PPP Flashcards
Define homeostasis.
The dynamic maintenance of physiological variables within a predictable range.
What is the medium to long-term purpose of homeostasis?
Health and well being, and reproductive capabilities.
What are examples of medium to long-term homeostatic variables?
- Temperature
- Metabolic rate
- Appetite
- GI secretions, motility and absorption.
- Steroid hormone levels.
What happens if two physiological variables are in conflict?
A variable that is of greater immediate importance may be maintained at the expense of other variables that are important in the long-term.
What is negative feedback?
When a change in a variable moves it away from the set-point causing a response that tends to move the variable back to the set-point (normalisation).
Name some circumstances where the physiological set point may need to be changed?
- Changed during fever.
- Over-ridden during exercise.
What is a feed-forward response?
Where a change is anticipated and a response to the change is initiated before the change can be detected by negative feedback sensors.
These are usually neuronal.
What is positive feedback?
Where a change in a variable triggers a response that causes further change in the variable (amplification).
Where are the neuronal integrating centres for homeostasis found?
Midbrain and brainstem i.e. hypothalamus, pons and medulla.
What are the neurotransmitters for the parasympathetic and sympathetic nervous systems?
Parasymp = Acetylcholine
Symp = Noradrenaline.
What is one important point to remember with endocrine homeostasis?
The response of a target tissue depends on the type of hormone receptor expressed.
What hormones does the hypothalamus produce?
Releasing hormones = GHRH, CRH, TRH, GnRH
Inhibitory hormones = Somatostatin, dopamine.
Oxytocin and ADH
What happens to hormones when they leave the hypothalamus?
Releasing and inhibitory hormones travel down a portal blood system to the anterior pituitary where they trigger the release of more hormones.
Oxytocin and ADH travel down the nerves to the posterior pituitary where they are secreted.
What hormones trigger which in the anterior pituitary?
GHRH -> GH
CRH -> ACTH
TRH -> TSH
GnRH -> LH, FSH
What hormones are released from the posterior pituitary?
- Oxytocin
- ADH
What type of molecules are hypothalamic and pituitary hormones?
Peptides, polypeptides or glycoproteins.
Which hormones are tyrosine derivatives?
- Catecholamines (i.e. adrenaline).
- Thyroid hormones (e.g. tyroxine).
What is the precursor molecule for all steroid hormones?
Cholesterol
What hormones are steroid hormones?
- Sex hormones
- Adrenal cortex hormones
What hormones do cell-surface receptors respond to?
- Peptides
- Proteins
- Glycoproteins
- Catecholamines
What hormones do intracellular receptors respond to?
- Steroids
- Thyroid hormones
What are local homeostatic responses? Give two examples.
Where negative feedback operates locally - the sensors, integrating centres and effectors are located in the same region or tissue.
- Local control of blood flow as a response to exercise.
- Control of blood volume in the kidney.
Give two examples of feed-forward responses.
- Anticipation of a meal = Pavlov’s reflex.
- Anticipation of physical exertion = fight or flight.
How much water does a typical 70kg young man contain?
60%
What are the three main fluid compartments?
- Blood plasma
- Intracellular space
- Interstitial space
What makes up total body water (TBW)?
- 40% = intracellular space (~28L).
- 15% = interstitial space (~10.5L).
- 5% = plasma space (~3.5L).
Give examples of other fluid compartments found in the body. What do these spaces belong to?
- CSF
- Aqueous and vitreous humors of the eye
- Synovial fluid
- Amniotic fluid (during pregnancy)
- GI tract secretions
- Lymph
These spaces are all part of the extracellular space.
Describe the method used to measure the volume of fluid compartments.
Dilution method = add a known amount of substance to an unknown volume and measure the concentration. Use this information to calculate volume.
Name some substances used in the dilution method and what features they need to have.
To measure plasma volume the substances need to be large enough to not cross capillaries:
- Evans Blue
- Labeled Inulin
- Albumin
To measure ECS the substance must not be able to enter cells easily:
- 24Na
- Sucrose
To measure TBW you need something that distributes with all water in the body:
- 3H20 (heavy water).
What are the major ions in body fluid and what do they determine?
Na, Cl and K
Determine osmolarity.
What is osmotic pressure and osmolarity determined by?
The total number of freely diffusible entities in a solution.
What is the osmolarity of plasma?
~290mosmol/L
What is crystalloid osmotic pressure?
The osmotic pressure set by small diffusible ions such as Na, K and Cl in body fluids.
What is oncotic/colloidal osmotic pressure? Why is it needed?
Because proteins are unable to travel through the plasma membrane they exert an oncotic/colloidal pressure of about 25mmHg.
Oncotic pressure is vital for fluid transport across capillaries.
How do hydrostatic and capillary plasma oncotic pressure vary across a capillary bed?
At the arterial end, the hydrostatic pressure is higher than the oncotic pressure so fluid will move out of the bloodstream into the surrounding tissues.
At the venous end, the oncotic pressure is higher than the hydrostatic pressure which forces fluid back into the bloodstream.
What is the ionic composition of plasma?
- Na = 140mmol/L
- K = 4mmol/L
- Ca = 2mmol/L
- Bicarbonate = 24mmol/L
What is the ionic composition of the intracellular matrix?
- Na = 10mmol/L
- K = 120mmol/L
- Ca = ~100nmol/L
What is the total quantity of plasma proteins?
~70g/L
What are the main proteins found in plasma and where are they used?
- Albumin (48g/L). Used in transport and pH buffering.
- α, β and γ globulins (0.7-13 g/L each). Used in haemostasis (stopping the flow of blood), transport and immune system.
- Fibrinogen (3g/L). Used in haemostasis.
What is the red blood cell count in males and females?
Male = 5.5 x10^12/L
Female = 4.8x10^12/L
What is the total white blood cell count?
4-11x10^9/L
Name the leucocytes found human blood and their function.
Lymphocytes (20-40%) produce immunoglobulins.
Monocytes (2-8%) migrate to tissues and form macrophages.
Granulocytes:
- Neutrophils = chemotactic, phagocytosis
- Eosinophils = phagocytosis, allergy
- Basophils = release histamine and heparin
What are platelets and what is the total platelet volume?
They are fragments of megakaryocytes that are produced in the bone marrow.
150-400x10^9/L
What do platelets do when there is an injury to a blood vessel?
Major role in haemostasis = they will move towards the broken endothelium and accumulate and release the contents of their granules which attracts more platelets. They also help maintain the coagulation of the blood at the site.
What are the average pressures of the systemic and pulmonary circulations?
Pulmonary = ~16mmHg
Systemic = ~92mmHg
How are pulmonary and systemic circulations arranged?
- Pulmonary is in series with the systemic circulation.
- The systemic circulation is in parallel with itself.
How do you measure cardiac output?
Stroke volume x Heart rate
What is TPR and what does it do?
TPR = total peripheral resistance.
This determines pressure load on the left side of the heart i.e. afterload.
What is known as preload?
The filling pressure of the heart which is determined by the central venous pressure (CVP).
What is bulk flow?
Transport within the blood or air as a result of pressure differences.
Describe Fick’s law.
Fick’s law is used to calculate the rate of diffusion in a solution.
Rate of diffusion = ΔC x A/Δx x solubility/√MW
Where:
- ΔC = difference in concentration of diffusing substance
- A = area over which diffusion occurs
- Δx = distance over which is has to travel
What affects how easily a substance diffuses?
- Temperature
- Solubility of the substance
- Square root of the molecular weight of the substance
What part of Fick’s law affects the permeability of a substance?
A/Δx * solubility/√MW
What is diffusion proportional to?
ΔC and permeability
What is flow proportional to?
Flow is proportional to the pressure difference and inversely proportional to the resistance to flow.
How do you calculate flow?
P1-P2/R - Darcy’s law
Difference in pressure divided by the resistance.
What sort of variable is resistance in relation to calculating flow and what does this mean?
Resistance is an independent variable.
This means that if either flow or pressure change, the resistance stays the same.
What determines resistance to flow?
Poiseuille’s law:
R = 8VL/πr^4
Where:
- L = length of tube
- r = radius of tube
- V = viscosity of fluid
What does a small change in tube diameter cause?
A large change in resistance and therefore flow.
What is laminar flow?
Viscous drag at the sides of the tube slows the fluid, so the fastest movement (flow) is in the centre.
What is axial streaming?
Where, as a result of laminar flow, red blood cells align themselves in the centre of the vessel where the flow is the fastest.
What is the Fåhræus–Lindqvist effect?
The Fåhræus–Lindqvist effect describes how the viscosity of blood changes with the diameter of the vessel. There is a decrease in viscosity as the tube’s diameter decreases. This is because erythrocytes move to the centre of the vessel, leaving only plasma near the wall of the vessel.
What is turbulent flow?
Where high velocity, sharp edges and branch points (such as plaques caused by atherosclerosis) can disrupt laminar flow leading to turbulence. This causes increased resistance and creates vibrations.
What are distensible vessels and give two examples.
Distensible vessels are able to expand and contract in response to changes in pressure.
- Pulmonary vessels
- Cerebral vessels
How do you calculate the total resistance in a series of tubes?
Adding together the individual resistances.
How do you calculate the total resistance of tubes in parallel?
1/total R = 1/R1 + 1/R2…
How can blood flow through organs/tissue be regulated independently of the arterial blood flow?
By regulating resistance.
If blood pressure is kept constant, then the flow in certain tissues can be controlled by changing resistance and keeping other tissues in parallel unaffected.
How do you calculate mean arterial blood pressure (MABP)?
Cardiac Output (CO) x Total Peripheral Resistance (TPR)
What happens to a cell when it is depolarised?
When the plasma membrane of a cell becomes positively charged (normally negatively charged).
What is the patch-clamp technique?
Where a glass electrode is used to clamp patch of cell membrane that contains a single ion channel which allows you to measure the voltage of that channel.
Why are electrochemical gradients established?
- The pump moves ions against their concentration gradient.
- There is restricted ion movement through channels.
- The membrane stores ionic charges on its inner and outer surfaces - it is a capacitor.
What is the membrane voltage in relation to paired charged molecules?
Voltage is the expenditure of energy (from ATP) used to move charge across a membrane i.e. to separate paired charged ions on either side of the membrane.
What is the equilibrium potential?
The point where the force of the concentration gradient pushing an ion out of the cell is matched by the electrical force pulling an ion back into the cell.
There is no net movement and the electrical forces which exactly balances the osmotic force is called the equilibrium potential.
What is a typical resting membrane potential and what is it determined by?
-70mV
Na and K
What is the equilibrium potential for an ion?
Where the net movement of an ion is 0. This is also the membrane voltage that a cell needs to be at to prevent movement of that ion down its concentration gradient.
This potential is very negative for K and very positive for Na.
Why is the membrane potential closer to Ek than ENa?
Because the membrane is about 50x more permeable to K than Na.
At a constant Vm (membrane potential) why is the net flow of ions 0?
Because the passive lead of K out is matched by the passive leak of Na in.
What happens when a cell becomes permeable to a particular ion?
The ion will move down its electrochemical gradient and will drive the Vm towards the equilibrium potential for that ion.
How do you calculate the driving force of an ion? What does the driving force tell us?
Vm-Eeq
Membrane potential minus equilibrium potential.
The driving force tells us the voltage being used to move the ions either in or out of the cell.
+ve forcing ions out
-ve forcing ions in
What is the Nernst equation?
E = RT/zF x Log([ion]o/[ion]i)
What is the Goldman equation?
Vm = RT/F x log((Pion x [ion]o) + (Pion x [ion]o)) / ((Pion x[ion]i) + (Pion x [ion]i))
What happens during 1) depolarisation, 2) repolarisation and 3) hyperpolarisation?
- Vm goes from negative to positive = Na channels open and Na rushes in causing more Na channels to open.
- Vm goes from positive to negative = K channels open slowly causing an efflux of K.
- Overshoot where Vm goes too negative then gets a little less negative to reach the resting Vm.
What are the properties of the action potential?
- Triggered by depolarisation.
- Threshold of depolarisation is required for an AP.
- All or none.
- Propagates without diminishing.
- At its peak Vm approaches ENa.
- After the AP the membrane is inexcitable due to the refractory period.
Why is there a threshold for depolarisation in an AP?
This allows Na to come into the cell very quickly i.e. faster than K is leaving the cell because the flow of K out can counteract the flow of Na in.
How do you calculate the charge stored in a membrane?
Charge (Q) (coulombs) = capacitance (C) x voltage (V).
Why are the number of ions required for an AP so small?
So that the change in ions needed for an AP does not affect the overall concentration gradient across the cell and does not cause osmotic changes.
What is longitudinal axoplasm resistance?
Where the strength of the AP decreases the further away you get from the stimulation site.
Transmembrane current can be either:
- Resistive = ions flow through channels.
- Capacitative = ion approaches one surface of the membrane and another is expelled from the other side.
Where do you find saltatory conduction?
Along nerves that are myelinated. The AP jumps between nodes of Ranvier (when one node is activated, the next node is almost instantaneously depolarised, small delay is present as the channels respond).
What does increased membrane resistance in an axon cause?
Causes the current to be forced through the axoplasm to the next node.
Why do unmyelinated axons conduct more slowly?
- Thinner axons lead to higher longitudinal axoplasmic resistance.
- Lower membrane resistance leads to the current dissipating faster and voltage falling more rapidly.
- Higher membrane charge stored means that the voltage across the membrane changes more slowly.
What is ephaptic coupling?
Where signal can be directly transmitted between cells without the need for a synapse. This happens in cardiac cells through intercalated discs.
What happens at the axon hillock?
The last site in the soma where membrane potentials propagated from synaptic inputs are summated before being transmitted to the axon.
Describe the stages involved in communication at the neuromuscular junction.
- Pre-synaptic cleft depolarises causing voltage-gated Ca channels to open causing a massive influx of Ca into the cell.
- High Ca concentrations trigger ACh filled vesicles to fuse with the membrane and release their contents into the EC space.
- The ACh then binds and opens ACh-gated cation channels. This channel allows Ca in and K out of the post-synaptic cell simultaneously.
What is the plateau on a muscular action potential due to?
The influx of Ca into the cell is much slower than that of K or Na.
What are end-plate potentials?
They are the depolarisations of skeletal muscle fibres which produce a sub-threshold signal and therefore do not produce an action potential.
Where are ACh channels located in the neuromuscular junction?
Directly beneath the pre-synaptic cleft and nowhere else along the muscle fibre.
What causes an end-plate potential?
When ACh channels are activated, some Na flows in and K out. The result of this is a small potential called the end-plate potential.
What causes the propagation of an AP in the neuromusclular junction?
The opening of Na and K channels along the muscle fibre.
What is an electrotonic (graded) potential?
Where the strength of an AP gets weaker the further away from the initiation site you go.
What are EPSPs and IPSPs?
Excitatory and inhibitory post-synaptic potentials. They are sub-threshold events which determine whether a neuron will reach threshold to fire an AP. EPSPs and IPSPs cancel each other out.
They are make up of miniature end-plate potentials (MEEPs).
What are the differences between the ultrastructure of skeletal and cardiac muscle?
- Fatter t-tubules in cardiac muscle.
- Dyads in cardiac and triads in skeletal muscle.
- Larger mitochondria in cardiac cells.
In which cells are t-tubules absent?
Atrial, neonatal and avian heart cells.
Draw a cardiac action potential.
Google answer.
What is the duration of a cardiac action potential?
200-400ms
What is the refractory period?
The time during an AP where the cell is incapable of firing a new AP.
Why is the cardiac AP so long and why is this beneficial?
Because of the long refractory period preventing a new AP to be fired.
The long APs prevent tetany (where APs summate and cause muscles to spasm) and protects against re-entrant arrhythmias.
What is the difference between cardiac and skeletal muscle contraction initiation?
Cardiac muscle requires Ca influx to initiate a contraction whereas skeletal muscle does not.
How does the AP trigger Ca release in cardiac muscle cells?
- Clusters of L-type Ca channels (also known as DHP receptors) are found on the t-tubules and are voltage-gated so open when the AP sweeps past.
- There are Ca release channels found on the sarcoplasmic reticulum (also called ryanodine receptors). These channels open when bound to Ca. This is called calcium-induced calcium release.
What are SR Ca release ion channels also known as?
Ryanodine receptors or ‘foot proteins’ because they are so large.
How do cardiac muscle cells relax?
- Ca is taken back up into the sarcoplasmic reticulum via an ATP-driven pump called SERCA.
- Remaining Ca is removed by the Na-Ca exchanger (Na goes in and Ca goes out).
Describe voltage-induced calcium release.
When the L-type Ca channels on the t-tubules are voltage-activated, they physically remove a ‘plug’ from the ryanodine receptor which allows Ca to flow into the cell. This is why skeletal muscle contraction is not Ca-dependant.
What two things are required for cross-bridge formation in muscle cells?
- Ca needs to bind to troponin C which pulls tropomyosin out of the way.
- ATP provides the energy to allow the myosin head to release from actin and swing forwards.
What is the myofilament calcium-tension relationship and what alters it?
It is a sigmoidal relationship.
Affected by temperature, pH, drugs, inorganic phosphate.
What is the length-tension relationship?
Where the sarcomere length determines the force generated by the muscle fibres. There is an optimal length - too small and too long produces very little force.
What is the optimal sarcomere length for cardiac muscle?
2.25µM
What does an increase in sarcomere length do?
It increases the Ca sensitivity (affinity for Ca to troponin C) and the maximally activated force.
What is the Frank-Starling law of the heart?
The law represents the relationship between stroke volume and end diastolic pressure. The law states that the stroke volume of the heart increases in response to an increase in the volume of blood in the ventricles, before contraction (the end diastolic volume), when all other factors remain constant.
What is the cellular basis of the length tension-relationship?
The Frank-Starling law of the heart.
What is the Bowditch/treppe effect?
It is an autoregulation method by which myocardial tension increases with an increase in heart rate.
What happens to the force-frequency relationship in a failing human heart?
It becomes negative i.e. force decreases with increasing frequency.
This is due to down-regulation of SERCA, up-regulation of Na/Ca exchange and an elevation of intracellular Na. This causes more Ca extrusion between beats and less Ca cycling through the SR.
What regulates smooth muscle?
The autonomic nervous system, hormones and locally released substances. The GI tract’s rhythmic contractions are initiated by pacemaker cells.
What are characteristic features of smooth muscle cells?
- Elongated shape.
- Lack of striations.
- Presence of dense bodies which anchor actin filaments.
- Presence of endoplasmic/sarcoplasmic reticulum to store Ca.
- Gap junctions.
- Higher ratio of actic to myosin compared to striated muscle.
What is an autocoid?
A physiologically active factor released by cells which typically acts locally and briefly on other cells.
What is a local hormone?
Any regulatory substance released by cells acting in an autocrine or paracrine fashion.
What are the main stimuli for vascular smooth muscle?
- ANS
- Autocoids
- Local hormones
- Vascular endothelium
- Blood-borne substances
What can happen in smooth muscle that cannot occur in cardiac or skeletal muscle?
Smooth muscle contraction can be actively suppressed by inhibitory stimuli.
Describe the structure of a typical muscular artery from the inside out.
- Lumen
- Endothelial cells
- Tunica intima (internal elastic lamina)
- Smooth muscle cells (tunica media)
- Tunica adventitia (blood vessels if large enough, collagen, sympathetic nerves and fibroblasts)
What are the constricting stimuli for blood vessels?
- Angiotensin II, adrenaline (blood-borne)
- Noradrenaline released by sympathetic nerves
- Local hormones
- Pressure/stretch
What are the relaxing stimuli for blood vessels?
- Tissue metabolites (adenosine, K)
- Flow causing endothelial cells to release NO
- Local hormones
Describe the mechanism of vascular smooth muscle contraction with noradrenaline as the agonist.
- NA binds to α1 receptors activating phospholipase C via g-proteins.
- Phospholipase C catalyses PIP2 -> DAG & IP3.
- IP3 causing Ca to be released from the sarcoplasmic reticulum.
- DAG opens a RGC (receptor-gated channel) on the membrane which non-selectively allows cations into the cell including Na and Ca causing the cell to depolarise.
- The membrane depolarisation causing the voltage-gated Ca channel to open allowing more Ca into the cell.
What do stretch-activated channels do in smooth muscle cells?
Their activation allows Na into the cell which causes depolarisation and starts the contraction cascade.
Describe the process of vascular smooth muscle relaxation with NO.
- NO diffuses straight into the cell and activates guanylate cyclase.
- Guanylate cyclase catalyses the reaction GTP -> cGMP.
- cGMP activates protein kinase G which phosphorylates K channels.
- Outflux of K from the cell causes hyperpolarisation which closes voltage-gated Ca channels.
- Protein kinase G also phosphorylates SERCA and PMCA (plasma membrane Ca ATPase) causing Ca to be pumped out of the cell.
Describe cyclic AMP mediated vasodilation.
- Substances (including adrenaline and adenosine) binds to β1 adrenergic receptors activating adenylate cyclase.
- Adenylate cyclase catalyses the reaction ATP -> cAMP.
- cAMP activates protein kinase A which phosphorylates K channels.
- Outflux of K from the cell causes hyperpolarisation which closes voltage-gated Ca channels.
- Protein kinase A also phosphorylates SERCA and PMCA (plasma membrane Ca ATPase) causing Ca to be pumped out of the cell.
What breaks down and terminates the action of cAMP and cGMP?
Phosphodiesterases
Describe smooth muscle cross-bridge contraction.
- Increase in Ca causes Ca to bind to calmodulin (similar to troponin) which binds four Ca’s to become activated.
- Active calmodulin interacts with myosin light-chain kinase which is then activated.
- Myosin becomes phosphoylated and cross-bridges form causing contraction.
What reaction controls the smooth muscle crossbridge cycle?
Myosin dephosphorylation catalysed by myosin phosphatase.
Describe smooth muscle crossbridge regulation.
- Reduced levels of Ca reverse the contraction process.
- Rho A activates Rho kinase which inhibits myosin phosphatase promoting contraction. Ca sensitisation.
- NO via cGMP stimulates myosin phosphatase promoting relaxation. Ca densensitisation.
What is a unique feature of smooth muscle crossbridge cycling?
It is much slower compared to striated muscle which leads to a lower requirement for ATP synthesis so smooth muscle can remain contracted indefinitely and doesn’t fatigue.
Describe the latch-bridge hypothesis.
Where myosin phosphatase is acting on myosin while it is still bound to actin. This ‘locks’ the myosin and actin together to maintain contraction which does not require ATP. Myosin and actin eventually fall apart but this takes a very long time.
What are slow waves?
These are spontaneous oscillations found in visceral smooth muscle that are generated by either the smooth muscle cells themselves or are driven by pacemaker cells.
What is the resting membrane potential for a smooth muscle cell?
-50mV
Describe multi-unit smooth muscle.
This is where each smooth muscle cell has a synaptic input which allows for finer control of the muscle. This is found in the iris, ciliary body and piloerector muscles of the skin.
Describe unitary smooth muscle.
This is where not all cells have synaptic input and excitation is spread through tissue by via gap junctions. This allows for co-ordinated contraction of many cells. This is found in the GI tract, genitourinary tracts, airways and most vasculature.
Define the autonomic nervous system.
The ANS is the neuronal groups and fibre connections that control the activity of the heart, visceral organs, blood vessels and glands.
What is the function of the ANS?
It maintains homeostasis by directly or indirectly facilitating the response of virtually every organ system to changing external and internal demands.
What are the functions of the parasympathetic nervous system?
Digestion, excretion and visual accommodation. It promotes effects that are associated with relaxation. Its innervation and effects are less widespread.
What are the functions of the sympathetic nervous system?
They are mainly important for the ongoing control of the cardiovascular system and reflex responses to stressful situations. It controls the ‘fright, fight and flight’ response. Its innervation and effects are more widespread.
Describe the parasympathetic efferent nerve pathway.
- Nerve originates in the CNS and the preganglionic nerve travels all the way to the ganglion which is in the tissue itself.
- ACh is released at the synapse and binds to nicotinic receptors on the post-ganglionic nerve.
- Post-ganglionic nerves also release ACh which bind to muscarinic receptors in the tissue causing a response.
Describe the main sympathetic efferent pathway.
- Nerve originates in the CNS and the pre-ganglionic nerve is short ending at the sypathetic chain where it synapses.
- ACh is released which binds to nicotinic receptors on the post-ganglionic nerve.
- The post-ganglionic nerves are long and travel to the tissues where noradrenaline is released and binds to adrenergic receptors (α or β) which cause a response.
Describe the two other types of sympathetic efferent nerve pathways.
1) Works in exactly the same way as the parasympathetic efferent pathway just the ganglion is located near the spinal cord not in the tissue.
2) Pre-ganglionic fibres travel to the adrenal medulla where they release ACh which binds to nicotinic receptors on the medulla. The medulla then releases noradrenaline and adrenaline into the blood which bind to adrenergic receptors (α or β).
What type of receptors are muscarinic receptors?
G-protein coupled receptors.
What are the two most important muscarinic receptors?
1) M2 = found in cardiac tissue that causes a decrease in cAMP causing heart rate to decrease.
2) M3 = found in smooth muscle and glandular tissue causes and increase in IP3 and DAG which is important in contraction of visceral muscle.
What type of receptors are nicotinic receptors?
They are non-selective cation channels that mainly admit Na and K leading to rapid cell depolarisation.
What are the two most important nicotinic receptors?
1) N1 = found in muscle.
2) N2 found in ganglia.
What is the effect of the α1 adrenergic receptor?
Activates Gq which stimulates IP3/Ca2+ and DAG second messenger pathways which raises cellular [Ca2+]. Found post-synaptically.
What is the effect of the α2 adrenergic receptor?
Activates Gi which inhibits adenylate cyclase and consequently decreases cAMP. It is often located presynaptically and acts to decrease the release of noradrenaline.
What is the function of β adrenergic receptors?
All three subtypes activate Gs which causes and increase in cAMP.
Where are the three subtypes of β adrenergic receptors found?
- β1 = main cardiac subtype. Found post-synaptically.
- β2 = main vascular and airways subtype. Found in non-synaptic sites.
- β3 = mainly found in adipose tissue but are also important in the bladder.
What is NANC?
Non-adrenergic, non-cholinergic transmission where nerves in the ANS conduct neurotransmission that is neither adrenergic or cholinergic.
Give two examples of NANC neurotransmission.
1) Some post-ganglionic sympathetic fibres release neuropeptide Y and ATP along with NA which promotes vasoconstriction.
2) Some postganglionic parasympathetic fibre branches release NO and vasoactive intestinal peptide along with ACh which causes vasodilation.
Which branches of the ANS causes ejaculation and erection?
Sympathetic = ejaculation.
Parasympathetic = erection.
What are the parasympathetic effects on the heart and what are they mediated by?
- Inhibition of the cardiac pacemaker (sinoatrial node) causing a decrease in heart rate, blood pressure and cardiac output.
- Decreases the conduction velocity in the atrioventricular node.
- Has a small direct effect on ventricular contraction.
All mediated by the vagus nerve.
Why does the PNS have little effect on total peripheral resistance? What is the one exception?
Even though there are cholinergic muscarinic receptors in blood vessels, normally there is no ACh in the blood so none of the receptors can be activated.
The one exception are the blood vessels in the penis which cause erection.
Describe the baroreceptor reflex.
When there is an increase in blood pressure:
- Afferent nerve endings found in the arterial walls are stimulated by stretch which signals to the nucleus tractus solitarius (NTS) in the brainstem.
- The NTS compares the increase in BP to a set point. As it is above the set point, it acts to:
- Increases parasympathetic input to the heart.
- Decreases sympathetic input to the heart, arteries and veins.
- All of these effects cause BP to fall towards the set point.
What are the parasympathetic effects on smooth muscle?
- Bronchioles constrict.
- Causes spontaneous contractions of the gut wall and relaxes the intestinal sphincters.
- Contracts the detrusor muscle of the bladder and relaxes the external sphincter.
What secretions do the parasympathetic NS stimulate?
- Bronchosecretions (mucus).
- Gastrointestinal (gastric acid, pancreatic enzymes).
- Salivary glands (watery saliva).
- Lacrimal glands (tears).
What are the parasympathetic effects in the eye?
1) Causes focusing by contracting ciliary muscles which relaxes tension on the lens allowing it to thicken and shorten the focal distance.
2) Causes pupil constriction (miosis) by contracting the sphincter pupillae muscle in the iris.
How is acetylcholine synthesised?
It is a product of the reaction Acetyl CoA + Choline which is catalysed by choline acetyltransferase.
Describe the re-uptake mechanism for ACh.
Acetylchonlinesterase is found on the post-synaptic cleft and breaks ACh down into choline and acetate. The choline is then taken up by the pre-synaptic cleft to be used to make ACh once more.
What medication is used to treat closed-angle glaucoma?
A long-lasting cholinesterase inhibitor called ecothiopate.
How is botulinum toxin used to treat an overactive bladder?
It prevents the stimulation of muscarinic receptors on the detrusor muscle by binding to and degrading SNAP-25 which prevents exocytosis of ACh and other neurotransmitters.
What forms the enteric nervous system?
A complex network of plexuses (myenteric and submucosal) of sensory, motor and interneurons which form two layers within the walls of the GI tract.
What are the three sites of drug intervention in the sympathetic nervous system?
1) Sympathetic nerves in the CNS. All drugs need to penetrate the BBB and effects are widespread.
2) Sympathetic ganglia. Because transmission is similar to all autonomic ganglia ( ACh mediated) the effects are widespread and non-specific.
3) Neuroeffector junction. This allows for specific targeting of receptors with minimal off-target effects.
