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Principles of Physiology and Pharmacology
Foundations of Biomedical Science 1
King's College London
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Principles of Physiology and Pharmacology
Lecture 1: Skeletal Muscle –
Sarcoplasmic Reticulum: Repeating series of networks around myofibrils Act as reservoirs for Ca2+. Mitochondria present to provide energy for muscle contraction T-tubules form between cisternae contain voltage gated proteins which are activated when membrane depolarises causing sarcoplasmic reticulum to release Ca2+ ions
Isometric contraction increases tension but there is no change in length.
Initiation of Muscle Contraction: 1. Acetylcholine (ACh) released from motor end plate 2. Binds to voltage gated Na+ ion channels causing them to open 3. Na+ enters the cell 4. Depolarisation spreads down T-Tubules 5. Ca2+ released into sarcoplasm and binds to troponin which causes change in shape of tropomyosin 6. This allows myosin head to attach and so contraction is initiated.
- Attachment – Myosin head bound to actin molecule of thin filament
- Release – ATP binds to myosin head and induces release of actin muscle is relaxed.
- Bending – ATP causes further changes to myosin head, causing it to bend. Bending movement initiates breakdown of ATP into ADP + Pi, which remain in myosin head
- Myosin head binds to new site and Pi released. This causes:
- Increases binding affinity of myosin for actin
- Myosin head generates force to straighten up + forces thin filament along thick filament, creating stroke shortens sarcomere. ADP lost from myosin head
- Reattachment – release of ADP results in reattachment of myosin head to actin filament.
Muscle Relaxation: 1. Calcium must be removed from cytosol 2. Ca2+ pumped back into sarcoplasmic reticulum by ATPase. 3. Ca2+ concentration decreases, and calcium released from troponin al lowing tropomyosin to re -cover the binding sites. 4. Cross bridges release and muscle relaxes
Action Potential and Twitch: AP shorter than twitch. When lots of AP occur before twitch cycle, summation occurs Summation = frequency of twitch occurs at a faster rate than calcium can be removed (AP causes twitch which releases calcium) Removal of calcium is necessary for relaxation and so muscle cannot fully relax between twitches If muscle cannot relax inc. Ca2+ exposes more myosin binding sites more cross bridges and greater tension works muscle harder.
Types of Muscle Fibres: Slow-Twitch Oxidative - Type I
Fast twitch oxidative – Type IIa Fast Twitch Glycolytic – Type IIb Function Sustained contraction – posture
Phasic movements - walking Phasic movements – jumping, quick movement Speed of max tension development
Slowest Intermediate Fastest
Myosin ATP activity Slow Fast Fast Diameter of fibre Small Medium Large Metabolism Oxidative – Aerobic Glycolytic but can become more oxidative with training
Glycolytic – anaerobic
Capillary Density High Medium Low Mitochondria High Moderate Few Endurance Fatigue Resistant Fatigue Resistant Easily fatigued
Type I: High endurance, little force
Type II: Great force, low endurance
Length-Tension Relationship: Tension generated = number of crossbridges formed between thick and thin filaments. In elongated fibre few crossbridges so little power generated. As sarcomere shortens, more crossbridges form and force increases until crossbridges reach Z disc no new binding sites tension decreases rapidly.
Osmolarity of ECF and ICF have to be equal to keep water where it is
Osmotic Pressure and Osmolarity: Determined by total number of freely diffusible entities in solution (e. ions) Osmole (6 23 entities = 1 mole) - Osmolarity = 1 mole per litre - Osmolality = 1 osmole per litre - E. 10mmol/litre CaCl 2 = 30 mosm/litre (3 ions) Relationship to pressure: - 1 osmole in 22 litres exerts 760 mmHg - 1 osmole / litre exerts 17000 mmHg Osmolarity of plasma controls plasma volume Osmolarity of plasma = 290mmol/litre strongly controlled Sometimes called ͞toŶiĐitLJ͟ – only when solutions separated by semi-permeable membrane Isotonic solution has same tonicity as plasma normal saline = 0% w/v NaCl
Crystalloid vs Oncotic Osmotic Pressure: Crystalloid osmotic pressure created by diffusible cations/anions Ions (Na+/Cl-) cross capillary walls easily, so no crystalloid osmotic pressure difference Proteins do not – as there is little protein in interstitial fluid they exert an oncotic (colloidal osmotic) pressure of about 25 mmHg Oncotic pressures vital for transport across capillaries
In practice, oncotic pressure in capillaries is balanced by outward hydrostatic pressure
Hydrostatic vs Oncotic Pressure: At capillary end, hydrostatic pressure > oncotic pressure At venule end, oncotic pressure (same as before) > hydrostatic pressure
Ionic composition: Ion Plasma (mmol/l) Intracellular (mmol/l) [Na+] 140 10 [K+] 4 120 [C a2+] 2 100 nmol/l Anions Cl -, bicarbonate Amino acids, cl-, proteins Major ion: Na+ major ion, controls blood volume K+ major ion, controls cell volume
Plasma Proteins (total quantity 70g/l): Albumin: 48g/l - Plasma oncotic (colloidal osmotic) pressure 25mmHg - Transport, buffering of pH Alpha, beta, gamma globulins: 0-13g/l each - Haemostasis, transport, immune system Fibrinogen: 3g/l (substrate for blood coagulation) - Haemostasis – stopping of blood flow
Erythrocytes (RBC): Lifespan about 120 days RBC count: male 5 vs female 4 (x10 12 /litre)
Mean cell volume is about 85 femtolitres Contain Hb (no nucleus) – male 160g, female 140g (per litre) Carriage of O 2 Buffering of pH
Low Hb is Anaemia: low RBCC, low Hb per cell, defective Hb
Leucocytes: Total WBCC: 4-11 x 10 9 / litre - Defend against foreign materials, inflammatory and allergic responses Lymphocytes (20-40%) - Immune system; produce immunoglobins Monocytes (2-8%) - Migrate to tissues and form macrophages Granulocytes: - Neutrophils ( 50 -70%) – chemotactic, phagocytosis - Eosinophils (1 -4%) – phagocytosis, allergy - Basophils (0%) - release histamine & heparin (similar to tissue mast cells)
Platelets: Total platelets 150 -400 x10 9 / litre Central role in haemostasis No nucleus, contain dense granules Change shape, release granules, stick together when activated
Lecture 3: Physiological Homeostasis
Homeostasis: dynamic maintenance of physiological variables within a predictable range - Dynamic – variable may fluctuate but still within normal range and average value will be predictable over longer periods of time
Purpose of homeostasis: Short term: immediate survival Long term: health and wellbeing, reproductive capability
Required for immediate survival: 1. Oxygen and glucose supply to all body cells – maintained by hormones, blood flow, lung ventilation 2. H+ and HCO 3 - content controls blood CO 2 and pH 3. Water intake/secretion + Na+/K+ content control osmolarity and volume
Required for long term survival: 1. Temp and metabolic rate optimal functioning of organs and tissues 2. Appetite and GI secretions, motility fulfilling dietary requirements
Required for survival of species: 1. Steroid hormone levels secondary sexual characteristics and reproductive capability
Variable that is of greater immediate importance may be maintained at the expense of other variables that are of importance in the longer time. When too much salt consumed increased water intake plasma osmolarity maintained at expense of increased blood volume so increased bp hypertension
Hypothalamus acts as neuroendocrine tissue: Releasing hormones: - Growth Hormone Releasing Hormone (GHRH) triggers GH - Cordicotopin Releasing Hormone (CRH) triggers ACTH - Thyotropin Releasing Hormone (TRH) triggers TSH - Gonadotrophin Releasing Hormone (GRH) triggers FSH & LH Inhibitory hormones: - Somatostatin & dopamine
Posterior Pituitary gland acts as neuroendocrine tissue: Oxytocin ADH
Types of Hormones: 1. Peptides – ADH & Oxytocin 2. Polypeptides – Growth hormone 3. Glycoproteins – LH, FSH, TSH (thyroid stimulating hormone) 4. Amino acid derivatives: - Tyrosine is precursor to adrenaline (formed in adrenal medulla) and thyroxine (T4) 5. Steroids: - Cholesterol is precursor molecule for all steroid hormones - Converted to pregnenolone - In ovaries pregnenolone progesterone and estrogens - In testes androgens - In adrenal cortex glucocorticoids, mineralocorticoids
Type of Hormone Receptor Location Mechanism of Action Peptides, proteins, glycoprotein, catecholamines
Plasma membrane Second messengers to change enzyme activity. Rapid, often transient response Steroid, thyroid hormones Intracellular: cytoplasm / nucleus
Alter gene transcription. Slow, prolonged response
Example of endocrine hormone reflex arc: Local homeostatic response: 1. Local control of blood flow through vasodilation/vasoconstriction 2.
Releasing hormones travel to anterior pituitary gland where they are released.
Feed forward mechanisms (usually neuronal): 1. Anticipation of meal ( Paǀloǀ͛s ƌefledž ) parasympathetic activation stimulation of saliva and gastric juice production preparation for food intake 2. Anticipation of physical exertion (fight/flight)
Positive Feedback (under special circumstances): Mostly hormonal, often involving steroid hormones Menstrual cycle: normal fluctuations in progesterone and oestrogen levels ensures regular cycles of ovulation and growth of endometrium
Parturition: (contraction of uterus to expel foetus)
Lecture 4: Flow and Pressure
We need cardiovascular system to overcome limits of diffusion.
Circulation is a closed system with 2 pumps in series: 1. Pulmonary Circulation – Low resistance and pressure (16mmHg) & in series with each other 2. Systemic Circulation – High resistance and pressure (92mmHg) & in parallel with each other.
Left ventricle pumps blood through the body whereas right ventricle pumps blood through lungs.
Flow out of heart: Volume per beat: Stroke volume (70ml) Volume per minute: Cardiac output (5L/min) CO = SV x Heart Rate Resistance to flow: Total Peripheral Resistance (TPR) determines pressure load on LV - Afterload Flow into heart: Volume per minute: Venous return (5l/min) – must match CO Filling of heart: Central Venous Pressure (CVP) – Preload
Movement of Substances in Blood: Bulk flow – transport within blood or air due to pressure differences Passive diffusion – movement down a concentration gradient (movement of O 2 or CO 2 )
FiĐk͛s Law: Rate of diffusion in a solution depends on:
Flow in Flexible Tubes: Distensible vessel (pulmonary circulation) - as pressure increases, vessels dilate to maintain flow.
Distensible vessel + myogenic tone (cerebral circulation) – vessels contract in response to increases in pressure to maintain same level of flow
Resistance in Series and Parallel: More series resistance = higher resistance
More parallel resistance = lower resistance
Pressure regulated between P1-P2: Pressure not regulated between P1-P2:
Lecture 5: Electrical Properties of Cells – Membrane Potentials
How electrical events in cells are measured: 1. Intracellular – electrode inside cell 2. Extracellular – electrode outside cell 3. Patch clamping – electrode sealed to cell surface
At rest inner membrane is negatively charged with respect to outside. When cells become active, inner membranes become positively charged – depolarised.
Intracellular:
Extracellular: ECG, EEG, EMG
Patch Clamping:
Electrochemical Gradients are established because: 1. Pump moves ions against their concentration gradients 2. There is restricted ion movement through channels 3. Membrane stores ionic charges on inner and outer surfaces – capacitor
Permeability of membrane to K+ = 50x greater than to Na+:
Lecture 6: Electrical Properties of Cells – Action Potentials
Properties of Action Potential: 1. Triggered by depolarisation 2. Threshold of depolarisation required for Action Potential 3. All or nothing principle 4. Same amplitude across axon 5. At peak: membrane voltage approaches sodium equilibrium potential 6. After AP, membrane is unexcitable during refractory period
AP caused by current flowing through sodium and potassium voltage gated channels Channels are either open or closed Probability of opening and closing dependent on voltage across channel Channels are highly ion selective
Permeability: If a cell becomes permeable to an ion, then ion will move down its electrochemical gradient and drive Vm (membrane potential) towards its equilibrium potential During AP, membrane becomes permeable to sodium first, and then potassium Membrane is driven first to ENa then to EK
Vm to ENa: Vmto Ek:
Prolonged depolarisation causes sodium inactivation
Be able to draw this:
Where is there a threshold? At rest cell is much more permeable to potassium than sodium You need to get enough sodium in to kickstart action potential
Charge separation across membrane: Very few ions need to be separated Negligible osmotic consequences
Propagation of Action Potential: OŶe ioŶ ďashes ioŶ Ŷedžt to it aŶd that͛s hoǁ its ĐoŶduĐted doǁŶ adžoŶ
Path of injected current – local circuit –
Transmembrane current is either 1. Resistive – ions flow through channel 2. Capacitive – ion approaches one surface of membrane and is expelled from the other side
Saltatory Conduction: Occurs slower than max speed due to time needed to open and close ion channels
Consequences of demyelination: Charge leaks out and action potential conduction is hit or miss (like in MS)
Why myelination increases conduction velocity: As axon diameter increases, resistance decreases Increased membrane resistance current forced through axoplasm is reduced Decreased membrane capacitance charge not stored at membrane
- Temporal Summation: High frequency of action potentials in the presynaptic neurone causes depolarisation AP
- Spatial Summation: Multiple presynaptic cells transmit action potentials to one postsynaptic neurone
Orthodromic propagation: AP goes in normal, physiological direction (from periphery to CNS in sensory neurones) Antidromic propagation: AP goes in opposite, non-physiological direction
Type of neuron Speed Unmyelinated, small diameter 0.5-2 m/s Myelinated, small diameter 2-15 m/s Myelinated, large diameter 60 -100 m/s
How drugs can affect synaptic transmission: 1. Availability of neurotransmitters: a. Can affect production of neurotransmitters b. Hydrazinopropionic acid inhibits biosynthesis of GAD enzyme required for GABA biosynthesis. 2. Rate of release of neurotransmitters: a. Some drugs can interfere with the process of exocytosis b. TAT-NSF polypeptide inhibits SNARE proteins, disabling exocytosis 3. Affinity of neurotransmitter receptors: a. Dƌugs ĐaŶ affeĐt ƌeĐeptoƌs͛ affiŶities b. Cocaine inhibits dopamine transporter (DAT), saturating the central nervous system with dopamine and overclocking the reward pathway. c. Antipsychotic drugs such as Quetiapine affect both dopamine and serotonin receptors and are used for treating Schizophrenia and bipolar disorder.
Knee Jerk Reflex: 1. Knee jerk reflex/ patellar reflex deep tendon reflex 2. Tapping patellar ligament stimulates muscle spindles in quadriceps 3. Impulses travel from muscle spindles to spinal cord 4. In spinal cord, synapses occur with motor neurons and interneurons 5. Motor (efferent) neurons send activating impulses to quadriceps causing muscles to contract and extend the knee 6. Interneuron (relay) forms connection between neuron and other interneurons (neither motor nor sensory) 7. Transmits impulses that inhibit antagonistic muscles (hamstrings)
Lecture 8: Cardiac Muscle –
Structure:
Type of axon Location/function + speed Fast sensory Touch, vibration, muscle length 80-100ms Slow sensory Temp, ache 0-10m/s Autonomic Para/sympathetic 5-25m/s Alpha-skeletomotor Innervating skeletal muscle 50-80m/s
Differences between cardiac and skeletal muscle: 1. In skeletal Terminal Cisternae, T-tubule and Terminal Cisternae interface form TRIADS 2. In cardiac Terminal Cisternae more discrete + T-tubules DYADS 3. Larger mitochondria in cardiac cell 4. Cardiac fibres branches vs skeletal muscle fibres which are unbranched
Ventricular myocytes brick shaped and fit together to form Syncytium
Cardiac Action Potentials: Phase 0 – depolarisation: Sodium rapidly in (calcium slow) Phase 1: Sodium channels close Phase 2 – Plateau phase: Potassium rapidly out Calcium slowly in Calcium from EC space + SR = plateau Phase 3 – Rapid repolarisation: Calcium channels close Potassium rapidly out Potassium + sodium ion positions reversed Phase 4 – Resting Potential: Leaky potassium channels Long absolute refractory period in cardiac muscles (phase 0 to 3) Prevents tetanus (state of maximal contraction)
Ion Translocating Proteins: 1. Ion channels – ions move down electrochemical gradient. Can have voltage gates/ filters 2. Ion Pumps – ions are driven across membrane using metabolic energy – usually against concentration gradient 3. Ion exchangers/ symports – ions driven by ionic gradient of another ion (often using energy in Na gradient
Why Cardiac AP is so long: In skeletal muscle, you need tetanus to maintain muscle contraction In cardiac muscle, you just want contraction and relaxation Long AP long refractory period prevents tetany & re-entrant arrythmias
Intercalated disc
Myofilament calcium – tension relationship (cross bridge formation):
Length-tension relationship: In cardiac muscle, only accounts for 20% of increase in force over physiological range of sarcomere length
Length Dependence of Ca Activity: Increasing sarcomere length increases Ca sensitivity + max force Effect on Ca sensitivity mediated by increase in sensitivity of troponin C for Ca Increase in max force mediated by effects on myofilament overlap
Increasing sarcomere length causes 1. Increase cross bridge overlap 2. Increased Ca sensitivity of myofilaments (troponin C)
Force-frequency relationship: In failing human heart, force decreases with increasing frequency. Due to down regulation in SERCA + up regulation of Na/Ca exchange Results in more Ca extrusion + less Ca cycling through SR
Force increases with increasing muscle length and force increases with increasing frequency.
Lecture 9: Smooth Muscle –
Location: walls of hollow organs, inc. blood vessels (EXCEPT capillaries) Funct ioŶ: to aĐt as ďodLJ͛s ĐoŶduit foƌ tƌaŶspoƌt of solid, liƋuid aŶd gases Morphology: Cells not striated worm shaped Regulation: 1. By ANS 2. By hormones and locally released substances 3. In GI tract, rhythmic contractions initiated by pacemaker cells
Organ Function (controlled by smooth muscle) Blood vessels controls diameter, vascular resistance, distribution of blood flow + pressure GI Tract controls mixing and propulsion of GI contents Bladder, ureters, urethra Controls urine storage and micturition Uterus (myometrium) Responsible for labour Resp. system Controls diameter of airway Vas deferens + corpus cavernosum Controls erection and ejaculation Iris + ciliary body Controls pupil diameter and focussing of lens
Characteristic features of SMCs: Elongated shape Lack of striations Presence of Dense bodies which anchor actin filaments Presence of ER/SR which stores calcium Gap junctions between cells through which current and small molecules flow Higher ratio of actin to myosin than striated muscle
How Smooth Muscle Contraction is regulated: Autocoids/Local hormone: any regulatory substance released by cell acting in an autocrine or paracrine fashion ANS: autonomic nervous system o Vascular, Airways, Intestinal, Myometrium and Bladder Intestinal smooth muscle also stimulated by Interstitial cells of Cajal
Overview of Smooth Muscle Contraction:
Smooth muscle contraction can be actively suppressed by certain inhibitory stimuli
Principles of Physiology and Pharmacology
Module: Foundations of Biomedical Science 1
University: King's College London
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