CVS session 4: cellular events and the ANS Flashcards
How is the resting membrane potential set up?
- K+ move out of cell down concentration gradient, due to open K+ channels
- leaves negative inside with respect to outside, forming an electrical gradient as charge builds up
- the electrical and concentration gradients are in opposite directions
- K+ efflux as tries to reach Ek, but doesn’t quite reach due to small inward leak of Na+ and Ca2+
Describe excitation-contraction coupling of cardiac myocytes
- AP causes increase in cytosilic Ca2+: through L type calcium channels, then bind to RYR and cause calcium-induced-calcium release from SR
- this allows myosin and actin interaction and so generates contraction
- 1 AP in pacemaker=1 AP in every cell of heart=1 heartbeat (ensures that once the AP begins in one part of the heart, it is long enough for that cell to still be depolarised when the last cell in the myocardium is depolarised)
Describe and draw a diagram of the cellular events in a ventricular action potential
- Opening of voltage gated Na+ channels so Na+ influx (upstroke)
- Rapid initial repolarisation: transient outward K+ current; may also reverse NCX
- Plateau: opening of L-type voltage gated Ca2+ channels (Ca2+ influx) and balanced with some open K+ channels (K+ efflux)
- Further repolarisation: Ca2+ channels inactivate, voltage gated K+ channels are open and K+ effluxes
How does Ca2+ cause contraction in cardiac myocytes?
Ca2+ binds to TnC → conformational change in tropomyosin exposing active site between actin and myosin
Myosin heads interact with actin filaments and “flex,” like oars on a boat, to “row” myosin along actin in an ATP-dependent reaction:
Hydrolysis of ATP by ATPase on myosin induces crossbridge formation between myosin head and active site on actin
The strength of cardiac contraction is proportional to the number of crossbridges formed.
Interaction between myosin head and actin trigger “firing” of myosin head, causing it to pull itself along the actin filament in a process known as the power stroke.
ADP is released from the myosin head, which then binds a new ATP, releasing the actin filament.
Length of cardiac action potential?
~280ms at rest (longer than neuronal; due to Ca2+ plateau phase)
Describe the cellular events in the SA node
- Flat first part: pacemaker potential. “If” (funny current). Influx of Na+, slow depolarisation, activated at MP more negative than -50mV, then HCN channels (hyperpolarisation-activated, cyclic nucleotide-gated channels) open to allow Na+ influx
- Upstroke: opening of voltage gated Ca2+ channels so these ions enter. Slower opening than Na+ channels in ventricular AP; Na+ channels inactivated by slow depolarisation (accommodation)
- Downstroke: voltage gated K+ channels open causing K+ efflux
How does the SA nodal AP differ from the ventricular AP?
SA nodal naturally automated (initiated by the SA nodal cells rather than conduction from neighbouring fibres)
SA nodal is slower
SA nodal does not have a plateau phase
Role of Purkinje fibres?
Conduct excitation through the ventricular myocardium. Have long AP. If conduction is blocked they may become important
Role of the SA node?
Sets rhythm and is pacemaker
Fastest to depolarise
Which other parts of the heart have automaticity? (but slower than SA node)
AV node
Bundle of His
Right and left bundle branches
Describe the structure of cardiac myocytes
Single central nucleus
Intercalated discs: cells joined structurally by desmosomes
Gap junctions: join cells electrically by gap junctions of ion channels, permit ion movement, formed by connexin proteins to make non-selective large ion channels to allow rapid transfer. Not seen microscopically
Consequences of increased cytosolic Ca2+?
Depolarisation opens L-type Ca2+ channels in T tubule system
Localised Ca2+ entry opens CICR channels in SR
Relaxation of cardiac myocytes?
Most Ca2+ pumped back into SR by SERCA
Some Ca2+ exits across the cell membrane by sarcolemmal Ca2+-ATPase and NCX
How is vascular tone controlled?
Contraction and relaxation of smooth muscle in the tunica media of arteries, arterioles and veins
Cellular structure of smooth muscle?
Actin and myosin are connected to dense bodies, therefore not striated
Spread outwards in oblique lines
How is vascular smooth muscle contraction initiated?
Depolarisation or activation of alpha-adrenoceptors
Describe the steps in vascular excitation-contraction coupling
- Increased [Ca2+] causes Ca2+ to bind to calmodulin
- When 4 Ca2+ have bound calmodulin, there is activation of MLCK, which phosphorylates the myosin light chain
- Myosin activated so can interact with actin
- MLCK is deactivated by MLCP (dephosphorylates myosin light chain). MLCK can also be inhibited by PKA
Describe the main features of the autonomic nervous system
An efferent and mostly involuntary system
Exerts control over smooth muscle, exocrine secretion and rate and force of contraction
One nerve cell in each pathway is located entirely outside the ANS in ganglia
Describe the structure of the ANS
Cell body of the preganglionic neurone is in the CNS
Cell body of the postganglionic neurone is in the PNS
Most organs are innervated by the sympathetic division. Describe its structural features
Thoracolumbar origin (cell bodies of preganglionic neurones are in thoracic and lumbar spinal cord:T1 to L2/3)
Includes adrenal medulla
Most synapse with postganglionic neurones in the paravertebral column
Some synapse in prevertebral ganglia: coeliac, superior and inferior mesenteric ganglia
Short preganglionic, long postganglionic
Describe the strucute of the parasympathetic divison
Craniosacral division (preganglionic nerves travel in cranial nerves III, VII, IX & X or sacral outflow S2-S4
Synapse with neurones in ganglia close to target tissue
Long preganglionic, short postganglionic neurones
Postganglionic can sometimes be embedded in wall of target organ
Neurotransmission in all preganglionic neurones?
ACh which acts on nicotinic ACh receptors on the postganglionic cell body
nAChR have integral ion channel for K+ and Na+
ACh binds receptor, opens ion channels, influx of Na+ due to negative MP, causes depolarisation and AP
Postganglionic sympathetic neurotransmission?
Usually noradrenergic: NA acts on adrenoceptors (alpha1, alpha2, beta1, beta2)
GPCRs so no integral ion channels
Exceptions:
- sweat glands: ACh which acts on muscarinic ACh receptors (cholinergic)
- adrenal medulla chromaffin cells: release adrenaline which circulates in blood
Postganglionic parasympathetic neurotransmission?
ACh acts as muscarinic ACh receptors in effector cells (M1, M2, M3)
mAChRs are GPCRs with no integral ion channels
What are cotransmitters?
Other transmitters released with noradrenaline/adrenaline at the synapse of the postganglionic neurone with effector cells
E.g. neuropeptide Y, ATP
ANS influences and transmitter/receptor for pupil
Sympathetic: dilatation (contraction of radial muscle of iris). NA (alpha 1 adrenoceptor)
Parasympathetic: constriction (contraction of sphincter muscle of iris). ACh (M3)
ANS influences and transmitter/receptor for salivary gland
S: thick amylase secretion. NA (alpha 1 and beta adrenoceptors)
P: profuse watery secretion. ACh (M3)
ANS influences and transmitter/receptor for airways
S: not from SNS, but circulating adrenaline on beta 2 receptors
P:constriction. ACh (M3)
ANS influences and transmitter/receptor for SA node
S: increase rate. NA (beta 1)
P: decrease rate. ACh (M2)
ANS influences and transmitter/receptor for atrial muscle
S: increase force (NA, beta 1)
P: decrease force (ACh, M2)
ANS influences and transmitter/receptor for ventricular muscle
S: increase force (NA, beta 1)
P: none
ANS influences and transmitter/receptor for blood vessels of most tissues
S: constriction (NA, alpha 1)
P: none
ANS influences and transmitter/receptor for blood vessles in skeletal muscle
S: constriction by NA (alpha 1), dilation by circulating adrenaline (beta 2)
P: no effect
ANS influences and transmitter/receptor for blood vessels in erectile tissue
S: constriction (NA, alpha 1)
P: dilation (ACh, M3?)
ANS influences and transmitter/receptor for gut secretion
S: inhibition
P: stimulation (ACh, M3)
ANS influences and transmitter/receptor for gut motility
S: decreased (NA; alpha 1, alpha 2 and beta 2)
P: increased (ACh, M3)
ANS influences and transmitter/receptor for gut sphincters
S: constriction (NA; alpha 2 and beta 2)
P: dilation (ACh; M3)
ANS influences and transmitter/receptor for adipose tissue
S: lipolysis (NA; alpha 1, beta 1, beta 3)
P: none
ANS influences and transmitter/receptor for liver
S: glycogenolysis and gluconeogenesis (NA; alpha and beta 2)
P: none
ANS influences and transmitter/receptor for kidney
S: stimulate Na+ reabsorption; increase renin secretion (NA; beta 2)
P: none
ANS influences and transmitter/receptor for sweat glands
S: secretion (ACh; M), or adrenergic on palms of hands by circulating adrenaline (alpha)
P: none
ANS influences and transmitter/receptor for male sex organs
S: ejaculation (NA; alpha)
P: erection (ACh; M3?)
How does the ANS control the CVS?
Controls HR, force of contraction and peripheral resistance in arterioles
Does not initiate electrical activity (but does control it): at rest the heart is under vagal influence. A denervated heart still beats, but at a faster pace
Describe the parasympathetic input to the heart
Preganglionic fibres (X cranial nerve [vagus]) synapses with post-ganglionic cells on the epicardial surface or at SA and AV nodes
Post-ganglionic cells release ACh, which acts on M2 receptors to:
-decrease heart rate (negative chronotropy)
-decrease AV node conduction velocity
Describe the sympathetic input to the heart
Post-ganglionic fibres from the sympathetic trunk innervate the SA and AV nodes and the myocardium.
Release NA which acts on beta 1 adrenoceptros to:
-increase heart rate (positive chronotropy)
-increase force of contraction (positive inotropy)
Beta 2 and Beta 3 adrenoceptors also present but mainly beta 1
Describe how cells in the SA node generate the pacemaker potential
Turn on a slow Na+ conductance: the funny current If
Opening of Ca2+ channels
AP firing in SA node sets the rhythm of the heart as it fires very quickly
How does the ANS contribute to the pacemaker potential?
Sympathetic activity: increases slope; mediated by beta 1 receptors, increase cAMP, speeds up pacemaker potential
Parasympathetic activity decreases slope; mediated by M2 receptors, increases K+ conductance and decreases cAMP so slows the pacemaker potential
NA acting on myocardial beta 1 receptors causes increased cAMP so activates protein kinase A. How does this increase force of contraction?
- Phosphorylation of Ca2+ channels increases Ca2+ during the plateau of the AP
- Increased uptake of Ca2+ in the SR
- Increased sensitivity of actin and myosin to Ca2+
Describe the sympathetic innervation of blood vessels
Most arteries, veins and arterioles have alpha 1 receptors; coronary and skeletal muscle also have beta 2
NA acts to cause vaso and veno constriction
Venoconstriction increases venous pressure so promotes the return of blood to the heart
[erectile tissue parasympathetic]
How is vasomotor tone controlled?
Increased S output–> vasoconstriction
Decreased S output–>vasodilation
Due to NA acting on alpha 1 receptors
Beta 2 receptors in skeletal muscle, myocardium and liver?
Circulating adrenaline has a higher affinity for B2 than A1 receptors
Physiological conc., circulating adrenaline preferentially binds to beta 2 adrenoceptors
At higher conc will also activate alpha 1 receptors
How does beta 2 adrenoceptor activation cause vasodilation?
Increases cAMP–>PKA activated–>opens K+ channels and inhibits MLCK–>relaxation of smooth muscle
How does alpha 1 adrenoceptor activation cause vasoconstriction?
Increases IP3 production–>increased intracellular Ca2+ due to release from stores and influx of extracellular Ca2+–>contraction of smooth muscle
What are the actions of local metabolites such as adenosine, K+, H+ and CO2?
Strong vasodilators that are produced more in active tissues. Important for ensuring adequate perfusion of skeletal and coronary muscle
Which receptors send information about pressure to the brain via afferent nerves?
Baroreceptors: high pressure side of system
Atrial receptors: low pressure side of system
What are baroreceptors and how do they work?
Nerve endings in the carotid sinus and aortic arch that are sensitive to stretch, which occurs due to increased arterial pressure. Higher arterial pressure=more APs, and vice versa.
Control centre in medulla oblongata detects fall in BP due to fall in APs, so increases sympathetic output in order to increase BP to normal
If arterial pressure is increased, the medulla decreases sympathetic output and increases parasympathetic, causing bradycardia and vasodilation
Describe and give examples of sympathomimetrics
Alpha and beta adrenoceptor agonists
In the CVS:
-adrenaline is used to restore function in cardiac arrest and anaphylactic shock
-dobutamine (beta 1 agonist) in cardiogenic shock
Give some examples of adrenoreceptor antagonists?
Prazosin-antihypertensive. Inhibits NA action on vascular smooth muscle alpha 1 receptors, leading to vasodilation
Propranolol-slows HR and FoC (beta 1) but also causes bronchoconstriction (beta 2) : non-selective beta adrenoceptor antagonist
Atenolol-cardioselective as only beta 1 antagonist, so less risk of breathing problems
Examples of cholinergics
Pilocarpine: for treating glaucoma. Muscarinic agonist so activates constrictor pupillae muscle
Atropine: increases HR. Muscarinic antagonist
