the molecular and ionic basis of cardiovascular control

Question 1

describe intrinsic regulation of the cardiac muscle? 4

Answer 1

• Frank-starling relationship
• Increased contractility
• Long and stronger
• ‘more crossbridge means more of everything’

Question 2

describe extrinsic regulation of the cardiac muscle? 4

Answer 2

• Sympathetic stimulation
• Faster and stronger
• No longer duration
• ‘extant crossbridge work harder and faster’

Question 3

How does increased end diastolic volume (more stretch) increase the force of contraction? 3

Answer 3

• Increased overlap of thin and thick filaments
• Increased overlap leads to increased force generators
• More of everything

Question 4

explain autonomic control of the heart? 3

Answer 4

• Isolated or denervated heart rate is around 100 beats pre minute
• 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

Question 5

how does the sympathetic control increase heart rates? 3

Answer 5

• Noradrenaline increased funny current (net inward current) = pacemaker channels, increases slope of pacemaker potential via Beta 1 receptor
• Noradrenaline increased calcium current= increase force of contraction
• Noradrenaline increased potassium current= delayed rectifier, shortens AP duration, allows faster heart rate

Question 6

describe the funny current? 3

Answer 6

• Net current Is inward= technically it conducts both Na in and K out, non-specific monovalent cation channel, the reversal potential is -10mV, it is not a sodium channel
• HCN channel opens when membrane gets more negative, controls the slope of the pacemaker potential, NA/Ca exchange also helps with PP
• Sympathetic stimulation leads to an increase in funny current

Question 7

what do alpha 1 receptors do when activated?

Answer 7

vasoconstriction in most organs and sweat

Question 8

what do alpha 2 receptors do when activated?

Answer 8

less insulin and more glucagon

Question 9

what do beta receptors do when activated? 4

Answer 9

• increase heart contractility,
• increase heart rate (funny current),
• increase skeletal muscle perfusion,
• cause bronchodilation

Question 10

what are the different K+ channels in cardiomyocytes? 3

Answer 10

• Relayed rectifiers
• Inward rectifiers
• Ach-sensitive K channels

Question 11

describe the neural action potential of after-hyperpolarisation? 5

Answer 11

• When voltage goes below -60mV, the inward rectifier K+ channels open again
• This causes the voltage to go more negative than at rest
• After hyperpolarisation (AHP): 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 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 AHP: the increase in K permeability and decrease in Na+ permeability causes the membrane potential to move closer to the EK

Question 12

Why is voltage during AHP more negative than at rest? 3

Answer 12

• Both the delayed rectifiers and inward rectifiers are open during early AHP. The inward rectifiers open when the membrane is more negative than -70. The delayed rectifiers are still open during the AHP because they are slow to close. At rest the delayed rectifiers are closed
• During AHP, the increased K+ permeability and decreased Na+ permeability causes the membrane potential to move very close to the EK
• The refractory period when there is so much positive current leaving the cell, it is impossible to depolarise it again.

Question 13

explain why the refractory period is effective? 3

Answer 13

• When it becomes nearly impossible to start a new action potential
• In cardiomyocyte, lasts for the duration of AP
• Protects the heart from unwanted extra action potentials between SA node-initiated heart beats. Extra Aps could start arrhythmias

Question 14

describe T tubules and terminal cisternae? 3

Answer 14

• A system for storing and released calcium in response to Vm
• T tubules= invaginations of plasma membrane into myocyte, so membrane currents can be treating contractile machinery. Contiguous with extracellular fluid. Adjacent to SR, T tubule depolarises which is detected by the terminal cisterna, the terminal cisterna then sends the AP throughout SR
• terminal cisternae= enlarged area of SR contiguous with SR, specialised for storing and releasing calcium

Question 15

explain E-C coupling? 4

Answer 15

• E-C coupling= the link between the depolarisation of the membrane and the consequent huge increase cytosolic calcium that leads to contraction
• Excitation= when a neuron stimulates a muscle cell
• The action potential per se does not control cardiac muscle contraction
• Diffusion of free Ca2+ into the cytoplasm is how a voltage change can cause a contraction

Question 16

describe excitation-contration coupling in skeletal muscle? 2

Answer 16

• During contraction= most of the calcium comes from the sarcoplasmic reticulum where large concentration of calcium is sorted, right next to the myocyte’s actin and myosin
• In skeletal muscle= membrane depolarises which leads to the membrane calcium channels undergoing a conformational change which causes calcium release channels in SR undergo a conformational change that opens them which causes calcium to flow from SR to cytosol

Question 17

describe excitation-contration coupling in cardiac myocyte? 4

Answer 17

• Ryanodine receptor (RYR) in SR membrane, channel that releases CA2+ is triggered by the intracellular CA2+ increase which causes a positive feedback loop
• SERCA in the SR membrane which pumps CA2+ back into the SR
• Pumping Ca2+ back into SR requires ATP
• Sympathetic stimulation leads to increased EC coupling which may cause calcium overload

Question 18

how does calcium enter the cell from the outside? 5

Answer 18

• This calcium is detected by calcium release channels on the SR
• The calcium release channels (RyR) open, allowing calcium to flood from 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

Question 19

explain calcium overload? 2

Answer 19

• Excessive intracellular calcium: also, possibly excessive calcium in SR
• Can cause risk of ectopic beats and arrhythmias calcium may spill out of SR into cytosol at inappropriate times in the cardiac cycle made worse by fast rates, sympathetic drive

Question 20

generalise some different types of calcium channel blockers? 2

Answer 20

On vessels: vasodilate, oppose hypertension: amlodipine

On heart: anti-anginal and antiarrhythmic agents: reduce nodal rates and conduction through AV node but makes heart failure worse

Question 21

name some non DHP- calcium channel blockers?

Answer 21

• verapamil
• diltiazem
• digoxin

Question 22

describe verapamil? 7

Answer 22

• Not a DHP
• Blocks Ca2+ channels
• Used as antiarrhythmic
• Blocks heart channels more than vessel channels
• Affects nodal cells
• Slows nodal rate
• Protects ventricles from rapid atrial rhythms slows conduction through AV node

Question 23

describe diltiazem? 7

Answer 23

• Not a DHP
• Blocks Ca2+ channels
• Used as anti-anginal also antiarrhythmic
• Blocks both heart and vessel channels (halfway)
• Slows nodal rate
• Vasodilates coronary arteries
• Prevents angina by reducing workload while increasing perfusion

Question 24

describe digoxin? 6

Answer 24

• Positive inotropic agent which increases stroke volume and contractility
• Also called a cardiac glycoside
• Works by inhibiting Na/K pump on membrane which leads to increased calcium in cytosol and stimulates vagus by slowing heart rate and increasing AV delay
• Was used for heart failure improves symptoms but not mortality, beta blockers are preferred for CHF leading to decreased mortality
• Digoxin’s use in heart failure is now controversial
• Sometimes used for AF

Question 25

describe myosin light chain kinase? 5

Answer 25

• Vascular smooth muscle cell contraction initiated by MLCK
• In smooth, myosin must be phosphorylated to contract instead of control by troponin and tropomyosin
• MLCK phosphorylates myosin at its light chain
• MLCK is activated calcium-calmodulin
• Relaxation occurs by dephosphorylating myosin done by a phosphatase activated by NO induced cascade

Question 26

describe nitrates as vasodilators? 4

Answer 26

• Glyceryl trinitrate (GTN)= nitro-glycerine
• Prodrug: in body it degrades to produce NO
• Leads rapidly to vasodilation
• Continuous administration tolerance pulsed use works best

Question 27

describe bradykinin? 4

Answer 27

• Peptide hormone which loosens capillaries and blood vessels, constricts bronchi and GI tract smooth muscle
• Dilates arterioles endothelium dependents, stimulates NO production in the endothelium
• Increases capillary permeability (increases saliva production)
• ACE inhibitors prevent degradation of bradykinin which causes a dry cough associated with ACE inhibitors

Question 28

describe biomarkers in the plasma? 9

Answer 28

• Troponin (Tn)
• Released from cardiomyocytes during necrosis
• Elevated during AMI, HF
• Not elevated during unstable angina
• Creatine kinase:
• Released from myocytes during necrosis
• C reactive protein:
  increases in response to inflammation
• Acute phase protein
• Risk of cardiovascular disease and future events