electrical and molecular mechanisms Flashcards
K+ permeability sets resting membrane potential (RMP)
- cardiac myocytes permeable to K+ ions at rest
- move out of cell down conc. gradient
- small outward movements of ions makes inside negative relative to outside- as charge builds up electrical gradient established
- RMP doesn’t exactly equal EK (-95mV) as other ions make RMP = between -90 to -85 mV
- AP triggers increase in cytosolic Ca2+ - from stores + exctracellular influx - rise in CA2+ needed for actin-myosin interactions leading to contraction
cardiac (ventricular) action potential
N.B. there are many type of K+ channels in cardiac myocytes and each behaves and contributes differently to the electrical properties of the cell
- RMP due to background K+ channels
- Upstroke due to opening of voltage-gated Na+ channel - influx of Na+
- Initial repolarisation due to transient outward K+ channels (V-gated ito)
- Plateau due to opening of voltage-gated Ca2+ channels (L-type) - influx of Ca2+ - balanced by K+ efflux (iKV)
- Repolarisation due to efflux of K+ through voltage-gated K+ channels (iKV iKR) and others
the SAN action potential
- initial slope towards threshold potential (50mV) caused by funny current - HCN channels bring NA into cells - the mkre negative the more it activates
- depolarisation (upstroke) caused by opening of voltage gated Ca ion channels - Ca ions move in
- Repolarisation caused by opening of voltage-gated K+ channels as potassium ions move out of cell returning cell to resting membrane potential
SAN is the pacemaker of the heart
SAN action potential has natural automaticity. funny current due to unstable membrane potential of pacemaker and its slow depolarisation to threshold
- APs throughout heart have varying waveforms
- SAN fastest to depolarise – sets rhythm- is the pacemaker – other parts of conducting system also have automaticity but are slower
AP variation issues
- If action potentials fire too slowly → bradycardia
- If action potentials fail → asystole - heart ceases to beat
- If action potentials fire too quickly → tachycardia
- If electrical activity becomes random → fibrillation (rapid, irregular + unsnchronised contraction of muscle fibres)
Hyperkalaemia 1
- normal [K+] = 3.5 to 5.5 mmol/L,
- hyperkalaemia when K+> 5.5
- If increase in the K+ plasma concentration, EK becomes more positive + so RMP depolarises a little bit
- leading to inactivation of some of the voltage-gated Na+ channels (which slows upstroke)
Hyperkalaemia 2
- Hyperkalemia can cause the heart to go into Asystole
- Initially might be increase in excitability of the heart
- mild = 5.5-5.9 mmol/l
- moderate = 6-6.4 mmol/L
- severe> 6.5mmol/L
treatment
- If heart has already stopped, the above won’t work
- Insulin + glucose
- Calcium gluconate
hypokalaemia
K+ less than 3.5mmol/L
- Lengthened action potential and delayed repolarisation
- Longer AP can lead to early after depolarisations (EAD)
- This can lead to oscillations in membrane potential
- Can result in ventricular fibrillation = no cardiac output
excitation - contraction coupling
- depolarisation of membrane of myocytes opens L type calcium channels in T- tubule system
- entry of Ca2+ ions causes CICR(calcium induced calcium release) channels to release more Ca2+ from sarcoplasmic reticulum
- 25% enters across sarcolemma, 75% released from SR
regulation of cardiac myocyte contraction and relaxation
- Ca2+ binds to troponin C - conformational change - moves tropomyosin to reveal binding site for myosin
relaxation- must return Ca2+ to resting levels
- most pumped back into SR by SERCA (raised Ca2+ stimulates the pumps)
- some exits across cell membrane
- sarcolemmal Ca2+ATPase
- Na+/Ca2+ exchanger
vascular smooth muscle contraction 1
- Ca2+ enters through VGCCs/IP3 binds to IP3 receptors on SR causing release of Ca2+
- Ca2+ binds to calmodulin (CaM)
- activates myosin light chain kinase (MLCK)
- MLCK phosphorylates myosin light chain enabling actin- myosin interaction → contraction
vascular smooth muscle relaxation
relaxation as Ca2+ levels decline
- myosin light chain phosphatase (MLCP) dephosphorlates myosin light chain
- note: MLCK can itself be phosphorylated
- Phosphorylation of MLCK by PKA inhibits action of MLCK – therefore inhibiting contraction as actin-myosin interactions not enabled
to conclude
the Autonomic Nervous System (ANS)
ANS important in regulation of many physiological functions
- heart rate, bp, etc. (homeostasis)
- exerts control of smooth muscle (vascular + visceral), exocrine secretion, heart chronotropy & inotropy
Divided into sympathetic and parasympathetic nervous systems, these divisions are based on anatomical grounds
- GI has a separate nervous system but is supplied by Symp. and Parasymp. Fibres
functions of ANS
- Regulation of physiological functions
- Symp. & Parasymp. Tend to have opposite effects where they both innervate the same tissue
- Stress increases sympathetic activity
- Parasympathetic system more dominant under basal conditions
- Symp. + Parasymp. Systems work together for balance
Sympathetic drive to different tissues is independently regulated but there can be a more coordinated sympathetic response i.e. fight or flight
control of CVS by ANS
controls heart rate, force of contraction of heart, TPR of blood vessels, + amount of vasocnstriction
ANS does not initiate electrical activity on the heart
- denervated heart still beats but at faster rate (around 100bpm)
- at rest heart is normally under vagal influence
parasympathetic input to heart
Vagus nerve = 10th cranial nerve = parasympathetic innervation of heart
- Synapse with postganglionic cells on epicardial surface or with in walls of heart at SA and AV node
- Post ganglionic cells release ACh- Acts on M2-receptors
- Decrease heart rate (negative chronotropic effect)
- Decrease AV node conduction velocity
Sympathetic input to the heart
- postganglionic fibres from sympathetic trunk
- innervate SAN, AVN, myocardium – release noradrenaline
- mainly acts on β1 adrenoceptors
- increases heart rate ( +ve chronotropic effect)
- increases force of contraction (+ve inotropic effect)
- β2 & β3 adrenoceptors are also present in heart, main effect is mediated by β1 adrenoceptors
SAN
- Initial slope to threshold – If (funny current)
- Activated at membrane potentials that are more negative than – 50mV
- The more negative, the more it activates
- HCN channels – Hyperpolarisation-activated, Cyclic Nucleotide-gated channels
– Allow influx of Na+ ions which depolarises the cells
Noradrenaline (NA) increases force of contraction
- NA ating on ß1 receptors in myocardium causes an increase in Camp → activartes PKA
- Phosphorylation of Ca2+ channels increase Ca2+ during plateau of the AP
- Increased uptake of Ca2+ in sarcoplasmic reticulum
- Increased sensitivity of contractile machinery to Ca2+
→ all lead to increased force of contraction
ANS effect on vasculature
Most vessel receive sympathetic innervation – some exceptions – e.g. some specialised tissue e.g. erectile tissue has parasympathetic innervation
Most arteries and veins have a1- adrenoreceptors – coronary and skeletal muscle vasculature also have β2- receptors
- Circulating adrenaline has higher affinity for β2 adrenoreceptors than α1 receptors
- At physiological concentration circulating adrenaline will preferentially bind to β2 adrenoreceptors
- At higher conc. → also activates α1 receptors
Effects of b2 and a1 adrenoreceptors on vascular smooth muscle
activating B2 adrenoreceptors causes vasodilation
- increases cAMP → activates PKA →opens potassium channels + inhibits MLCK →relaxation of smooth muscle
Activating α1 adrenoreceptors causes vasoconstriction
- Stimulates IP3 production
- increase in [Ca2+] in from stores and via influx of extracellular Ca2+
- contraction of smooth muscle
local metabolites
- Active tissue produces more metabolites e.g. adenosine, K+, H+, increase PCO2. Local increases in metabolites have a strong vasodilator effect
- Metabolites are more important for ensuring adequate perfusion of skeletal and coronary muscle than activation of β2-receptors
baroreceptors
- Baroreceptors (high pressure side of system)
- Atrial receptors (low pressure side of system)
- Changes in state CVS communicated back to brain via afferent nerves
- brain then alters the activity of efferent nerves
- Baroreceptors are found in the carotid sinus and the aortic arch.
baroreceptor reflex
- The baroreceptor reflex is important for maintaining blood pressure over short term.
- It compensates for moment to moment changes in arterial BP HOWEVER…. Baroreceptors can re-set to higher levels with persistent increases in blood pressure (hypertension)
Sympathomimetics – mimic sympathetic NS
α-adrenoceptor agonists & β-adrenoceptor agonists
cardiovascular uses
- administration of adrenaline to restore function in cardiac arrest
- β1 agonist – dobutamine may be given in cardiogenic shock (pump failure)
- adrenaline administered for anaphylactic
- other uses – β2 agonists – salbutamol for treatment for treatment of asthma
adrenoreceptor antagonists
α-adrenoceptors
α-adrenoceptors:
- α1-antagonists – e.g. prazosin
- anti-hypertensive agent – but only to be used with resistant hypertension - inhibits NA action on vascular smooth muscle α1 receptors → vasodilation
adrenoreceptor antagonists - ß adrenoceptors
- propranolol – non-selective β1 /β2 antagonist
- slows heart rate and reduces force of contraction (β1)
- also acts on bronchial smooth muscle (β2) -> bronchoconstriction
- Atenolol – selective β1 (cardio-selective) – less risk of bronchoconstriction
Cholinergics
Muscarinic agonists
- e.g. pilocarpine – used in treatment of glaucoma
- activates constrictor pupillae muscle
Muscarinic antagonists
- e.g. atropine or tropicamide
- increases heart rate, bronchial dilation
- used to dilate pupils for examination of the eye
