molecular & ionic basis of cv control Flashcards
what are the key characteristics of intrinsic regulation of cardiac muscle?
- Frank-Starling relationship
- increased contractility
- longer and stronger
- more crossbridges means more of everything
what are the key characteristics of extrinsic regulation of cardiac muscle?
- sympathetic stimulation
- faster and stronger
- not longer durations
- extant crossbridges work harder and faster
how does increased EVD (more stretch) lead to increased force of contraction?
- increased overlap of thin and thick filaments
- increased overlap leads to increased force generators
- more of everything
how is heart rate controlled autonomically?
- isolated or deneraved heart rate: approx 100 beats per min
- the normal resting heart rate (about 60bpm) is due to tonic parasympathetic stimulation
- heart rate is determined mostly by the slope of the pacemaker potential
what happens when noradrenaline increases funny current?
- pacemaker channels
- increases slope of pacemaker potential
- via beta 1 receptor
what happens in nodal and ventricular areas with the sympathetic control of heart rate?
- noadrenaline —> increased Ica: increased force of contraction
- noadrenaline —> increased Ik: Ik = delayed rectifier, shortens AP duration, allows faster HR
what happens with the funny current if net current is inward?
- technically it conducts both Na in and K out
- non specific monovalent cation channel
- the several potential of If is -10mv
- it is not a sodium channel
what does sympathetic stimulation do to If?
increases If
what happens when HCN channel opens when membrane gets more negative?
- controls slope of pacemaker potential
- Na/Ca exchange also helps with PP
what happens with vagal heart rate?
- parasympathetic —> slower
- acetylcholine —>increased K current Ik (Ach): hyperpolarises membrane, decreases slope pacemaker potential
- Ach-activated K channel: G-protein (Gi) coupled, muscarinic
what are the types of K+ channels in cardiomyocytes?
- delayed rectifiers
- inward rectifiers
- Ach-sensitive K channels Ik (Ach)
what happens during the neural action potential after hyperpolarisation?
this causes the voltage to go more negative than at rest:
- after hyperpolarisation: at the end of an AP the voltage inside temporarily goes slightly more negative than at rest, followed by a return to the resting membrane potential
- during the AHP the delayed rectifiers are still open, as the rest the delayed rectifiers are closed
the related rectifiers are open during the AHP because they are slow to close
- during the AHP almost all the Na+ channels are inactivated
- at rest there is a tiny amount of Na+ permeability
during the AHP: increased K+ permeability and decreased Na+ permeability —> membrane potential moves closer to Ek
why is the voltage during after-hyperpolarisation more negative than at rest?
both the delayed rectifiers & inwards rectifiers are open during early AHP
- the inward rectifiers open when the membrane is more negative than -70mV
- the delayed rectifiers are still open during the AHP because they are too slow to close
- at rest the delayed rectifiers are closed
during AHP: increased K+ permeability and deceased Na+ permeability —> membrane potential moves very close to Ek
what is the refractory period?
when there is so much positive current leaving the cell it is impossible to depolarise it again
what is an effective refractory period?
- when it becomes nearly impossible to start a new action potential
- in cardiomyocytes, lasts for duration of AP
- protects the heart from unearned extra action potentials between SA node imitated heart beats: extra APs could start arrhythmias
what are T tubules?
invaginations of plasma membrane into monocyte
what are the purpose of T tubules?
- so membrane currents can be near contractile machinery
- contiguous with extracellular fluid
- adjacent to SR
- T tubule depolarises
- terminal cisterna detects it
- terminal cisterna sends it through ER
what is the terminal cisterna?
enlarged area of SR
what are the key characteristics of the terminal cisterna?
- continuous with SR
- specialised for storing and releasing calcium
what is E-C coupling?
the link (molecular process) between the depolarisation of the membrane (with a tiny influx of calcium) and the consequent huge increase cytosolic calcium that then leads to contraction
what is excitation?
when a neuron stimulates the muscle cell
how does voltage change lead to contraction?
diffusion of free calcium into the cytoplasm
where does most the calcium come from during contraction?
sarcoplasmic reticulum
what are some key characteristics of the sarcoplasmic reticulum?
- where large concentrations of calcium is stored
- right next to the myocytes actin and myosin
what happens to excitation-contraction coupling in skeletal muscle?
- membrane depolarises
- membrane calcium channels undergo a conformational change that opens them
- calcium flows from SR to cytosol
what are the key characteristics of ryanodine receptors (RyR)?
- in SR membrane
- channel that releases Ca2+
- triggered by intracellular Ca2+ release
- positive feedback loop
where is SERCA found and what does it do?
found: SR membrane
function: pumps calcium back to SR
what does sympathetic stimulation lead to in excitation-contraction coupling in cardiac myocytes?
increased Ec coupling which may cause calcium overload
what happens with the process of calcium induced, calcium released?
- this calcium is detected by calcium release channels on the SR
- the calcium release channels (RyR) open, allowing calcium to flood form the SR to the cytosol
- positive feedback loop
- after a time delay, the calcium release channels close
- SERCA pumps the calcium back into the SR
what are the issues with calcium overload?
can cause risk of ectopic beats and arrhythmias:
- calcium may ‘spill out’ of SR into cytosol at inappropriate times in cardiac cycle
- made worse by fast rates and sympathetic drive
where doe the 2 types of calcium channel blockers work?
- on vessels: vasodilation, oppose hypertension
- on heart: anti anginal & antiarrhythmic agents
what do the calcium channel blockers on the heart do?
- reduce nodal rates and conduction through AV node
- makes heart failure worse
what is Verapamil?
- not a DHP
- blocks calcium channels
- used as antiarrhythmic
what is Diltiazem?
- not a DHP
- blocks calcium channels
- used as antianginal and antiarrhythmic
what is digoxin?
positive inotropic agent
what does digoxin do?
- increases stroke volume
- increases contractility
how does digoxin work?
- it slightly inhibits Na/K pump in the membrane leading to increased calcium in the cytosol
- stimulates vagus slowing heart rate and increasing AV delay
what is digoxin used for?
- atrial fibrillation
- can be used for heart failure but that is controversial
how does myosin light chain kinase (MLCK) work?
- vascular smooth muscle cell contraction initiated by MLCK
- in smooth muscle, myosin must be phosphorylated to contract, increased of control by troponin and tropomyosin
- MLCK phosphorylates myosin
- MLCK is activated by calcium-calmodulin
- relaxation occurs by dephosphorylating myosin: done by a phosphate activated by NO induced cascase
how does nitric oxide (NO) work?
- NO is made inside endothelial cells leading to vasodilation
- relaxes vascular smooth muscle cells
- as dissolved molecules, NO travels through VSMC membrane
- inside VSMC, it activated an enzymatic cascade
- cascade ends by dephosphorylation myosin which relaxes muscles
which nitrates are used as vasodilators?
- glyceryl trinitrate (GTN) = nitroglycerine
- prodrug: in body it degrades to produce NO
how do nitrates work as vasodilators?
- leads rapidly to vasodilation
- continuous administration leads to tolerance
- pulsed use works best
how does bradykinin work as a peptide hormone?
- loosens capillaries and blood vessels
- constricts bronchi and GI tract smooth muscle
how does bradykinin dilate the arteriole?
- endothelium dependent
- stimulates NO production in endothelium
what are the 3 biomarkers in plasma?
- troponin
- creatine kinase (CK or CPK)
- C reactive protein (CRP)
what do you look for with troponin as a biomarker in plasma?
- released from cardiomyocytes during necrosis
- elevated during AMI, HF and many others
- not elevated during unstable angina
what do you look for with creatine kinase as a biomarker in plasma?
released from myocytes during necrosis
what do you look for with C reactive protein as a biomarker in plasma?
- increases in response to inflammation
- acute phase protein
- risk of CVD and future events
