PHOL Revision Notes - Mammalian Physiology (University College London) PDF

lOMoARcPSD|34136402 PHOL revision notes Mammalian Physiology (University College London) Studocu is not sponsored or endorsed by any college or university Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 Recommended Reading Notes: Body Fluid Compartment: Chapter 2, p14-25 Wha...

lOMoARcPSD|34136402 PHOL revision notes Mammalian Physiology (University College London) Studocu is not sponsored or endorsed by any college or university Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 Recommended Reading Notes: Body Fluid Compartment: Chapter 2, p14-25 What is the principle chemical elements of the body and their percentage of body weight? Oxygen (65%), Carbon (18%), Hydrogen (10%), Nitrogen (3.4%), Calcium (1.5%), Phosphorous (1.2%), Potassium (0.28%), Sulphur (0.25%), Sodium (0.17%), Chlorine (0.16%), Magnesium (0.05%), Iron (0.0007%), Zinc (0.002%), Iodine (0.00004%) What are hydrogen bonds? When a hydrogen atom of a polar bond is attracted to a neighbouring oxygen or nitrogen atom a hydrogen bond is formed. They are weaker than covalent and ionic bonds. What is a polar bond? When the shared electrons in a covalent bond are not equally distributed between the 2 atoms, so the electrons are more associated with one atom more than the other. What is the law of conservation of matter? The number of atoms remain the same but their arrangement changes. What is a solvent? A solvent is a liquid that can dissolve a substance (solute) to form a solution. What is molarity? Molarity is the number of moles or millimoles per litre of solution. Eg: 0.1M solution of glucose contains 0.1 moles of glucose per litre of solution What are some examples of polar substances? NaCl, sucrose, ethanol, acetic acid What are the main strong electrolytes in physiology? Sodium, potassium, calcium, magnesium and chloride ions. What are the main weak electrolytes in physiology? Bicarbonate and phosphate ions. What does rate of diffusion in a solvent depend on? - Temperature Conc gradient Molecular characteristics of solute and solvent (diffusion coefficient) Area available for diffusion Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 What is Fick’s law of diffusion? The role of different factors affecting diffusion is expressed in Fick’s law of diffusion. Amount moved = Coefficient x area x conc gradient Large molecules diffuse slower than small ones. What is osmosis? Osmosis is the movement of water through a semipermeable membrane which allows the movement of water but not other solute particles. What is osmotic pressure? A hydrostatic pressure enough to stop the flow of water through osmosis is called osmotic pressure. Solutions that have the same molality have the same osmolality. EXCEPTION: aqueous salt solutions, you must double their molality to work out osmolality because they separate into their constituent ions so will exert an osmotic pressure double that of its molal conc. Instead of measuring osmotic pressure directly, the osmolarity/osmolality is stated. Define osmolality: Moles solute particles per kg of water. 1g mole of a non-dissociating substance in 1kg of water has an osmotic pressure of 1 Osmol kg -1. Define osmolarity: Moles solute particles per litre of solution 1M solution of glucose has a concentration of 1 Osmol L-1. Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 What is the osmolality of the blood plasma? 0.3 Osm kg -1 (300 mOsmol kg -1) Principle ions (Na+, K+, Cl-, HCO3-) = 290 mOsmol kg-1 Glucose and other small molecules = 10 mOsmol kg-1 Proteins = 1 mOsmol kg-1 What is the colloid osmotic pressure/oncotic pressure? The small osmotic pressure exerted by proteins, plays an important role in fluid exchange between body compartments. What is tonicity of solutions? The influence of the osmolality of the solution on the volume of cells. Eg: - red blood cell placed in 0.9% NaCl solution (0.9g in 100 ml of water) will not change because solution has osmolality of 310 mOsmol kg-1 which is like that of blood plasma. (isotonic saline solution) Body Fluid Compartment: Chapter 3, p27-43 What are the principle minerals found in tissues? Order of abundance: - calcium phosphorous potassium sodium What is lean body mass? Mass of body without adipose tissue What is the water content of the lean body mass? 70-75% But, body fat (adipose tissue) contains 10% water, proportion of body weight contributed by water varies between sexes and age. 60% in adult males and 50% in adult females. Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 What is meant by fluid and what is it divided into? Fluid is the water plus the dissolved materials of cells and tissues. Can be divided into extracellular fluid and intracellular fluid. What is the extracellular fluid divided into? Plasma – the liquid fraction of the blood Interstitial fluid – fluid that lies outside the blood vessels and bathes the cells, contribution of lymph is also within this fluid What is meant by transcellular fluid? The extracellular fluid in the serosal spaces (ventricles of the brain, abdomincal cavity, joint capsules, ocular fluids) What does the interstitial space consist of? - Connective tissue Chiefly collagen Hyaluronate Proteoglycan filaments What does the water of the interstitial fluid do and what is the purpose of this? It hydrates the proteoglycan filaments and forms a gel. This stops the extracellular fluid from flowing to the lower regions of the body due to gravity. How is the body water divided? How can the amount of water in the main fluid compartments be determined? By diluting specific markers. What qualities must the marker have? - The marker disperses only in the compartment measured The marker disperses evenly in the compartment Must have no effect of its own o the distribution of fluids Marker is metabolically inert Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 How is the plasma volume estimated? Dilution of Evans Blue – does not readily pas across capillary walls into interstitial space and is bound to albumin Radio-labelled albumin is also used How is the total body water estimated? Known amount of radioactive (tritiated) water 3H2O or deuterium oxide 2H2O is injected and given time to be distributed throughout the whole body. A sample of blood is taken and the concentration of the marker is calculated. How is the extracellular fluid volume measured? Inulin/mannitol – passes freely between circulation and the interstitial fluid but does not enter cells. How is the volume of intracellular fluid measured? Difference between total body water and volume of extracellular fluid How is the volume measured? Individual with a body weight of 70 kg was injected with 10 ml of a 1 per cent (w/v) solution of the dye. Further assume that a sample of blood was taken after 10 min, and the plasma was found to contain 0.037 mg ml−1 of dye. What is the plasma volume? Volume = amount of dye/concentration Total amount of dye injected = 1% of 10 ml = 0.1 g = 100 mg Plasma conc after 10 mins = 0.037 mg ml -1 therefore: Plasma volume = 100/0.037 = 2702 ml What are some assumptions made and limitations doing this method? - Dye is evenly distributed All of the dye remains in circulation Some dye is lost via excretion and corrections for that loss have to be made Water in bone and dense connective tissue equilibrates slowly so are nit included in estimates How is the limitation overcome to give an accurate estimate of total body water? Volume = amount of marker infused – amount excreted / concentration in plasma Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 The Transport Functions of Cells: Chapter 5, p66-81 - The nature of the cell membrane. How molecules cross the cell membrane. – Channels, carriers and metabolic pumps The difference between active and passive transport. How ion gradients are established across the cell membrane. How these gradients are exploited by cells. The mechanisms of constitutive and regulated secretion. Endocytosis. How does the intracellular fluid composition differ from the extracellular fluid? Rich in potassium ions but poor in both sodium and chloride ions. Rich in protein enzymes, structural proteins and small organic molecules involved in metabolism and signalling such as amino acids, ATP, fatty acids. What is the overall ionic composition of the intracellular and extracellular fluid of mammalian skeletal muscle? What is the resting membrane potential? -90 mV What is the membrane potential? Mammalian cells have an electrical potential across plasma membrane and its magnitude varies from -35 mV to -90 mV. Inside of the cell is always negative with respect to the outside. Existence of membrane potential influences diffusion of charged molecules and ions, positively charged molecules are attracted inside whilst negatively charged molecules are repelled. What factors determine the direction of movement of ions and charged molecules across a cell membrane? - Conc gradient Charge of molecule or ion Membrane potential What is an electrochemical gradient? A combination of conc gradient, charge of molecule or ion and membrane potential gives the electrochemical gradient. Can be calculated by from difference between equilibrium potential for an ion and the membrane potential. Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 What is passive transport? When ions/molecules diffuse across a plasma membrane down their electrochemical gradient. What determines the rate at which a substance crosses a plasma membrane? Number and properties of channels and carrier proteins present. The more channels/carriers present the greater the permeability of the membrane. What is the equilibrium potential? It is the potential where the tendency of the ion to move down its conc gradient is exactly balanced by the membrane potential. The rate at which ions enter the cell is exactly balanced out by the rate at which they leave. How is equilibrium potential measured? Nernst Equation: E = RT/zF ln[C]o/[C]I F is 96,487 C mol-1 What are ion channels? Specific membrane proteins with pores that span the membrane and provide a route for a specific ion to diffuse down its electrochemical gradient. What are some main features of ion channels? - Allow high permeability of natural membranes to various ions such as sodium, potassium and chloride Exists in 2 states: open and closed High capacity for transport High selectivity Named after the principle ion which they are permeable for What are non-selective cation channels? Allow passage of a variety of positively charged ions to cross plasma membrane but do not allow negatively charged ions What are carrier proteins? Bind to specific substances (small organic molecules like gluclose) and undergo a conformational change. What is the capacity of a cell to transport a molecule limited by? - Number of carrier proteins available Number of molecules each carrier can translocate in a given period of time (turnover number) Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 What are some features of carrier proteins? - Transport fewer molecules than channels (typical values are between 102 and 103 Selective for molecules, can differentiate between optical isomers Some can transport molecules/ions against electrochemical gradients this is active transport. What are uniports, symports and antiports? Uniports: bind to a specific molecule on one face of the membrane and then transfer it to the other side Symports: Type of cotransport/coupled transport, both molecules move in the same direction across the membrane Antiport: Type of cotransport/coupled transport, movement of an molecule into a cell is coupled to the movement of a second molecule out of the cell. What is active transport? Requires a cell to expend embolic energy either directly or indirectly and involved carrier proteins. What is primary active transport? When the activity of a carrier protein is directly dependent on metabolic energy derived from hydrolysis of ATP. What is secondary active transport? When the transport of a substance against its conc gradient occurs by the coupling of its uphill movement to the downhill movement of sodium ions into the cell, and this depends on the ability of the sodium pump to keep intracellular conc of sodium lower than the ECF. What experiment was done on the giant squid axon? - Rate at sodium ions being pumped out of axon was worked out by injecting the axon with radioactive sodium ions Adding cyanide stopped the pumping of sodium because it is an inhibitor for ATP generation Injecting ATP into cyanide poisoned axon restored sodium pumping Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 What did the experiment on squid axon show? - Sodium pump requires intracellular ATP If potassium was removed from extracellular fluid then sodium efflux is inhibited Shows that intake of potassium is coupled to efflux of sodium How can the sodium pump be inhibited? Glycoside – ouabain, binds to extracellular face of the protein Why is the intracellular sodium ion conc kept low? The sodium pump maintains the total osmolality of the intracellular compartment equal to that of the extracellular fluid so the cell volume is kept relatively constant. If this was not the case, then there is a tendency for the intracellular conc of ions to become equal to that of extracellular fluid by diffusing down electrochemical gradient. This means the osmolality of the intracellular fluid would increase as the large impermeant molecules cannot pass out of the cell to compensate for the inward movement of small ions. Why are intracellular hydrogen ion conc regulated? - Readily react with and bind to proteins such as enzymes Change function of ion channels and contractile proteins like actin and myosin How do cells regulate intracellular hydrogen ion conc? - - - Cell maintain intracellular conc close to 10-7 moles/l Extracellular fluid conc = 4 x 10-8 mol/l Sodium-hydrogen ion exchange – antiport (outward movement of hydrogen against electrochemical gradient and inward movement of sodium down electrochemical gradient) – secondary active transport Cotransport of sodium and bicarbonate ions into cells to increase intracellular bicarbonate – symport: transports sodium and bicarbonate ions into the cell against electrochemical gradient, bind to excess hydrogen ions to form carbonic acid. 1 molecule of CO2 leaving = 1 H+ used to make molecule of water Chloride-bicarbonate exchange – At high altitudes = low CO2 conc so cell are more alkaline. Intracellular bicarbonate exchanged for extracellular chloride (reversible) How do cells regulate intracellular calcium? - Intracellular conc of calcium = 10-7 – mol/l Extracellular conc of calcium = 1-2 x 10-3 mol/l Low level conc maintained at rest 1. Calcium pump: uses ATP to pump ions against conc gradient 2. Sodium-calcium exchanger: Influx of Na+ down conc gradient provides energy for efflux of Ca2+ - secondary active transport 3. SERCA pump (Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase): Ca2+ stored in sarcoplasmic reticulm 4. Mitochondria: Ca2+/H+ antiporter which is high affinity but low capacity OR calcium uniport which is low affinity but large capacity Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 What is constitutive secretion? - Performed by all cells to release/insert newly synthesised lipids and proteins such as carriers and ion channels into their plasma membranes Tightly regulated Happens over many minutes What is regulated secretion? - Triggered by chemical or electrical signal such as rise in intracellular Ca2+ like hormone or neurotransmitter release (physiological event) Happens over seconds/ fractions of a second What is endocytosis? Membrane retrieval where small areas of the plasma membrane are pinched off to form endocytotic vesicles. Is a response to high levels of exocytosis What is pinocytosis? Called cell drinking as the formation of vesicle traps extracellular fluid What is fluid phase endocytosis? When proteins and macromolecules are absorbed with extracellular fluid during vesicle formation. What is receptor mediated endocytosis? - Protein binds to specific surface receptors Activation of a cell surface receptor causes structural changed in the protein in the cytosolic side and induces internalisation What is phagocytosis? - Large particles are ingested by the cell Only triggered when receptors on surface of cells are bound to particle to be engulfed Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 The Membrane Potential: Chapter 5, p73-81 The origin of the membrane potential Define membrane potential: - Sodium pump causes accumulation of potassium inside cell Plasma membrane is slightly permeable to potassium ions but less permeable for sodium ions Potassium ions leak outside of plasma membrane but sodium cannot replace them by diffusing into cell Loss of potassium cells causes a negative charge inside the membrane Negative charge causes a potential difference across membrane and this is called the membrane potential What is meant by the potassium equilibrium potential? - Negative value of membrane potential attracts positively charged potassium into the cell but they diffuse out of the cell down conc gradient, the potential at which these tendencies are exactly balanced is eqm potential, this is very close to resting membrane potential. The relationship between the ionic permeability of the membrane and the membrane potential How does changes in ionic permeability alter the membrane potential? - - Electrochemical gradients for different ions differ because they have different eqm potentials Membrane potential depends on ionic gradients across the cell membrane and on the permeability of the membrane to the different ions present For potassium at resting membrane potential, the potassium ion distribution is close to the eqm potential so tendency for potassium to diffuse out is balanced by the tendency of inward movement due to membrane potential (charge) For sodium, at resting the electrochemical gradient favours influx but the channels are not open so permeability is low. When channels open permeability is high so membrane potential is close to sodium’s eqm potential (depolarised = less negative) Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 What shows the relationship of membrane potential, ionic gradients and permeability of membrane to specific ions? Goldman equation: The properties of ion channels: – ligand-gated channels – voltage-gated channels What is a ligand-gated channel? - When ion channels open when they bind to specific agonist or ligand Used to send signals from one cell to another Cell is specialised and is adapted to respond to specific agonist What is the difference between ligand and agonist? - Ligand binds to another molecule Agonist binds to and activates a physiological system What is a voltage gated ion channel? - When ion channels open when the membrane potential changes when it becomes depolarised Channels spontaneously close after a short period of time – inactivation Channel exists in 3 different states: closed/resting sate, open and allow ions to cross, inactivated state Cell signalling: Chapter 6, p83-97 The main types of signalling between cells. – paracrine, endocrine, and synaptic signalling What is paracrine signalling: The chemical signals are released by local mediators which act on neighbouring cells through diffusion over short distances. What is autocrine signalling: Secreted chemicals also act on cells that secreted it. Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 What is endocrine signalling? When hormones are secreted into the blood by specialised glands (endocrine glands) and this acts on various tissues around the body. What is synaptic signalling? When nerve cells release chemicals at their endings and affect the cells they contact. How cells detect chemical signals. How do cells detect chemical signals? - Specific receptor molecules Process of transduction happens where there is a link between the detection of the signal and the response What are some properties of receptors? - Are proteins Located in plasma membrane where hydrophilic molecules from extracellular fluid can bind to Cells have cytoplasmic and nuclear receptors for hydrophobic signalling molecules Receptors exist intracellularly too for secondary messengers How cells respond to various chemical signals. How do cells respond to various chemical signals? - Individual cells have different types of receptors so they respond to different types of extracellular signals Response of a cell to a signal depends on which receptor is activated How does the response to acetylcholine differ? - Cause muscle to contract – when released by nerve terminals of motor nerve fibres onto skeletal muscle Slows heart rate – when released from endings of vagus nerve Nicotinic receptors – activated by alkaloid nicotine and is found on skeletal muscles Muscarinic receptors – activated by muscarine and is found in the heart What are the 10 chemical classes signalling molecules are divided into and what are the examples? Esters – acetylcholine (synaptic signalling/ligand gated ion channels/GPCRs) Amino acids – glutamic acid(synaptic, ligand gated ion channels) Amines – adrenaline / epinephrine (hormone, ligand gated ion channels) Peptides – ADH (vasopressin) (hormones, GPCRs) Proteins – insulin, growth hormone (hormone) Steroids – testosterone, oestradoil (hormone, gene expression) Iodinated amino acids – thyroid hormones (binds to nuclear receptor, gene expression) Eicosanoids – prostaglandin (GPCRs) Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 Inorganic gas – nitric oxide (binds to guanylyl cyclase) Nucleosides and nucleotides – adenosine How do receptors control activity of the target cells? – Changes in ion channel activity. - Change in membrane potential/ entry of Ca2+ Ligand gated ion channels are open for a short time This transiently alters membrane potential of the target cell Change in membrane potenical causes depolarisation of target cell Depolarisation activates voltage-gated ion channels and triggers a cellular response How does the stimulatory effect of acetylcholine or adrenaline achieve this effect? - Secreted by chromaffin cells in adrenal gland Acetylcholine released by splanchnic nerve and binds to nicotinic receptors causing the increase in permeability of sodium and membrane becomes depolarised Voltage gated ion channels open and calcium ions flow down conc gradient into the cell Intracellular calcium conc increases and triggers secretion of adrenaline – Second messenger cascades. - GPCRs changing the intracellular conc of second messangers What are GPCRs? - A large protein family of receptors that sense external molecules and go on to activate inside signal transduction pathways. What is a second messenger? - The intracellular signalling molecule What are some examples of second messengers? - - - cAMP – activates protein kinase A which regulates the activity of many enzymes made by adenylyl cyclase activated by binding to α subunit of Gs increase in intracellular cAMP means it can bind to intracellular proteins and alter their activity activation of adenylyl cyclase means that the cell can amplify the signal many times signal is terminated by converting cAMP to AMP by phosphodiesterases IP3 – triggers release of calcium from intracellular stores PIP2 is catalysed by phospholipase C and makes IP3 and diacylglycerol (DAG) IP3 is a water-soluble molecule and diffuses through the cytoplasm and binds to receptors which releases calcium from the endoplasmic reticulum. DAG – regulates activity of enzymes through protein kinase C Hydrophobic molecule generated by PIP2 Diffuses through the membrane and interacts with and activated protein kinase C Protein kinase C is an anzyme and activates other enzymes so regulates various cellular responses including DNA transcription Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 What are the signal transduction pathway of the second messenger formation of IP 3 and DAG? How does adrenaline cause the breakdown of glycogen to glucose? – The control of gene expression. - Signal acts on intracellular receptor to modulate the transcription of specific genes Steroid hormones are able to bind to cytoplasmic and nuclear receptors How do steroid hormones control gene expression? 1. Hormone crosses the plasma membrane through diffusion and binds to specific cytoplasmic receptor 2. Receptor – hormone complex migrates to the nucleas and this increased the transcription of DNA into appropriate mRNA 3. mRNA is used as a template for protein synthesis How does signalling via the thyroid hormone differ from this? Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 - For hormone to enter the tissue it does so by specific transporter proteins Receptors for steroid and thyroid hormone are art of the nuclear receptor super family Not all receptors are found in the cytoplasm, some are bound to DNA in the nucleus What happens in the absence of specific ligand? - Members of nuclear receptor superfamily bind to regulatory protein = inactive complex How does the inactive complex become activated? - When ligand is bound, the receptors have a conformational change and causes dissociation of regulatory proteins Activated receptor regulates transcription of gene What is the primary response? - When the hormone-receptor complex activates small set of genes quickly, less than an hour What is the secondary response? - When the proteins made in the early phase activate other genes What determines the physiological response when binding to a nuclear receptor? - The presence of appropriate intracellular receptor and set of regulatory proteins What are some features of signalling through gene expression? - Long lasting and slow What are gap junctions? When specific membrane proteins associate to form a structure called connexons. When 2 connexons are aligned the cells become joined by a water-filled pore. They allow the exchange of small molecules and ions between neighbouring cells. - Allow electric currents to flow from one cell to another and allow the electrical coupling of cells allowing individual myocytes to be coordinated. Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 Skeletal Muscle: Chapter 8, p120-131 The principal morphological characteristics of the three main types of muscle What is the structure of the skeletal muscle? - Each skeletal muscle made up of many muscle fibres (long, thin, cylindrical cells with many nuclei) Are striated Length of muscle fibre ranges from few mm to 10cm or more Diameter of muscle fibre ranges from 50 to 100 micrometer Features include endomysium, perimysium, muscle fascicles, epimysium/fascia The detailed structure of skeletal muscle What is an endomysium? A connective tissue where individual muscle fibres are embedded in What is a perimysium? A connective tissue that binds together groups of muscle fibres What are muscle fascicles? Bundles of perimysium grouping together muscle fibres What is the epimysium/fascia? Coat of connective tissue which covers the whole muscle and binds individual fascicles together. What secretes the connective tissue matrix of the muscles? Fibroblasts – lie between individual muscle fibres and contain collagen and elastic fibres that merge with the connective tissue of the tendons, transmitting mechanical force generated by the whole muscle to the skeleton. What regulate the muscle length? Muscle spindles Excitation-contraction coupling in skeletal muscle The mechanism of contraction in skeletal muscle The sliding filament theory The mechanical properties of skeletal muscle Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 Introduction to endocrinology: Chapter 20, p295-299 The main endocrine glands What are hormones? Chemical agent produced by cells within endocrine tissues that travel in the bloodstream to target cells where they exert a regulatory effect. What are the main endocrine glands and what do they secrete? Hypothalamus Pituitary gland Thyroid Gland Parathyroid Glands Adrenal glands Pancreas Ovaries Testes Releasing hormones: GHRH, CRH, TRH, GnRH, vasopressin Inhibitory hormones: somatostatin, dopamine Growth hormone, oxytocin, prolactin, vasopressin, ACTH, MSH, TSH, FSH, LH Thyroid hormones (T3 AND T4), calcitonin Parathyroid hormone Adrenal cortex: cortisol, aldosterone, adrenal androgens Adrenal medulla: adrenaline, noradrenaline Insulin, glucagon Oestrogen, progesterone Testosterone Name organs which secrete hormones: Kidneys Liver Heart Fat cells Gastro-intestinal tract Renin – blood pressure Erythropoietin – red cell production Vitamin D3 – plasma calcium Insulin-like and Growth Factors (IGR-l and IGF-ll) – growth Atrial Natriuretic factor (ANF) – Na excretion by kidneys Leptin – Regulates appetite Gastrin, secretin, cholecystokinin – digestive processes What hormones regulate What processes do hormones regulate? - Growth, development of physical, sexual and mental characteristics – growth hormone, thyroid hormones, testosterone, oestrogen Utilisation of nutrients by cells – insulin, glucagon, cortisol, growth hormone, adrenaline Adjustment of salt and water balance – aldosterone, vasopressin (ADH), atrial naturiatic factor (ANF) Metabolic Rate – thyroid hormones Dealing with stress – cortisol, adrenaline Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 Chemical nature of hormones What are the chemical natures of hormones and how are they carried in the blood? Steroids Peptides Specific amino acids Derived from cholesterol: testosterone, oestrogen, cortisol, aldosterone, adrenal androgens, active metabolites of vitamin D Hypothalamic thyrotrophin releasing hormones (3aa), GH, FSH (200 aa) Catecholamines (adrenaline) – derived from tyrosine and thyroid hormones which are formed by the combination of iodinated tyrosine residues. What are hydrophilic hormones? - Do not enter cells and bind to cell surface receptors Receptors are integral membrane proteins Hormones stored in secretory granules/vesicles Eg: adrenaline, growth hormone, vasopressin What are hydrophobic hormones? - Enter cells and receptor is a soluble protein inside the cytoplas, Can enter the nucleus Cannot be stored and are synthesised on demand Eg: estrogens, thyroid hormones T3, Vitamin D3 Transport of hormones in the blood How do hydrophilic hormones travel in the blood? Amino acid and peptide hormones travel in the plasma How do hydrophobic hormones travel in the blood? Steroid and thyroid hormones are hydrophobic so are carried in the blood by binding to plasma proteins such as albumin, sex hormone binding globulin, cortisol binding globulin and thyroid hormone binding globulin. Unbound free hormones are active, so there is an eqm for the proportion of hormone existing in free state, change in binding protein affects the conc of free hormone conc. What happens to the clearance of hormones bound to carrier proteins? - Clearance from circulation is slower than travelling in free solution Half lives in the blood are prolonged – sustained endocrine response and constant rate of tissue delivery How hormones work How do hydrophobic hormones work? 1. Hormone dissociates from carrier protein 2. Hormone binds to the receptor causing a conformational change and releasing the regulatory protein Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 3. The hormone-receptor complex diffuses into the nucleus and expresses a small set of genes quicky and hormone is transcribed 4. mRNA of hormone is translated 5. Hormone binds to carrier plasma protein and the target cell’s function is altered. *steroid hormones and thyroid hormones bind directly to receptors in the nucleus *action of steroid hormones are longer than protein hormones How do hydrophilic hormones work? Bind to receptors in plasma membrane and exert effects either through: - Second messengers like: calcium, cAMP, IP3 Calcium – calmodulin is a calcium binding protein within the cell where on binding of 4 calcium ions the calmodulin becomes an activator of signalling cascades like protein phosphorylation and dephosphorylation, regulation of the cytoskeleton and metabolism of second messengers. How do G-proteins work? 1. Inactivated state: GDP bound to α and hetertrimeric structure is associated together 2. Binding of hormone such as adrenaline/vasopressin, causes heterotrimer to activate and GDP is converted to GTP and causes G protein to dissociate. 3. These dissociated forms move laterally in the membrane to modulate the activity of membrane bound enzymes of ion channels. Activating membrane-bound kinases – receptor tyrosine kinase – binding of hormones like insulin, growth hormone, prolactin activates autophosphorylation of tyrosine residues which phosphorylates other downstream protein substates. Absence of agonist the receptor is a monomer or inactive dimers - Binding of agonist causes conformational change – active receptor dimer Autophosphorylation of receptor Phosphorylated region of RTK is recognised by other proteins and activates further downstream signalling Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 The pituitary gland and hypothalamus: Chapter 21: p300-306 Hypothalamic control of the Anterior and Posterior Pituitary What are the acronyms of the main hormones? GnRH – Gonadotrophin Releasing Hormone GHRH – Growth Hormone Releasing Hormone FSH – Follicle Stimulating Hormone LH – Luteinizing Hormone TSH – Thyroid Stimulating Hormone ACTH – adrenocorticotrophin IGF – Insulin-like Growth Factor T3/T4 – Thyroid Hormone Describe the interaction between the hypothalamus and the pituitary - - - Hypothalamus and posterior pituitary derived from neural tissue Pituitary is a composite because anterior derived from non neural tissue and posterior derived from neural Hypothalamus provides neural input to the endocrine system 2 types of neurones – from hypothalamus to posterior pituitary the pituitary secretes 2 hormones from the synaptic terminals– secrete oxytocin or vasopressin – called neurosecretion Oxytocin and vasopressin are made of 9 amino acids, 7 aa are identical, but receptors are specific Oxytocin – contractile during childbirth Vasopressin – absorption of water Short neurones in hypothalamus connected to blood supply in the hypothalamus and is connected to anterior pituitary (SO HORMONES DO NOT GET DILUTED) Hypothalamus Anterior Pituitary: GnRH, TRH, GHRH, Dopamine, CRH Anterior then stimulates release of second set of hormones: TSH, ACTH, GH, FSH, LH, Prolactin *Hormones that are RH- coming from hypothalamus *Hormones that are SH -coming from anterior pituitary FSH, LH, TSH – glycoproteins made of alpha and beta subunits so are long lasting AP has different cells types can synthesise and secrete 6 hormones stored in specific cells: GH – stored in somatotrophs Prolactin – stored in Lactotrophs FSH/LH – stored in gonadotrophs ACTH – stored in corticotrophs TSH – stored in thyrotrophs Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 Negative feedback: - too much cortisol inhibits hypothalamus and AP - too much ACTH inhibits hypothalamus What hormones act on GPCRs? - TRH GnRH GHRH CRH ACTH What hormones act through regulation of tyrosine phosphorylation? - Prolactin GH IGF-1 How are prolactin and GH different from other pituitary hormones? - They do not act on GPCRs they act on tyrosine kinase receptors How is sex determined in an embryo? - Y chromosomes has SRY gene SRY gene dictates that testes are made Testosterone and Mullerin inhibiting Hormone (MIH) – needed for male development Without this female characteristics are made Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 - More active form of testosterone = Dihydroxytestosterone (DHT) for development of external genitalia Before 7-8 weeks = sex of embryo indeterminate Mullerian duct = fallopian tube and uterus Wolffian duct = MIH causes Mullerian duct to degenerate and testosterone differentiates Wolffian duct, gives rise to vas deferens and seminal vesicles Describe the male reproductive organ - Testis in epididymis where sperm is maturation, connected vas deferens with seminal vesicles which adds fluids Infertility can be caused by defects in the PLC Testes – source of germ cells and hormones important for reproductive function Seminiferous tubules where spermatozoa are made Secretion of androgens for full masculine development How sperm are made? - Main accessory glands are – seminal vesicles and prostate Sperm made in seminiferous tubules Prostate makes PSA (prostate specific antigen – enzyme) – to liquify sperm Amount of PSA increases with age Seminal vesicles secrete alkaline solutions and fructose as nutrients for the sperm Sperm production is controlled by LH and FSH which act on Leydig cells – testosterone is made – FSH acts on Sertoli cells – spermatogenesis is initiated Basal membrane separates the sperm Sertoli cells from rest of circulation – stops the immune response Leydig cells – synthesise testosterone – diffuses to Sertoli cells – converted to Dihydrotestosterone Secretion of testosterone decreases and sperm count decreases by age Average sperm count? - 108 sperm/litre 206 sperm/litre = infertility Describe the testis and their function - Development of sperm is in the seminiferous tubules Seminiferous tubules connected to vas deferens Epididymis – 21 days for maturation How do the testis interact with hypothalamus and pituitary? - Hypothalamus => GnRH => Anterior Pituitary => LH => Leydig cells => Testosterone => sperm, bone, beard, lower voice Hypothalamus => GnRH => Anterior Pituitary => FSH => Sertoli cells for spermatogenesis, differentiation of spermatids to spermatozoa (maturation) Secretion of GnRH is episodic Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 How do ovarian and uterine cycle relate to one another? Ovarian – produce mature oocyte every 28 days Uterine – provides environment for the fertilised ovum to develop - oestrogen secreted by thecal and granulosa cells thickens endometrial lining and then progesterone and oestrogen makes endometrial glands secrete thick fluid Ovarian cycle – secretes hormones Uterine cycle – physical changes due to cycle of hormones What happens in the ovary? - Primordial follicle – 25 microns Primary follicle matures to granulosa cells (60 microns) and then to granulosa cells (150 microns) – under hormonal control Mature follicle ovulates Mature corpus luteum is left which secretes progesterone and oestrogen if fertilisation takes place No fertilisation: corpus luteum => corpus albicans Describe the ovarian cycle 1. Follicular phase – before ovulation - Dominated by oestrogen - Primary follicle matures – granulosa cells have receptors for FSH and oestrogen – also make oestrogens – positive feedback loop – causes further activation of proliferation of granulosa cells – so oestrogen levels are increasing - Thecal cells have receptors for LH Testosterone from thecal cells stimulate granulosa cells and is converted into estradiol = endometrial thickening 2. - Luteal phase : corpus luteum makes and secretes oestrogens and progesterone under influence of LH/FSH Progesterone – supports secretory phase of endometrium but depressed LH secretion Oestrogen – alters pituitary sensitivity to GnRH so LH/FSH declines Corpus luteum is maintained by LH, so when LH declines it becomes corpus albicans No more corpus luteum so oestrogen and progesterone decline and endometrium sheds and cycle restarts Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 Describe the uterine cycle - Menstrual phase, proliferative phase due to oestrogen, secretory phase due to oestrogen and progesterone Oestrogen – makes endometrial glands have receptors for progesterone Progesterone makes endometrial glands secrete thick fluid rich in sugars, glycoproteins and amino acids and thickens What hormones are involved in pregnancy? How? - Fertilised egg secretes: HCG – human chorionic gonadotrophin – like FSH and LH – corpus luteum is maintained for 3 months until placenta can secrete progesterone and oestrogens – detected in urine HPL – human placental lactogen – like prolactin – growth of mammary glands Progesterone and oestrogen maintain endometrial lining and increases during pregnancy until parturition (birth) Describe parturition - Adrenal gland of foetus responds to foetal stress ACTH secreted Cortisol secreted Decrease in placental progesterone Prostaglandins from placenta Uterine contractions Posterior Pituitary releases oxytocin More contractions until foetus expelled How is lactation regulated? - Suckling – prolactin – synthesis of milk Suckling – oxytocin – ejection of milk by contraction of myoepithelial cells of mammary glands Prolactin suppresses release of GnRH – release of FSH and LH declines and low fertility Lactation can be suppressed by dopamine which depresses prolactin release Dopamine antagonist allows prolactin release and milk synthesis Describe the structure of adrenal glands - Top of kidneys Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 - Composed of 2 tissues- medulla (sympathetic nervous system), cortex – mesodermal tissue Medulla – derived from neuroectodermal tissue, secrete adrenaline and noradrenaline Cortex: Zona glomerulosa – aldosterone (regulates Na/K) – mineralocorticoid Zona Fasciculata – cortisol (increases glucose in blood stream) – glucocorticoid Zona Reticularis – androgens (sex steroids) List the functions of adrenal glands - Regulate blood glucose levels – cortisol Protein turnover – cortisol Survival during stress – cortisol and adrenaline Tissue response during injury and infection - cortisol Na/K balance – aldosterone Describe the pathways of cholesterol metabolism in the adrenal glands pregnenolone => aldosterone 17-alpha-pregnenolone => cortisol Dehydroepiandrosterone => testosterone How is adrenal cortex involved in ionic balance? - - Conserves Na ions and secretes K ions to maintain normal extracellular fluid volume High K+ levels (>4-5 mM) – stimulates adrenal cortex – releases aldosterone – stimulates kidney to excrete K+ at the expense of Na+ - DOES THIS BY PRODUCTION OF SODIUM CHANNELS IN APICAL MEMBRANE AND PRODUCTION OF NA K ATPASE Na deprivation/loss of volume – release of renin (enzyme) from kidney – converted go angiotensin II – adrenal cortex – aldosterone – kidney – excrete K+ Renin is inhibited by ANF of heart Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 Describe the renin-angiotensin system angiotensinogen is in the plasma How is cortisol secretion regulated? - Stress, low glucose and diurnal rhythm stimulates hypothalamus for CRH production Short and long feedback loops from cortisol in adrenal cortex to inhibit ACTH and CRH production, ACTH also inhibits CRH What are the functions of cortisol? - Raise blood glucose by regulating metabolisms Adaptation to stress – immunosuppressive, anti-allergic, anti-inflammatory Gluconeogenesis Glycogenesis What is Cushing’s syndrome? What are the symptoms? - Too much cortisol, redistribution of body fat, wasting of muscle, hyperglycaemia What causes too much cortisol? - Increased output of ACTH Increased secretion of CRH Lung tumours – produce ACTH Inflammatory disorder given corticosteroids List and characterise all the hormones opposing insulin - CORTISOL – protein and fat breakdown to make glucose GROWTH HORMONE – changes energy usage from carbohydrates to fats ADRENALINE AND GLUCAGON – action on liver to mobile glucose by breakdown of glycogen and stimulate synthesis of glucose Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 Describe synthesis and secretion of catecholamines from the adrenal medulla - Medulla made of chromaffin cells which are postganglionic neurones Cells filled with granules of adrenaline, ATP, opioid peptides Granules are secreted by exocytosis Blood from cortex enters the medulla so cortisol stimulates production of adrenaline as the enzyme is upregulated. Tyr – adrenaline Cholinergic synapse signal causes increase of calcium Vesicles of adrenaline and noradrenaline are released Tyr – DOPA – dopamine – NorA – adrenaline – secretory granules – blood stream - β – cAMP - α – PLC What are the consequences of insulin deficiency? - Diabetic patient – levels of glucose go up dramatically Decreased glucose uptake – hyperglycaemia – (glycosuria) loss of glucose in urine – loss of water (osmotic diuresis) – dehydration – coma and death Increased lipolysis – increased plasma levels of FA – Ketogenesis and ketonuria – metabolic acidosis Increased protein breakdown – increased aa levels in plasma – loss of muscle mass – weight loss, weakness Increased aa levels in plasma – increased gluconeogenesis – increased urinary nitrogen What are the consequences of permanently elevated glucose levers? Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 - Glycosylation of proteins like haemoglobulin Lens of eyes become opaque Degenerative change in retina and peripheral nerves Thickening of filtration membrane of nephron Describe insulin signalling - - insulin is an anabolic hormone islet of Langerhans β cells – insulin actin of insulin – liver, muscle and adipose tissue uptake of glucose and aa by muscle and adipose tissue storage of fuels – synthesis of triglycerides, protein and glycogen resting level of glucose: 5.6mM (1mg/ml) After a meal: 7-8mM Tyrosine kinase activity 1. Insulin binds to insulin receptor kinase 2. Adaptor protein IRS1 is phosphorylated 3. PIP3 is made by phosphorylating PIP2 by enzyme PI3Kinase 4. Akt is activated by PI3K allows exocytosis of GLUT4 vesicles at plasma membrane 5. Glucose uptake Type 2 diabetes: - Insulin resistance Defects in glucose uptake due to signal transduction Akt phosphorylation defects Defects in protein that mediates GLUT4 translocation Describe the synthesis, control, and secretion of thyroid hormones 1. 2. 3. 4. 5. Thyroid hormones T3 and T4 – T3 is more active than T4 Parathyroid embedded in thyroid – parathyroid hormone (PTH) + Calcitonin – calcium homeostasis Calcitonin is from thyroid, made by Parafollicular (C) cells TRH from hypothalamus through hypophyseal portal vessels to anterior pituitary TSH stimulated to thyroid glands Thyroid follicle in thyroid glands with lots of thyroid cells and they cover a colloid where thyroid hormones are made and stored – have good blood supply Conc of T4 – 60-150 nM T3 – 1.2-2.9 nM Negative feedback loop from T3/T4 – TSH secretion, T3/T4 – TRH secretion Synthesis: Process of synthesis stimulated by TSH from ant.pit, by binding to receptors on thyroid epithelial cells it makes: iodine transporter, thyroid peroxidase, thyroglobulin (backbone to make hormones). Reverse T3 is made which has no biological activity and is a form of regulation. 1. 2. Production and accumulation of raw materials Synthesis of hormones on a scaffold of precursors Release of the free hormones from the scaffold and secretion into blood Uptake and concentration of iodine into the gland Oxidation and incorporation of the iodine into tyrosine on thyroglobulin Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 3. Coupling of two iodinated tyrosine molecules to form T3 and T4 4. Thyroid specific transporters on membrane enable thyroid to be released 5. Release thyroid hormones linked to thyroid binding globulin – transporter protein What is the morphology of Thyroid Glands? - Have microvilli on follicular cells – thyroid cells make precursors of hormones and release into the colloid, the colloid is digested and the hormones are absorbed for reuptake and release What is the thyroid hormone structure? - Amino acid – tyrosine Have iodine T4 – has 4 T3 – has 3 T3 has shorter half life and is biologically active Thyroid hormones are 2 tyr linked together Number and position of iodine is important What is cretinism? - Happens due to iodine deficiency Large goitres and hypothyroidism Post natal iodine deficiency – intellectual impairment, deafness, paralysis Can be screened – heel prick analysis What is Hashimoto’s disease? - Autoimmune destruction of thyroid so no thyroid hormones are made Sensitive to cold, loss of hair, impaired memory, mental dullness, weight gain, decreased BMR Lack of TH during childhood – mentally impaired What is Graves disease? - Hyperthyroidism – antibodies stimulate TSH receptor a lot of TSH Leads to goitre, protrusions of eyeballs, weight loss, nervousness, increased BMR Describe the mode of action of thyroid hormones - Enter cells and bind to receptor in the nucleus and initiate gene transcription Acts on: liver, heart, kidney, NS, skeletal muscle Tissues are sensitised to adrenaline and stimulate cellular respiration, metabolic rate and oxygen consumption, stimulate lipolysis, stimulate protein synthesis and Na/K ATPase Heat production – form of thermoregulation In combo with GH they have important effect on development – absence can cause impairment in neural and sexual development Type 1/2 Selenodeiodinase enzyme increases activity converts T4 - T3 Type 3 selenodeiodinase – decreases activity by inactivation of T2 and T3 by converting to reverse T3 and and T2 Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 What is growth? - Complex process influenced by genetics, endocrine function and variety of environmental factors, including nutrition Cell division and net protein synthesis Teens is when we grow the most, growth of spine Growth is due to hyperplasia – cell division Hypertrophy – content of cells increases – size of cells Neoplasia – unregulated cell growth Growth plates close due to androgens (M) and oestrogens (F) during puberty List hormones important for growth - GH – anabolic build up of muscle and break down of fat Thyroid Hormones – fetal development Vitamin D metabolites – calcium regulation Parathyroid Hormones - calcium regulation Gonadal steroids – puberty Insulin – take up glucose for energy Cortisol – too much can inhibit growth How is secretion of GH controlled? - In hypothalamus there are 2 neurons: SRIF – somatostatin – inhibits action of GHRH neuron at the somatotroph to inhibit release – both in close position Somatotroph released GH into circulation Negative feedback loop where IGF-1 can increase activity of SRIF neuron Ghrelin stimulates somatotroph for release GHRH and somatostatin act on GPCR on somatotrophs GHRH – activates adenylyl cyclase and transcribes GH in the nucleus Somatostatin – inhibits adenylyl cyclase GH is stored in cells Half life – 15 mins List long term and short term effects of GH - Acts on: liver, muscle, bone and adipose tissue Ghrelin – somatotroph – GH – releases energy from stores like adipocytes Long term – amino acid uptake by muscle and liver and increases protein synthesis, stimulates growth and calcification of cartilage into bone resulting in bone length growth Short term effects: fat and carbohydrate metabolism, during starvation – persistent low glucose will increase GH and spare glucose for CNS and fat utilisation Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 List diseases associated with growth - GH deficient children with human GH Achondroplasia – short arms and legs – defect in growth factor which allows bone elongation GH deficiency – very small and young face Laron Dwarfism – normal GH levels but receptor does not work Hypothyroid – lacking TH so can’t stimulate GH gene activation Gigantism – tumour in pituitary gland and over produce GH Acromegaly – eyebrows are heavy, big features, excess GH, cartilage keeps growing Describe the neutral calcium balance in an adult. What functions has calcium in the body? Describe calcium homeostasis What is pseudoparathyroidism? Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 Renal System Kidney function: - Regulates blood ionic composition Regulations of blood pH Regulate blood volume Regulate blood pressure Maintenance of blood osmolarity Production of hormones – calcitriol/erythropoietin Regulation of blood glucose levels Excretion of wastes from metabolic reactions and foreign substances Kidneys in lower back Each nephron has an individual capillary Pathway of blood in kidneys: Renal artery – segmental artery – interlobar arteries – arcuate arteries – interlobular arteries – afferent arterioles – glomerular capillaries – efferent arterioles – peritubular capillaries – interlobular veins – arcuate veins – interlobar veins – renal vein Sympathetic nervous system – vasomotor (affecting diameter of blood vessels)– affect smooth muscle (Poiseuille’s law) Nephrons: Functional unit of kidneys Renal corpuscle – where filtration occurs, filters the blood plasma: - Glomerulus – capillaries Glomerular capsule – surrounds the glomerulus – double walled Renal tubule – extended tube networks - Proximal convoluted tubule Descending and ascending loop of Henle Distal convoluted tubule – collecting duct to the ureter 2 types of nephrons: - Cortical – outer layer of kidneys – 80% of nephrons Juxtamedullary nephrons – inner layer extension into the medulla, longer loops of henle, more reabsorption and concentrated urine – 20% of nephrons, blood coming from peritubular capillaries and vasa recta Features of renal corpuscle - Bowmans capsule makes up renal corpuscle – have thin layer of parietal cells Thin walled capillaries with mesangium cells in between Filtration membrane made of: parietal cells, basement membrane, podocytes Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 - Distal convoluted tubule – regulation area in nephron with juxtaglomerular cells and macula densa apparatus cells which senses pressure and sends signals to smooth muscles lining afferent and efferent arteriole - Proximal convoluted tubules – microvilli with brush borders Juxtaglomerular apparatus – regulate blood pressure in the kidney Macula densa – final part in ascending loop of henle Juxtaglomerular cells – have smooth muscle fibres in afferent and efferent arterioles Distal convoluted tubule and collecting duct – ADH and aldosterone act on principle cells Intercalated cells – blood pH homeostasis - Total blood flow – 1.25 l/min – 25%of resting cardiac output Intrinsic control – can keep renal flow constant without nervous stimulation and when BP changes between 80-200 mmHg Autoregulation: intrinsic protective mechanism where renal blood flow remains constant and independent on changes to arterial blood pressure (80-200 mmHg) Poseuille’s law – fluid flow controlled by resistance to laminar flow, to change the flow is through changing diameter of the blood vessel (afferent and efferent arterioles) Mechanisms for autoregulation: - - - Myogenic hypothesis: If afferent arterioles are stretched: Increase in perfusion pressure Distension of afferent arteriole wall Smooth muscle fibres stretch Muscles contract after being stretched for too long Increases vascular resistance Decreases blood flow Smooth muscle relaxes Tubuloglomerular Hypothesis: Glomerular filtrate increases, increase in filtration More filtrate flow through the nephron Juxtaglomerular apparatus releases renin to reduce blood pressure Afferent arteriolar resistance is increased by constriction so that flow and GFR are normalised and blood pressure decreases Metabolic Hypothesis: Renal tissue metabolites maintain vasodilation so if there is an increase in perfusion pressure then there is increased blood flow which will cause the metabolites to be Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 washed away from the renal tissue = decreased vasodilation more vasoconstriction meaning the blood pressure decreases Eg: humoral factors from vascular endothelium (NO) is a vasodilator When blood flow changes drastically: There are extrinsic factors: - Renal nerves: both sympathetic (vasoconstriction) and parasympathetic (vasodilation) Humoral factors in blood: adrenaline/noradrenaline (vasoconstriction in cortex) and vasopressin (vasoconstriction) Renal failure – due to reduction in renal flow Ultrafiltration: plasma flows through the glomerular capillaries 20% is forced into the Bowmans capsule due to hydrostatic pressure of the blood, capillaries have fenestrations in endothelial cell walls Bowman’s capsule has same composition to blood plasma but NO PROTEIN Glomerular filtrate is cell and protein free Molecules < 1.8nm freely filtered but >3.6nm not filtered Cations readily filtered than anions Negative charge of serum albumin stops it from being filtered The ultrafiltration barrier: - Fenestrated endothelium – stops filtration of blood cells but allows all other components to pass through Basement membrane – divert medium sized protein, has a negative charge Podocytes – has negative charge, slits – fine filtration slit (foot processors) Starlings forces: Single nephron GFR (snGFR) – rate at which single nephron forms ultrafiltrate “balance of hydrodynamic forces” - Hydrostatic pressure – key driving pressure Osmotic/plasma protein oncotic pressure/colloid oncotic pressure – as plasma proteins remain in blood plasma Oncotic pressure opposes the hydrostatic force Small oncotic pressure from Bowman’ space opposing hydrostatic pressure – NET FILTRATION PRESSURE Starling Forces in Glomerular Filtration: 1. Hydrostatic pressure of glomerular blood (GBHP)= 55 mmHg 2. Capsular hydrostatic pressure (CHP) (pressure from fluid in the bowman’s capsule)= 15 mmHg 3. Blood colloid osmotic pressure (BCOP) = 30mmHg Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 Net Filtration pressure: GBHP – CHP – BCOP = 10 mmHg K = constant, how leaky If blood pressure increases, then hydrostatic pressure increases, and GFP increases. If blood pressure drops, hydrostatic pressure decreases, GFP decreases If kidney stones, increase in hydrostatic pressure in Bowman’s capsule, decreases GFP If protein level drops in blood (liver failure), oncotic pressure drops, GFP increases If protein level in Bowman’s capsule increases (renal failure), increases GFP GFR can be estimated By measuring the rate of excretion of substances that are: EG: INULIN - Freely filtered Not reabsorbed or secreted by tubules Have no influence on renal function Clearance of inulin: 125 ml/min = 180 litres of plasma filtered every 24 hours Rate of excretion = concentration in urine (Uc)x amount of urine produced per min Clearance = concentration in urine x amount of urine produced per min / plasma conc of inulin RENAL CLEARANCE = the volume of plasma completely cleared of a given substance in 1 min, used to estimate GFR If substance has a clearance < GFR = amount filtered > amount reabsorbed = substance has been reabsorbed If substance has a clearance > GFR = amount filtered < amount reabsorbed = substance has been secreted (DRUG) Inulin is not convenient, so you use CREATINE = SMALL AMOUNT IS SECRETED INTO PROXIMAL TUBULE Homeostasis and autoregulation are important for GFR = linked to net filtration pressure Downloaded by Jincheng Luo ([email protected]) lOMoARcPSD|34136402 Normal GFR is >90 End stage renal failure 98%. Iron and calcium transport regulated according to body needs, hence much lower absorption of these solutes. 4. Route of absorption: transcellular (across cells), paracellular (between cells) 5. Regional specificity for uptake: Differences between duodenum, jejunum, lower ileum, colon. 2. Absorption of protein and carbohydrate digestion products Protein Proteins are hydrolysed to amino acids and small peptides (