Molecular and Ionic Basis of Cardiovascular Control

Question 1

Intrinsic Regulation

Answer 1

Frank Starling relationship (increased EDV (more stretch) -> increased force of contraction - increased overlap of thin and thick filaments = increased force generators)
Longer and Stronger
More crossbridges means more of everything

Question 2

Extrinsic Regulation

Answer 2

Sympathetic stimulation
Faster and Stronger
Not longer duration
Extant crossbridges work harder and faster

Question 3

Heart Rate

Answer 3

Isolated or denervated heart rate ~100bpm
Normal resting heart rate (60-100bpm) is due to tonic parasympathetic stimulation
Heart rate is determined mostly by the slope of the pacemaker potential
Sympathetic: noradrenaline -> increase in funny current (pacemaker channels increases slope of pacemaker potential via beta 1 receptor), and -> increase in I(Ca) (increased force of contraction) and I(K) (shortens AP duration allowing faster HR)
Vagal: acetylcholine -> increased K current - hyperpolarises membrane, decreases slope PP; Ach-activated K channel - G protein (Gi) coupled & muscarinic

Question 4

Funny Current - If

Answer 4

Net current is inward: conducts Na in and K out; reversal potential of If is -10mV
HCN channel opens when membrane gets more negative: controls slope of pacemaker potential; Na/Ca exchange also helps with PP
Sympathetic stimulation -> increased If

Question 5

Neural AP: after hyperpolarisation

Answer 5

Voltage goes below -60mV - inward rectifier K+ channels open again
This causes the voltage to go more negative than the rest
During AHP the delayed rectifiers are still open - they are slow to close
(at rest delayed rectifiers are closed)
During the AHP almost all the Na+ channels are inactivated
The increase in K+ permeability and decrease in Na+ permeability during AHP leads to the Vm moving closer to E(K)

Question 6

Effective Refractory Period (ERP)

Answer 6

In cardiomyocytes, it lasts for the duration of AP

Protects the heart from unwanted extra APs between SA node initiated heart beats (extra APs could start arrhythmias)

Question 7

T tubules and Terminal Cisternae

Answer 7

A system for storing and releasing calcium in response to Vm
T tubules = invaginations of plasma membrane into myocyte (so membrane currents can be near SR) - T tubule depolarises -> terminal cisterna detects it -> terminal cisterna sends it throughout SR
Terminal cisternae = enlarged area of SR, specialised for storing and releasing calcium

Question 8

Excitation Contraction Coupling

Answer 8

The link between the depolarisation of the membrane (with a tiny influx of calcium) and the consequent huge increase in cytosolic calcium that then leads to contraction
Excitation = when a neuron stimulates a muscle cell
The AP does not control cardiac muscle contraction - diffusion of free calcium into the cytoplasm is how a voltage change leads to contraction

Question 9

EC coupling in skeletal muscle

Answer 9

During contraction, most of the calcium comes from the SR
In skeletal muscle, membrane depolarises -> membrane calcium channels undergo a conformational change -> calcium release channels in SR (RyR) undergo a conformational change that opens them -> calcium flows from SR to cytosol

Question 10

EC coupling in cardiac myocytes

Answer 10

Ryanodine Receptor (RyR): in Sr membrane, channel that releases Ca2+, triggered by intracellular Ca2+, positive feedback loop
SERCA: in SR membrane, pumps Ca2+ back into SR (requires ATP), sympathetic stimulation -> increased EC coupling, which may cause calcium overload

Question 11

Calcium Induced Calcium Release

Answer 11

Is how EC coupling works in cardiomyocytes
Initially calcium enters the cell from outside (detected by calcium release channels on SR); the calcium release channels (RyR) open, allowing calcium to flood from the SR to cytosol; positive feedback loop; after time delay, the calcium release channels close; SERCA pumps the calcium back into SR

Question 12

Calcium Overload

Answer 12

Excessive intracellular calcium (and possibly in SR)
Can cause risk of ectopic beats and arrhythmias - calcium may spill out of the SR into cytosol at inappropriate times in cardiac cycle; made worse by fast rates, sympathetic drive

Question 13

Calcium Channel Blockers

Answer 13

Different types of calcium channel blockers
Some act preferentially on vessels, and others on the heart
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 14

Non-DHP calcium channels blockers

Answer 14

Verapamil: blocks Ca2+ channels, used as an antiarrrhythmic; blocks heart channels more than vessel channels, affect nodal cells, slows nodal rate, protects ventricles from rapid atrial rhythms (slowing conduction through AV node)
Diltiazem: blocks Ca2+ channels, antianginal and anti-arrhythmic; blocks heart and vessel channels, slows nodal rate, vasodilates coronary arteries, prevents angina by reducing workload and increasing perfusion

Question 15

Digoxin

Answer 15

Positive inotropic agent (increases stroke volume and contractility)
Works by slightly inhibiting Na/K pump on membrane (leads to increased calcium in cytosol)
Stimulates vagus (slows heart rate, increases AV delay)
Used to be used for HF
Sometimes still used for AF

Question 16

Myogenic Control of Blood Pressure - Endothelium

Answer 16

Endothelium detects stretch and plasma factors
Endothelium produces hormone bradykinin
Endothelium produces NO, which relaxes vascular smooth muscle cells (VSMC) - travels through VSMC membrane and activates enzymatic cascade; cascade ends by dephosphorylating myosin - which relaxes muscle

Question 17

Myosin Light Chain Kinase (MLCK)

Answer 17

Myosin Light Chain is active when phosphorylated
VSMC contraction initiated by MLCK (rather than control by troponin and tropomyosin)
MLCK phosphorylates myosin, and is activated by calcium-calmodulin
Relaxation occurs by dephosphorylating myosin - this is done by a phosphatase activated by NO induced cascade

Question 18

Bradykinin

Answer 18

Peptide hormone: loosens capillaries and blood vessels; constricts bronchi and GI tract smooth muscle
Dilates arterioles: endothelium dependent, stimulates NO production in endothelium
Increases capillary permeability: e.g. increases saliva production
ACE inhibitors prevent degradation of bradykinin, which causes dry cough, associated with ACE inhibitors

Question 19

Biomarkers in the Plasma

Answer 19

Troponin: released from cardiomyocytes during necrosis; elevated during AMI, HF and others; not elevated during unstable angina
Creatine Kinase: released from myocytes during necrosis
C reactive protein (CRP): increases in response to inflammation; acute phase protein; risk fo CVD and future events