T1 L20: Molecular and ionic basis of cardiovascular control

• What are the effects of calcium channel blockers on cardiovascular activity?

  weaken: heart contractility

  strengthen: coronary artery vasodilation
• How does increased End diastolic volume increase force of contraction (Frank-Starling Law)?

  increased overlap of actin and myosin filaments

  increased force generation
• What kind of heart failure are beta blockers recommended for?

  compensated heart failure

  low concentrations
• How do low concentrations of beta blockers help compensated heart failure?

  reduce cardiac workload → reduce future damage / remodelling → reduce mortality
• Why are high concentrations of beta blockers disastrous in decompensated heart failure?

  they reduce workload substantially → lower cardiac output & worsen symptoms → hasten mortality
• How is heart rate determined based on the pacemaker potential?

  slope of pacemaker potential
• What is the normal resting heart rate and what is it due to?

  about 60bpm

  tonic parasympathetic stimulation

  
• What is the isolated / denervated heart rate?

  around 100 bpm

  
• How is heart rate controlled sympathetically?

  Noradrenaline:

  • increases funny current / net inward current via pacemaker channels (HCN) (beta 1 receptor)
  • increases Ca channel current: increases force of contraction
  • increases K channel current:
  • K channels are delayed rectifier channels
  • shortens AP duration
  • allows faster HR
• What are HCN channels in heart?

  'pacemaker channels'

  only in pacemaker / nodal cells

  Net current is inward: “non-specific monovalent cation channel”

  HCN Channel opens when membrane gets more negative

  current increased by sympathetic stimulation
• Why is it called the 'funny current'?

  mixed Na+ and K+ permeability

  activation upon hyperpolarisation
• How do alpha 1 receptors work?

  GPCR activates Gq → activate phosphokinase C → make IP3 & DAG → increase in intracellular Calcium

  Effects:

  • vasoconstriction in GI tract
  • sweat production

  
• How do beta receptors work?

  GPCR activates Gs → activate Adenylyl Cyclase → make cAMP

  Effects:

  • increase heart contractility (B1)
  • increase heart rate (funny current)
  • increase skeletal muscle perfusion (B2)
  • bronchodilation (B2)

  
• How is the parasympathetic stimulation of heart rate?

  Vagal

  Acetylcholine

  activates ACh-sensitive K+ channel:

  • make membrane more negative (K+ out)
  • decrease slope of pacemaker potential

  Opposes funny current
• What kind of ion channel is the ACh-activated K channel?

  G-protein (Gi) coupled

  Muscarinic
• What are the 2 types of cholinergic receptors?

  Nicotinic: Open ion channel directly

  Muscarinic: G-protein coupled
• How does atropine work?

  blocks parasympathetic slowing of HR

  so increases HR

  
• What are the types of K+ channels in cardiomyocytes?

  • Delayed Rectifiers: Repolarise both ventricular and nodal myocytes
  • ACh-sensitive K channels IK(ACh): Respond to parasympathetic to slow nodal rate
  • Inward Rectifiers: Clamp ventricular myocytes to resting potential
• What does beta-1 activity result in cardiac muscle?

  Stronger Contraction,Faster Rates & Faster Relaxation
• What happens in after-hyperpolarisation?

  voltage goes below -60mV → inward rectifier K+ channels open → K+ moves out → potential more negative than resting

  increased K+ permeability

  decreased Na+ permeability

  membrane potential moves closer to EK (-90mV)
• What is the refractory period?

  When there is so much positive current leaving the cell, it is impossible to depolarise it again

  
• What is ERP and how long does it last in a cardiomyocyte?

  effective refractory period

  Protects the heart from unwanted extra action potentials between SA node initiated heart beats

  lasts duration of AP
• Why is ERP important for a cardiomyocyte?

  Extra APs could start arrhythmias
• What is Amiodarone?

  Antiarrhythmic agent (for tachyarrhythmias)
• How does Amiodarone work?

  blocks K channels during repolarisation, slowing it down

  lengthens refractory period
• What are the adverse effects and contraindications of Amiodarone?

  Amiodarone-induced fibrosis of lung:

  • deadly, causes SOB, often irreversible (6-15% patients)
  • cumulative effect over time

  Arrhythmias:

  • delays repolarisation
  • contribute to long QT syndrome; ECG changes + sudden death

  Others:

  • Photosensitivity
  • made of iodine; which accumulates in cells and thyroid
• What is Excitation-Contraction Coupling?

  depolarisation of membrane with little calcium → consequent massive cytosolic calcium increase → contraction
• How does Excitation-Contraction (EC) Coupling work in cardiac myocytes?

  two proteins in SR membrane:

  • Ryanodine Receptor (RyR): triggered by intracellular Ca2+ increase, release Ca2+ (positive feedback loop)
  • SERCA: pumps Ca2+ back into SR using ATP
• Sympathetic stimulation of cardiomyocytes increases excitation-contraction coupling, which may cause calcium overload.
• How does Calcium-induced Calcium Release work?

  calcium detected by calcium receptor channels on SR → RyR channels open → calcium floods into cytosol → positive feedback loop → time delay → RyR channels close → SERCA pumps calcium back into SR using ATP
• What are the risks of calcium overload?

  ectopic beats, arrhythmias

  calcium may spill out of SR into cytosol at inappropriate times in cardiac cycle

  made worse by: fast rates, sympathetic drive
• What are the effects of calcium channel blockers on vessels, and what is an example?

  vasodilate, oppose hypertension

  eg Amlodipine (a DHP)
• What are the effects of calcium channel blockers on heart?

  anti-anginal & antiarrhythmic agents

  reduce nodal rates and conduction through AV node

  but makes HEART FAILURE worse
• What are some examples of Non-DHP calcium channel blockers?

  Verapamil, Diltiazem
• How does Verapamil work?

  blocks heart calcium channels mainly

  affects nodal cells

  slows nodal rate

  protects ventricles from atrial rhythms

  (slows conduction through AV node)
• How does Diltiazem work?

  antianginal & antiarrhythmic

  blocks both heart and vessel channels

  slows nodal rate and vasodilates coronary arteries

  prevents angina by reducing workload while increasing perfusion
• What id Digoxin?

  Positive inotropic agent:

  Increases stroke volume

  Increases contractility

  Also called a “cardiac glycoside”
• How does Digoxin work?

  inhibits Na/K pump: increased calcium in cytosol

  stimulate vagus: slow heart rate, increase AV Delay
• What is Digoxin used for?

  was used for heart failure:

  • improves symptoms but not mortality
  • beta blockers now preferred to decrease mortality

  now sometimes used for AFIB
• How does the myogenic control of local blood pressure control work?

  endothelium:

  • detects: stretch & plasma factors
  • produces: nitric oxide