autoregulate GFR. As GFR changes, so does the amount of sodium that is delivered to cells in the distal tubule; these cells monitor sodium levels as a reflection of GFR and then trigger TGF. The Juxtaglomerular Apparatus  Tubuloglomerular Feedback (TGF) JGA: macula densa cells in the distal tubules detect salt levels to monitor GFR. They send signals to the afferent arteriole to adjust GFR back to normal.  Due to acute changes in GFR, salt delivery to the distal tubule is increased. Which of the following is consistent with this circumstance? ) The acute condition resulted in a decreased GFR b) The compensatory action by the kidney will be afferent arteriole constriction and decreased glomerular pressure ) The compensatory action by the kidney will be afferent arteriole constriction and increased glomerular pressure d) The acute condition is likely renal artery stenosis  A decrease in which factor will produce the largest increase in net filtration pressure across the glomerulus? a) Efferent arteriole resistance b) Glomerular renal blood flow c) Glomerular renal plasma flow d) Afferent arteriole resistance  A 23-year-old woman comes to the physician because of acute onset of cloudy urine and back pain. Laboratory studies show increases in both renal plasma flow and GFR. Which of the following is the most likely underlying cause of the increases in these two values? ) Constriction of afferent arteriole b) Constriction of efferent arteriole ) Loading… Dilation of afferent arteriole d) Dilatation of efferent arteriole ) Stenosis of the renal arteries ) Stenosis of the renal veins  The Urinary System: Proximal Tubule and Loop of Henle Functions Bowman’s Space Filtrate Filtrate in Bowman’s space: Reflects composition of plasma. Contains same solutes and concentrations as plasma except for proteins. Includes water, nutrients, electrolytes and wastes 300 mOsm. Most of the solutes and water are reabsorbed in the proximal tubules.  Proximal Tubule Overview Reabsorption big picture: 67% of filtered Na+ reabsorbed. 67% of the filtered water reabsorbed. The tight coupling between Na and water reabsorption is called isosmotic reabsorption. This bulk reabsorption of Na and water is Loading… critically important for maintaining ECF volume. Approximately 67% of other electrolytes (Cl-, K, Ca, Mg etc.) 100% of nutrients (glucose, amino acids, etc.) reabsorbed 80% of filtered HCO3- is reabsorbed here, the other 20% in other nephron segments. 50% of the urea (waste product) is reabsorbed.  Early Proximal Tubule Na+ co-transported with Basolateral side Apical (glucose, amino acids, phosphate, lactate, citrate) into the cell from the filtrate, down their concentration gradients. These solutes exit the cell via specific transporters on basolateral surface to then be reabsorbed into the blood. Process is known as secondary active transport.  Water Reabsorption in PT 2. Loading… 1.  Glucose Reabsorption in PT Glucose co-transported with sodium at the apical membrane. The major mechanism for glucose entry into the cells is sodium glucose linked transporter (SGLT). Glucose is then concentrated inside the cell and moves outward through the basolateral membrane via GLUT2 transporter, which does not rely on Na+. Na+ moves out of basolateral side via Na- K pump. Energy from pump drives the entire process, so glucose transport considered secondary active transport. Why does someone with diabetes have glucose in their urine? TM and Reabsorption of Glucose-Normal Plasma Glucose When plasma glucose is normal (N) filtration = reabsorption; no glucose excreted in the urine because all the glucose is reabsorbed. TM and Reabsorption of Glucose- Renal Threshold Renal threshold (T) is plasma [glucose] when glucose first starts to appear in urine. At this point not all the glucose can be reabsorbed. Glucose filtration > reabsorption; glucose begins to appears in urine. TM and Reabsorption of Glucose- TM As plasma [glucose] rises beyond renal threshold, all transporters will eventually become saturated; now reached transport maximum TM. TM is an index of transporter function which is an index of the number of functioning nephrons. Oral Glucose Tolerance Test During Pregnancy  Urea Reabsorption-PT Urea is a waste product from protein degradation. As water is reabsorbed the urea concentration within the tubular fluid increases. A concentration gradient is created Loading… for urea to passively be reabsorbed. 50% of the filtered urea is reabsorbed this way. The level of urea in the blood - blood urea nitrogen (BUN) - is measured clinically as a crude assessment of kidney function; ↑BUN means impaired function.  Organic Ion Secretion-PT Proximal tubule contains 2 distinct carriers for secreting organic ions, one for organic anions and one for organic cations. Most important function of these systems is to secrete foreign organic substances. The liver can convert many foreign substances to an anionic metabolite, which its rate of secretion and elimination from the body by the organic anion secretory pathway in the kidneys. Secretion of these substances may be viewed as a supplement to glomerular filtration to help eliminate these compounds from the body.  H2 Urea Glucose O NaCl & Amino Acids HCO3- Cortex Step 1: Filter Waste products H2O Salts (NaCl, etc) Medulla HCO3- H+ Urea Glucose; Amio Acids Some drugs Step 2: Reabsorption Active Transport Passive Transport Step 3: Secretion Urine to renal Active Transport pelvis The graph shows three relationships as a function of plasma glucose. Curves X and Z are superimposed because: a) Reabsorption and excretion of glucose are equal b) Filtered load of glucose is equal to the amount reabsorbed c) Renal threshold for glucose has been exceeded d) Glucose cotransport has been inhibited e) Glucose clearance is equal to GFR A new drug is being developed to treat a form of diabetes. The goal of this medication is to lower blood glucose levels by increasing glucose excretion in the urine. Which of the following is the likely action of this drug? a) Stimulates the Na/K pump in the late distal tubules b) Blocks the SGLT transporter in the proximal tubules c) Stimulates the GLUT transporter in the proximal tubules d) Increase the plasma renal threshold for glucose transport e) Decrease the filtered load of glucose At plasma concentrations of glucose higher than its Tm: a) excretion rate of glucose equals the filtration rate b) glucose is found in the blood and urine c) reabsorption rate of glucose equals the filtration rate d) renal vein and renal artery blood glucose levels are equal  The Nephron Proximal Convoluted Tubule Molecules are reabsorbed and secreted through both passive and active transport mechanisms % Reabsorbed Na Loop of Henle Water Descending Limb: Electrolytes water reabsorption Nutrients Ascending Limb: Bicarb NaCl reabsorption Urea  Loop of Henle Summary 1. Filtrate enters the loop of Henle isotonic (300 mOsm) 2. Descending limb permeable to water, not salt. Water drawn out of descending limb by vertical osmotic gradient (15 % reabsorbed into vasa recta) 3. At the tip of loop filtrate is hypertonic (1200 mOsm) 4. Ascending limb permeable to salt not water. Salt diffuses out of thin ascending limb and actively transported out of thick ascending limb. 5. Some of the salt is reabsorbed into the plasma of the vasa recta. Some of this salt remains in the interstitial space to contribute to the vertical osmotic gradient (25%). 6. Filtrate leaves loop of Henle hypotonic (100 mOsm) 7. Known as counter-current system Note: loop of Henle and collecting ducts are  important in water conservation H2 Urea Glucose O NaCl & Amino HCO3- Acids Vertical Osmotic Gradient 300 mOsm Cortex 400 mOsm Step 1: Filter Waste products H2O 500 mOsm Salts (NaCl, etc) Medulla 600 mOsm HCO3- H+ NaCl 700 mOsm Urea Thick 800 mOsm Glucose; Amio ascending Acids limb 900 mOsm H2 Some drugs O Thin 1000 mOsm aquaporins ascending Step 2: Reabsorption limb 1100 mOsm Active Transport 1200 mOsm Passive Transport NaCl Step 3: Secretion Urine to renal Active Transport pelvis  Filtrate Osmolarity Entering PCT 300 mOsm 300 mOsm Leaving the PCT Isotonic 300 mOsm Entering descending 300 mOsm Hypotonic 100 mOsm limb of Loop of Henle 100 300 mOsm Bottom of Loop of 100 Henle 1200 mOsm 100 Leaving thick ascending limb of Loop of Henle Hypertonic 100 mOsm 1200 mOsm 100  + + + ++ Mg2+ and Ca2+ Thick Ascending Limb (TAL): Na/K/2Cl- transporter (NKCC2) This is an electroneutral transport resulting in the reabsorption of about 25% of the filtered sodium, chloride, and potassium. Back flow of K+ into filtrate, produces a positive net + voltage in the urine and promotes reabsorption of calcium and magnesium between cells.  What’s the name of the transporter in the cells of the thick ascending limb of the Loop of Henle? What side of the cell? How does Na get out of the basolateral side of cell? How does Cl- get out of the basolateral side of cell? How does K+ get out of the cell? Which is it most likely to go through? Why is that important?  Loop Diuretics Loop diuretics (Lasix/ Furosemide – loop diuretics inhibit NKCC2 transporters More electrolytes left in x x filtrate, so water remains in filtrate. Weakens the vertical osmotic gradient, so less water reabsorbed in collecting ducts. Large diuretic action; but also causes electrolyte loss. In the thick ascending loop of Henle, the tubular fluid undergoes which of the following changes? a) Decreased volume and decreased osmolarity b) Decreased volume and increased osmolarity c) No change of volume with decreased osmolarity d) No change of volume with increased osmolarity e) Increased volume and decreased osmolarity f) Increased volume and increased osmolarity  An investigator collects urine from a subject who has been on a very low sodium diet and finds that the person is excreting urine with low osmolalities as well as low sodium concentrations. The investigator tests the graduate student's knowledge of renal physiology by asking, "In which part of the nephron does the renal tubular fluid first become hypoosmotic to plasma?” a) Proximal tubule b) Thin descending limb of the loop of Henle c) Thick ascending limb of the loop of Henle d) Distal tubule e) Collecting tubule 25  Which of the following is important in maintaining the renal vertical osmotic gradient? a) Descending limb of the loop of Henle b) Ascending limb of the loop of Henle c) Collecting ducts d) ADH e) Vasa recta 26  The Urinary System: Distal Tubule Functions focus on electrolyte balance (sodium, potassium, calcium and hydrogen ions)  Bowman’s Capsule Proximal Convoluted Tubule The Nephron Molecules are reabsorbed and secreted through both passive and Distal Convoluted active transport Tubule mechanisms reabsorption and secretion of Loop of Henle various molecules Descending Limb: water reabsorption Ascending Limb: NaCl reabsorption  Distal Tubule Functions 1. Na+ reabsorption: – early DT; 5% of Na+ reabsorption; utilizes Na/Cl cotransporter on apical surface; cells also involved in controlled calcium reabsorption via parathyroid hormone – (PTH). Loading… late DT and early collecting ducts; Principal Cells; 2-3% Na+ reabsorption, variable control via actions of aldosterone, fine adjustments to urine concentration; utilizes Epithelial Na channels (ENaC) on apical surface. 2. Secretion of H+ and K+.  Distal Tubule: 5% of Na+ Reabsorbed NaCl crosses the apical membrane via a Na/Cl transporter. The Na+ is pumped across the basal membrane via the Na/K- ATPase and Cl- diffuses down its electrochemical gradient through channels.  Distal Tubule: Reabsorb Calcium Calcium enters via hormone-regulated calcium channels. Under the control of parathyroid hormone (PTH). Calcium exits basolateral side via active transport (Ca- ATPase) or 3Na-Ca antiporter.  Late Distal Tubule: Principal Cells and Aldosterone The principal cells are the site of controlled Na+ reabsorption (3%) and K+ secretion; controlled by the hormone aldosterone. How much of the 3% of the remaining sodium that is reabsorbed depends on the concentration of aldosterone. Where does aldosterone come from and what stimulates its release?  The Juxtaglomerular Apparatus Juxtaglomerular Afferent Glomerulus [Granular] Cells Arteriole (Capillaries) Bowman’s Capsule Macula densa Distal Convoluted Proximal Tubule Convoluted Tubule Efferent Arteriole Juxtaglomerular Apparatus Juxtaglomerular [Granular] Cells Macula densa  The Juxtaglomerular Apparatus Macula densa – Functions as intrarenal chemoreceptors – Sensitive Juxtaglomerular to NaCl [Granular] Cells moving past – Functions as intrarenal baroreceptors – them byand Innervated into nervous sympathetic the tubular system lumen – Stimulated by the macula densa – Stimulates the JG cells in Secrete renin in response to response ↓ Blood Pressureto… ↓ Blood Volume ↓ [Na+] JG Macula ↓ urine velocity densa Cells  Low number Arterial ECF volume of Na+ ions Blood decreases present Pressure decreases Juxtaglomerular [Granular] Macula densa Cells cells detect a Intrarenal baroreceptors detect a decrease in NaCl decrease in BP Increased sympathetic activity Increased Renin secretion = increased Na+ reabsorption by Renin is the distal and collecting tubules. secreted With Na+ being reabsorbed into the body H2O follows the Na+ increasing ECF and restoring plasma volume.  The Renin – Angiotensin-Aldosterone System (RAAS) Helps correct ↓ NaCl/ ↓ ECF Volume/ ↓ Arterial blood pressure + H2O is conserved Na+ Angiotensin- osmotically converting enzyme + holds more Renin + (ACE) H2O in ECF Na+ is Angiotensinogen Angiotensin I Angiotensin II Aldosterone conserved ↑ Na+ Vasopressin reabsorption (ADH) Arteriolar Thirst by kidney Vasoconstriction tubules ↑ H2O ↑ Fluid reabsorption by intake kidney tubules  Aldosterone and Sodium ↑ Aldosterone