Physiology Flashcards
How are physiological systems controlled?
Homeostasis!
The ability to maintain a relatively stable internal state that persists despite changes in the external environment.
Achieved by control systems and negative (and sometimes positive) feedback systems.
Positive feedback:
- Haemostasis (thrombin generation)
- Oxytocin secretion in labour
What is osmosis?
The net movement of water caused by a concentration gradient of water through a semi-permeable membrane.
What forces determine fluid movement?
- Capillary pressure: pushes fluid out
- Interstitial fluid pressure: draws fluid in
- Plasma colloid oncotic pressure: albumin in blood draws fluid in
- Interstitial fluid colloid oncotic pressure: pushes fluid out
Also impacted by net endocrine influence of aldosterone, ADH, ANP, RAAS, relaxin and progesterone.
What are the different anions and cations present intracellularly and extracellularly?
Cations:
Na extracellularly, K intracellularly and small amounts of Ca and Mg
Anions:
Cl extracellularly, PO4 intracellularly and smaller amounts of HCO3 (E), organic anions (I) and protein (I)
What is the Anion gap?
Difference between measured cations (Na) and measured anions (Cl) and (HCO3).
Indicator of acid:base imbalance.
Normal can be different for different patients.
What is Hyponatremia?
Low Na <135 mmol/L
Caused by dehydration (loop diuretics, ECF vol decreases) or overhydration (euvoleamic hyponatremia), or excess ADH which forces water to be drawn in.
What is Hypernatremia?
High Na >145 mmol/L
Caused by dehydration through DI or excessive sweating or overhydration through excessive aldosterone secretion (may be due to tumour in zona glomerulosa).
What happens to cells when you add isotonic, hypotonic and hypertonic solution to them?
- Isotonic (0.9% NaCl): EC volume expands, IC remains unchanged. Osmolarity remains unchanged. Little/no flux of water. Cell neither shrinks or swells.
- Hypotonic (<0.9% NaCl): More water in solution. EC and IC volume expands. EC and IC osmolarity reduced. Cells swells causing demyelination injury.
- Hypertonic (>0.9% NaCl): EC volume expands, IC volume reduces. EC osmolarity increased and IC osmolarity increased. Cells shrink.
What is water intoxication?
Massive intake of water leading to hyponatremia, driving salts out.
Can lead to a coma or swelling of the brain.
What do the cell’s organelles do?
Nucleus: Genetic information Ribosomes: Protein synthesis Rough ER: Protein synthesis and processing Smooth ER: Lipid synthesis Golgi apparatus: Protein processing and sorting Lysosomes: Digestion and recycling Mitochondria: ATP production Microtubules: Structure to cell Plasma membrane: Selective permeability
What is the phospholipid bilayer permeable and impermeable to?
Phosopholipid bilayer’s fluidity is modified by cholesterol and temperature.
Freely permeable to water (aquaporins), gases (CO2, N2, O2), small uncharged polar molecules (urea, ethanol).
Impermeable to ions (Na, K, Cl, Ca), charged polar molecules (ATP, glucose-6-phosphate), large uncharged polar molecules (glucose).
What are the different types of membrane transport?
- Simple diffusion: blood gases, water, urea, free fatty acids, ketone bodies.
- Facilitated diffusion: glucose, GLUT family e.g. GLUT4 for insulin.
- Primary Active transport: uses ATP to transport ions, water-soluble vitamins.
- Secondary Active transport: works by gradient set up by primary active transport. Transports glucose, symporters/co-transport.
- Pino/phago-cytosis: use of vesicles
Why are membranes and membrane proteins needed?
- Signal transduction receptors: ion channels, membrane-bound steroid receptors, neurotransmission, growth factors and nuclear steroid receptors.
- Compartmentalisation: ionic gradients (membrane potentials) and membrane vesicles.
How is epithelial integrity maintained?
Epithelia require polarisation of plasma membrane.
Allows for cell-specific function (secretion/absorption).
Allows for strong adherence to neighbouring cells (tight junctions) where only water can pass. Or integrated holes between cells for sharing of metabolites (gap junctions).
What are the optimal conditions for enzymes?
Most enzymes like to work at pH 7 and 40 degrees.
Both pH extremes damage the protein and inhibit function.
Too cold - proteins slow down, membrane is less fluid.
Too hot - proteins denature, increased membrane fluidity.
What are chromosomes?
Vehicles of genetic inheritance.
46 chromosomes (23 paternal and 23 maternal).
Numbered in order of decreasing size.
Diploid (2n).
How might you describe chromosomes of different lengths?
Metacentric: p=q, centromeres in the middle
Submetacentric: p slightly shorter than q
Acrocentric: p is much smaller than q
Telocentric: no p (not in humans)
What is the cell cycle?
G0: goes to sleep, not replicating anymore (quiescence, senescence or terminal differentiation)
G1: grows a bit
S: DNA synthesis - chromosome number doubled
G2: grows a bit more
M: Mitosis - physically divides, cytokinesis
What is Mitosis?
Mitosis is a type of cell division in which one cell (the mother) divides to produce two new cells (the daughters) that are genetically identical to itself.
One diploid somatic cell (2n), one DNA replication (cell effectively tetraploid 4n), one cytokinesis, two genetically identical daughter cells (each one 2n).
What is Meiosis?
Reductive cell division to produce gametes. A division process that takes us from a diploid cell—one with two sets of chromosomes—to haploid cells—ones with a single set of chromosomes.
One diploid germ cell (2n) undergoes one DNA replication (4n) - crossing over between homologous chromosomes and recombination or gene shuffling.
Two cytokinesis events.
Four genetically distinct daughter cells (n).
What are the checkpoints in the cell cycle?
G1:S-phase checkpoint: stops cell cycle if poor environment/DNA damage (HPV E7 protein inhibits this checkpoint)
G2:M-phase checkpoint: stops cell cycle if errors detected in DNA. (Inactive damage sensors inhibit this checkpoint).
Spindle checkpoint: stops cell cycle if errors in mitotic spindle (checkpoint here leads to aneuploidy/polyploidy).
Anti-metabolite chemotherapy is only incorporated by rapidly dividing cells to stop the S phase. Includes methotrexate, fluorouracil and azacytidine.
How is DNA used to make proteins?
Begins with DNA double helix
“Sense strand” is copied by RNA polymerase in transcription
New RNA molecule incorporating Uracil not Thymidine
mRNA translated into protein by cytosolic ribosomes and rough ER
What are the different types of gene abnormalities?
- Chromosomal non-disjunction: failure of paired chromosomes to separate during cell division so both chromosomes go to one daughter.
- Chromosomal translocation: a chromosome breaks and a portion of it reattaches to a different chromosome
- Frame-shift mutation: caused by addition or deletion of base pair, shifting the way the sequence is read.
- Truncated mutation: point mutation that results in a premature stop codon.
- Tri-nucleotide repeat: mutation in which repeats of 3 nucleotides increase in copy numbers until they meet a threshold and become unstable.
- Splice-site mutations: inserts, deletes or changes a number of nucleotides in the specific site at which splicing occurs.
- Exon deletion: most commonplace. One or more pieces of coding gene are missing.
- Mis-sense mutation: a point mutation in which a single nucleotide change results in a codon for a different amino acid.
What are the difference types of inheritance?
Autosomal dominant: disruption of 1 gene of a gene pair
Autosomal recessive: disruption of both, giving the option to be a carrier (1) or an affected (2)
X-linked recessive: mutation on X chromosome, males affected
X-linked dominance: severe in males, early neonatal death
What is the function of blood?
Heat exchange Communication/endocrine Immunity Gas exchange and nutrient exchange Fluid balance
What is the composition of blood?
45% cells (depends on size, sex and age)
RBC, platelets, WBCs (neutrophils, lymphocytes, monocytes, eosinophils, basophils).
55% plasma
Water, albumins, globulins, fibrinogen, lipids, glucose, aminoacides, water, ions.
What is diapedesis?
The passage of blood cells through the intact walls of the capillaries, typically accompanying inflammation.
Cytokines and other biochemical products of the inflamed tissue caused increased expression of selectins and ICAM-1. Adhesion molecules bind to complementary receptors on the neutrophils, causing it to adhere to the capillary wall where it then migrates to the site of injury.
How are RBC synthesised?
Kidney secretes erythropoietin which will activate hematopoietic stem cells which will become proerythroblasts which become RBCs.
What are the steps of haemostasis?
Tear to endothelial lining. Vasconstriction induced by trauma. Platelet plug formation by vWF secretion. Formation of fibrin meshwork. Cascade of enzymatic reactions. Amplification of clotting factors.
What are the two pathways that lead to haemostasis?
Intrinsic: exposure of blood to collagen
Extrinsic: traumatised vascular walls (rapid activation)
Common end point: pro-thrombin activator complex leading to thrombin-catalysed cleavage of fibrinogen to fibrin.
How can a fibrin clot be dissolved?
The crosslinked fibrin multimers in a clot are broken down to soluble polypeptides by plasmin, a serine protease.
- Tissue plasminogen activator (tPA) is released from damaged cells to convert plasminogen to plasmin,
- Tranexamic acid (Lys analogue) prevents plasminogen activation by tPA.
What is the lethal triad?
The trauma triad of death is the combination of hypothermia, acidosis and coagulopathy. This combination is commonly seen in patients who have sustained severe traumatic injuries and results in a decreased plasma pH and core body temperature.
What drugs can be used for clot prevention?
Heparin: anticoagulant which removes activated thrombin
NSAIDs: inhibits prostaglandin synthesis
Warfarin/Diacoumarol-based drugs: inhibit hepatic Vit. K synthesis and abnormal prothrombin synthesied.
What are the functions of the colon?
Absorption of water (osmosis) and electrolytes (active transport)
Production of vitamins
Excretion of waste
What are the layers of the colonic wall?
Inner Mucosa Muscularis mucosae Submucosa Muscularis propria Subserosa Serosa Outer
What is the unique feature of the muscular layer in the large bowel?
Continuous circular muscle
3 stripes of longitudinal muscle - taeniae coli
What is the histology of the colon?
Columnar epithelium
With goblet cells
What is the colonic microbiome?
Loads and loads of appropriate bacteria present in the colon.
Some which you find in all of us, some which is unique to the individual
Produce gases (methane, oxygen, nitrogen) - dependant on diet and microbiome
Smell comes from small amount of hydrogen sulfide
What is the nerve supply to the colon?
Intrinsic: Meissners and Auerbach’s plexus
Extrinsic: Parasympathetic (speed up) and sympathetic (slow down)
Presence of fecal material causes contraction back and forward to keep the poo in the colon so that there is maximal water absorption
What is the gastro-colic reflex?
Stomach stretching and food in the jejunum leads to mass movement in the colon
What is the anal sphincter?
Internal part: continuation of the smooth muscle of the colon
Pelvic floor hold bladder, rectum, anus up.
External part
What is the status of the muscle when the rectum is empty?
Both sphincters are contracted
Puborectalis muscle is contracted
How do we know we need a poo?
Rectum fills - pressure sensors in the pelvic floor
Reflex relaxation of internal anal sphincter
Sampling reflex
How does defecation occur?
External sphincter relaxes
Puborectalis relaxes
Rectum contracts
Valsalva maneuver - pressure changes
How does posture affect defecation?
Sitting posture - Puborectalis muscle “chokes” rectum to maintain continence
Squatting posture - Puborectalis muscle relaxes and straightens pathway to anus
What causes constipation?
Consistency of stool - lack of water, lack of fibre
Bowel motility - slows down as you get older
Physical blockage to the bowel - scans/colonscopy
Pelvic floor disorders
What physiological issues can lead to diarrhoea?
Diseased bowel mucosa
Reduced rectal capacity
Pelvic floor disorder
What are the functions of bones?
Support Protection Blood cell synthesis Calcium store Movement
What is the epiphysis, metaphysis and diaphysis?
The epiphysis is the rounded end of a long bone, at its joint with adjacent bone(s). Between the epiphysis and diaphysis (the long midsection of the long bone) lies the metaphysis, including the epiphyseal plate (growth plate).
What is the functional organisation of bone structure?
Cortical (aka compact) - the outer compact, strong but heavy outer layer
Trabecular (aka Cancellous) - the spongy, strong and lightweight inside, large surface area (Ca2+, PO43- homeostasis)
Lots of fine meshwork at the points of major stress for the bone – transmits the force down the shaft
Reservoir of calcium – remodelling of the bone occurs here
How does bone develop?
Derived from somatic mesoderm
Osteogenesis begins sixth – seventh week of pregnancy
Two modes of formation:
Intramembranous ossification – within cartilagous tissue itself
Endochondral ossification
Same end point – mature bone
What are the different types of bone growth?
Appositional growth
Growth in diameter
Bone lamellae
Interstitial growth
Growth in length
Epiphyseal plate – small rich region of bone growth
What is Intramembranous Ossification?
Mesenchymal stem cells form clusters in early catilagous tissue, they then differentiate into osteoblasts and ossification centres form (random to a degree).
Osteoid secreted (rich strong protein matrix)
Traps osteoblasts
Differentiate into osteocytes
Trabecular matrix and periosteum form
Compact bone develops over trabecular bone
Blood vessels condense into red bone marrow
e.g. dermal bones - skull
What is Endochondral Ossification?
Mesenchymal cells form cartilaginous bone model
Chondrocyte hypertrophy then degradation.
Blood vessels enter central part
Perichondrial cells convert to osteoblasts
Oesteoid secreted
Bone secreted onto shaft
Epiphyses: Blood vessels form secondary ossification centre Compact bone externally Spongy bone internally Articular surfaces remain as cartilage
How do hormones control growth at the Epiphyseal Plates?
Growth hormone promotes chondrocyte expansion:
Mitosis (hyperplasia), get bigger (hypertrophy), degrade; osteoblast invasion, new bone added to diaphysis
Mitosis and expansion of chondrocytes maintains epiphyseal cartilage matrix, bone elongates
Balance between chondrocyte growth/degradation important – need to happen at the same rate
Steroids (testosterone) can close growth plates prematurely
What components make up the bone?
Osteoid matrix (90% collagen; 10% other proteins)
Also contains CaHPO4 mineral component (crystals)
Hydroxyapatite crystals - Ca10(PO4)6(OH)2
“reinforced concrete”
Three main cell types:
Osteoblasts (build bone)
Osteoclasts reabsorb bone
Inhibited by pyrophosphate
Osteocytes (sense and monitor mechanical strain to see whether bone needs to be added or removed)
What occurs during bone turnover?
Bone is continuously remodelled to maintain tissue integrity – trabecular bone sites most common
- Osteoclasts resorb old bone by eroding with secreted acid ~10 days
- After resorption macrophage-like cells recruited to remodelling site
- Osteoblast precursors recruited, proliferate and differentiate into mature osteoblasts
- Osteoblasts secrete osteoid which is then mineralised
New bone generated
Complete cycle - 90-130 days
What problems can occur with bone turnover?
Problems arise when Resorption predominates over synthesis
- Osteoporosis (~50% females; 20%males)
- Osteopenia – thinning but not quite as severe as osteoporosis
Problems arise when there is a reduced bone mineral density
- Endocrine imbalance
- Zero gravity (astronauts)
Fracture-prone – less force required to produce the same fracture
How does oestrogen and testosterone affect bones?
Oestrogen inhibits osteoclast function
Loss of oestrogen increases bone loss
Testosterone – provides bone strength
- Reduced testosterone (Hypogonadism) 20% male osteoporosis
- Menopause - loss of oestrogen increases bone loss
What is the effect of Bisphosphonates on bone?
Alendronic Acid (Fosamax) Inorganic pyrophosphate analogue Binds to hydroxyapatite minerals - Inhibits osteoclast function - Potentially induces apoptosis - Reduces bone resorption
How does osteoporosis treatment affect the teeth?
Osteoporosis treatment like Fosamax (alendronic acid) can influence dental healing.
These drugs can inhibit remodelling of bone, meaning that there is slowing of dental healing, making it more prone to infection.
What is the process of fracture healing?
- Initial response – fracture haematoma; acute inflammation
- Macrophages accumulate at fracture site to phagocytose avascular bone fragments; haematoma; inflammatory exudates (3-5 days)
- New vascular supply initiated
- Induce significant bone repair and remodelling
activates periosteal and intraosseous osteoblasts at fracture site - Creates a callus between opposed bone ends -
Large bulge of osteoblastic tissue to stop it getting worse, will gradually go away
New organic bone matrix
What is Ca involved in?
Muscle contraction Tooth formation Enzyme co-factor (clotting factors) Stabilises membrane potential Second messenger (cell signalling) Bone mineralisation (99%)
What are the normal Ca concentrations?
Total extra-cellular Ca ~ 2.2-2.6mmol/l (~9.4 mg/dl) Ionised extra-cellular Ca2+ ~ 1.0-1.25mmol/l Intra-cellular Ca2+ ~100 nmol/l
How are levels of calcium determined?
Obtained from diet
Absorbed throughout gut
Small intestine – 60-70%
Influenced by age, diet (lactose promotes; oxalates inhibit) and Vit. D availability.
What are the different types of calcium in the serum?
45% Free ionised Ca2+
Biologically active
55% bound
Not biologically active
45% bound to albumin
10% anions – phosphate; lactate active form
How can the ratio of serum calcium cause acidosis and alkalosis?
Acidosis: less Ca2+ bound to plasma proteins, H+ ions bound preferentially over Ca2+. renal Ca2+ excretion (distal convoluted tubule).
Alkalosis: more Ca2+ bound to plasma proteins
Decreased H and decreased renal Ca excretion.
Alkalotic patients more susceptible to hypocalcaemic tetany (characterized by spasms of the hands and feet, cramps, spasm of the voice box (larynx), and overactive neurological reflexes)
What occurs in Hypocalcaemia?
Causes tetany; occasionally seizures.
Nervous system progressively more excitable due to increased neuronal membrane Na+ permeability
Action potentials reach threshold more easily
If there is 50% reduction plasma Ca2+
- Peripheral nerve fibres discharge spontaneously
- Tetanic muscle contraction ensue:
Carpopedal spasm – prelude
Laryngeal muscle spasm… - can’t breathe
What occurs in Hypercalcaemia?
Depresses nervous system and muscle activity.
Decreases the cardiac QT interval
Reduced appetite
Constipation (reduced bowel peristalsis?)
Effects appear at ~12 mg/dl
>17 mg/dl calcium phosphate crystals precipitate throughout the body – crunching sound during cannulation
How is calcium homeostasis controlled when there is decreased Ca?
Sensor: Parathyroid glands
Effectors: Kidneys and intestines
Reservoir: Bones
Decreased serum Ca, often has increased serum phosphate
Picked up by the parathyroid which release PRH, causes the release of Ca and phosphate
This increased Ca reabsorption and decreases phosphate reabsorption
Stimulate the enzyme 1alpha-hydroxylase which converts calcidiol (vit D precursor) to calcitriol (vit D active).
Calcitriol increases Ca and phosphate absorption
Effects on the gut too
Increased the level of Ca in the serum
Negative feedback mechanism
How is calcium homeostasis controlled when there is increased Ca?
If there is too much serum Ca, the thyroid release calcitonin
This turns off bone resorption and Ca release
What is primary hyperparathyroidism?
Frequent cause of hypercalcaemia
Third most common endocrine disorder
Defect in parathyroid glands – benign tumour – they get bigger, there is more tissue to secrete PTH from
(rarely – malignant tumour)
See: increased PTH, calcitriol, Ca2+, decreased PO43-
Normal feedback signals seen
BUT! Increased cell numbers mean PTH levels increased overall
What is secondary hyperparathyroidism?
Arises through defective feedback control compensation for hypocalcaemia
Usually associated with chronic kidney disease
Concept of Renal Bone Disease…
- No renal response to PTH causing…
- Poor renal Ca2+ reabsorption
- No vit. D activation
- Poor intestinal Ca2+ reabsorption i.e. hypocalcaemia
Bone is only site of PTH action
High bone demineralisation as Ca2+ released
Renal osteodystrophy
Negative feedback mechanisms fail; PTH levels remain elevated
How is calcium reabsorbed in the kidney?
Glomerulus: 55% filtered
About 99% reabsorbed along tubule
PCT: 60-70% reabsorbed, paracellular (80%), transcellular (20%). No PTH required.
TALH: 20-25% reabsorbed, 50% transcellular, 50% paracellular, PTH, calcitrol, calcitonin
DCT: 5-10% reabsorbed. Virtually all trans-cellular (PTH, calcitrol)
CD: 0.5-1% reabsorbed, active transport
Urine: 1-2% excreted
How is Phosphate Excretion regulated by the kidney?
Glomerulus: Absorption depends on glomerular fluid PO43- concentration <1mmol/l most PO43- reabsorbed >1mmol/l - excess is excreted PCT: 75%-805 reabsorbed, majority via transcellular, no PTH required TALH: Very little reabsorbed DCT: Very little reabsorbed CD: Very little reabsorbed Urine: 10% excreted
What effect does PTH have on phosphate regulation?
PTH promotes bone resorption - Concomitant increase in extracellular fluid phosphate ions from bone salts
PTH decreases renal tubule phosphate transport maximum - More tubular phosphate now lost in urine
What are healthy and deficient vitamin D levels?
Vitamin D: "Normal” range: 50-100 nmol/l Influenced by geography, ethnicity, ag Insufficiency - <50nmol/l Deficiency 0 <15-20 nmol/l In deficiency, there is decreased bone mineralisation Children - Rickets Adults – osteomalacia
What happens to the bones in Rickets?
Can’t absorb the Ca
Elongated growth plate
Poor mineralisation
Bones bend/deform under load
Other deformities: Soft skull bones (craniotabes) Chest wall deformities - Harrison sulcus - Pigeon chest Bone pain; teeth defects
What are the different types of muscle?
Roughly 50% off body is muscle:
~40%skeletal muscle
~10% cardiac and smooth muscle
How does the length of the muscles change during contraction?
Force of muscle contraction is a function of the overlap of actin:myosin filaments.
Normal resting length (~ 2.0 mm)
~maximum force of contraction at activation
(i.e. maximal active tension seen)
Stretched muscle (> 2.2 mm)
Reduced active tension seen
What are the different types of muscle contraction?
Isometric tension/contraction
muscle does not shorten during contraction
“static” contraction – muscle tone
E.g. carrying shopping
Isotonic contraction
muscle shortens but muscle tension remains constant throughout contraction
“Dynamic” contraction
What are the different types of muscle fibre?
Every muscle has fast and slow muscle fibres
~98% are fast muscle fibres
~2% slow muscle fibres
SLOW Twitch Fibers (Red muscle; Type 1) - Long latency period, Smaller than fast fibres, Innervated by smaller nerve fibres, Extensive vascular supply, Increased mitochondrial numbers for prolonged oxidative metabolism, Contains myoglobin “red muscle”
FAST Twitch Fibers (White Muscle; Type II)
Short latency period, Large - large strength of contraction, Extensive sarcoplasmic reticulum - rapid Ca 2+ release initiating contraction, Numerous glycolytic enzymes for rapid energy release via glycolysis, Less extensive vascular system and fewer mitochondria (reduced oxidative metabolism), No red myoglobin “white muscle”.
What are the energy sources of muscle contraction?
Storage of high energy phosphate bond in creatine phosphate:
ATP + Creatine = ADP + Creatine phosphate
By Creatine phosphokinase
Glycolysis of stored muscle glycogen to pyruvate
Aerobic (oxidative) mechanism - glucose, pyruvate, fatty acids
What is a motor unit?
All the muscle fibres innervated by a single nerve fibre – might have multiple projections but is still a singular nerve. Individual motor neuron from spinal cord innervate many muscle fibres
Muscle fibres in each motor unit interdigitate with other motor units – gives you an even simultaneous contraction across the muscle
How is fine and gross motor control different?
Fine motor control – low ratio of muscle fibres:nerve fibres (e.g. 2:1)
Gross motor control (larger muscles) high ratio of muscle fibres:nerve fibre (100:1)
What is summation?
Adding together of individual twitch contractions to increase the intensity of overall muscle contraction
1) Increasing the number of motor units contracting simultaneously - multiple fibre summation
2) Increasing contraction frequency - frequency summation, leads to tetany
What is multiple fibre summation?
Initial muscle contraction stimulus
Smaller muscle motor units stimulated preferentially over larger motor units (Smaller motor units are driven by small motor nerve fibres - more excitable therefore excited first)
Progressive increase in stimulus strength recruits larger and larger motor units
SIZE PRINCIPLE:
Permits gradations (steps) of muscle force during weak contraction to occur in small steps
Steps become progressively greater when large amounts of force are required.
What is frequency summation?
Initial strength of contraction may be weak
If muscle is stimulated before relaxation cycle has finished:
- Second contraction partially added to first
- Total strength of contraction increases
- Progressive increase in force of contraction with increased contraction frequency until plateau
- Tetanus will result
- Further stimuli do not increase contractile force
What is Bowditch Staircase?
Initial strength of contraction may be weak but…
…if muscle is stimulated after relaxation cycle has finished
Progressive increase in force of contraction seen
Strength of contraction increases to a plateau
Mechanism unclear
But could be due to progressive increases in [Ca 2+]i after each stimulation but failure to re-sequester all ions
What are the features of the nerve fibre and nerve terminal at the neuromuscular junction?
Nerve fibre:
Stimulates variable number of muscle fibres
Point of contact with muscle at neuromuscular junction
Nerve fibre remains outside sarcolemma
Nerve terminal:
Rich in mitochondria - requires ATP for ACh synthesis
ACh stored in synaptic vesicles (~300,000)
In the synaptic space, acetylcholine esterase (AChE) rapidly deactivates Ach (Choline and acetate)
How is an action potential transmitted across a neuromuscular junction?
Motor nerve impulse open synaptic voltage-gated Ca2+ channels
Increased Ca promotes synaptic vesicles migration to the pre- synaptic membrane
ACh released into the synaptic cleft
Two ACh bind ACh-gated Na+ channel (post-synaptic membrane)- Nicotinic cholinoreceptor (NAChR)
Increased Na depolarises the muscle fibre (end plate potential)
T-tubule system propagates EPP by release of Ca2+ from sarcoplasmic reticulum (excitation-contraction coupling)
EPP terminated by AChE
What is a depolarising blockade of the neuromuscular junction?
Prolonged activation of NAChR abolishes effector response.
Presence of nicotinic agonist inhibits post-synaptic membrane recovery.
Suxamethonium (Sux; succinylcholine) and rapid sequence induction (RSI) – given to paralyse muscles (general anaesthetic)
Sux not metabolised by AChE
What is a non-depolarising blockade of the neuromuscular junction?
Competitive inhibition of the NAChR - May block Na+ channel
e.g. d-tubocurare (curare)
(Chondrodendron tomentosum)
No depolarisation of the muscle
What effect do Organophosphates have on the neuromuscular junction?
Organophosphates (malathione, diisopropylfluorophosphate; DFP)
Potent AChE inhibitors
Prevent ACh hydrolysis
Promote prolonged end plate depolarisation
What is end plate potential depolarisation?
If stimulus is of sufficient magnitude, threshold is reached
Muscle fibre depolarises
-85mV - +40 mV
Magnitude of EPP proportional to amount of ACh released
What is excitation-contraction coupling?
EPP induces an action potential in the T tubule system
Voltage change sensed by dihydropyridine (DHP)-sensitive Ca2+ channels (L-type)
Ca2+ released from sarcoplasmic reticular cisternae
Increased [Ca2+]i - depolarisation now propagated deep into muscle belly
Muscle contracts
What are the basic requirements for control of muscle function?
Continuous feedback of sensory information from muscle (Afferent fibres)
Excitation of muscle by spinal cord anterior motor neurons (Efferent fibres)
What are the two types of sensory receptors?
Muscle spindles: Distributed throughout muscle belly
Monitor: Muscle length and Rate of change of length
Golgi tendon organs: Situated in muscle tendons
Monitor: Tendon tension and Rate of change of tension
Gives intrinsic muscle control - virtually subconscious operational level
Some transmission spinal cord, cerebellum, cerebral cortex - higher-level “conscious” regulation
What are the characteristics of a muscle spindle?
Made up of intra-fusal fibres – tiny skeletal muscle fibres
which are joined to extra-fusal fibres (main muscle fibres)
Central part lacks actin/myosin
No contraction
Only end section contract
What happens during a Patellar tendon Reflex (Knee-jerk)?
Dynamic stretch reflex
Quadriceps muscle stretched – stretches spindle receptor
Primary afferent activated
Alpha motor efferent activated – muscle contracts
Reflex functions to oppose sudden changes in muscle length
What are the functions of the kidney?
Excretes waste - urea, acid, drugs Electrolyte balance (osmosis) Facilitation of plasma Ca Controls red blood cell numbers (EPO) Gluconeogenesis Controls blood pressure (renin) Controls acid-base balance (pH) Controls extra-cellular fluid volume
What are the different parts of the kidney?
The kidneys are paired organs found within fibrous renal capsule at the posterior abdominal wall 11cm long, 6cm wide, ~140g Made up of: Outer cortex Inner medulla Have a complex blood supply to nephrons
How does the renal blood supply work?
TWO CAPILLARY BEDS
- Glomerulus: high hydrostatic pressure and rapid fluid filtration
- Peritubular capillaries: lower hydrostatic pressure and rapid fluid reabsorption
Vasa recta are a specialised blood supply and allow for counter-current blood flow around Loop of Henle
What is the kidney nephron?
Functional unit of the kidney - 1 million per kidney
Tubule structure - 5cm long, wall of single epithelial cells, cell type reflects function of tubule at a given locus
Made up of:
Bowman’s capsule (Renal Corpuscle)
Glomerulus
Proximal convoluted tubule – high degree of reabsorbtion (increased SA)
Loop of Henle – losing water, thin layer of epithelial cells
Distal convoluted tubule
Collecting duct
