Dr Henderson - Cardiovascular and Renal Flashcards
What is the structure of the Na+ VGCs α subunit?
4 homologous domains - each with 6 TM segments
Part of S4 = voltage sensor
Cytoplasmic loop between III and IV is important in inactivation (also S6 in IV andS5/6 linker)
Region between S5 and S6 forms the pore (S6 is the selectivity filter)
What is the structure of the Na+ VGC?
It has three subunits - α, β1 and β2
α1 forms the pore of the channel
Which section of the Na+ channel forms the selectivity filter?
S6 of the 4 homologous domains of the α subunit
How does local anaesthetics act upon Na+ VGCs?
They bind to channel stabilising it in its inactivated state and make it harder for them to reactivate
What is the structure of a Ca2+ VGC?
Has α1, α2, β, γ and δ subunits
What are the functions of the different subunits of the Ca2+ VGC?
α1 = the channel
α2δ and β enhance channel trafficking and regulate expression
Where do dihyrdopyridines act on Ca2+ channels?
Two binding sites - one on the segment S6 of domain 4 and the other is the S5-S5 loop of IV
Where do phenylalkylamine bind?
Bind to S5/S6 link of domain 4
Where do benzothiazepines bind?
They bind to the outside of domain IV (?)
What are the features of L-types Ca2+ channels?
Need large depolarisation to open Open for a long time Responsible for the plateau Large conductance (22-27Ps) Sensitive to inactivated channels
What are the features of T-type Ca2+ channels?
Gated with only a small change in potential Open transiently Low conductance (8pS) No sensitivity to dyhydropyridines Occur with L-type
What are the features of K+ VGCs?
S4 segment is voltage sensor
4 channels probably aggregate to form a channel (but one is enough)
What are the two ways by which K+ VGCs inactivate? explain them both
N-type - N terminus forms a ball which is ‘sucked’ into the pore occluding it, as the result of electrostatic changes associated with depolarisation
C-type - Is slower and seems to be the result of movement of residues near the extracellular surface of the pore
What is the role of inward rectifying K+ channels?
Prevent excessive loss of K+ from depolarised cells
What is effect does parasympathetic activity have on the heart?
Stimulation of M2 receptors by ACh reduces the activity of adenylyl cyclase = activation of HGIRK1 (Kir 3.1)
This is a inward rectifying K+ cell and hyperpolarises the pacemaker cells = reduced excitability and reduced HR
Produces the current called I(K-ACh)
What are ATP-sensitive Kir channels?
Produces the current I(K-ATP)
These channels open in the presence of low intracellular ATP, but close as intracellular ATP rises
In pancreatic beta cells their closure leads to insulin release
In the heart they act to protect against hypoxic conditions
I(Na)
The current produced by Na+VGCs = depolarising phase of the AP
I(Ca-L)
Produced by L-type Ca2+ channels
The main current during the plateau
I(Ca-T)
Produced by T-type Ca2+ channels and present in nodal and conductive tissue
I(Na-Ca)
The current that is the result of the electrogenic activity of the Na+/Ca2+ exchanger
I(TO1) & I(TO2)
Produced by K+ VGCs of a rather unusual nature
Activate rapidly in Phase 0 and then inactivate rapidly
Responsible for the small ‘notch’ of the AP that constitues Phase 1
I(Ks)
Delayed rectifier
Contributes outward current during the plateau and control timing of depolarisation (in Phase 3)
Is the result of two different K+ channels KCNE1 and KLQT2
I(Kr)
Another delayed rectifier
Kv11.1 channel
I(Kur)
The third delayed rectifier
Probably due to a channel called Kv1.5
I(Kp)/I(Cl)
I(Kp):-
Caused by a plateau K+ channel that shows no rectification of voltage sensitivity
Produced by TWIK channels
I(Cl):-
Chloride current from CFTR
I(K1)
Inward-rectifier stabilising the resting potential and prevent K+ loss
(I(K-ACh) and I(K-ATP) produce the same sort of current
I(f)
Pacemaker current
What is the structure of Kir channels? What contributes to their inward rectifying nature?
Two membrane spanning domains
Mg2+ and spermine
Draw a graph of I against V for the inward rectifying channels
Well done have a cookie
What are the stages of a ‘typical’ cardiac AP?
0 - Rapid depolarisation 1 - Notch 2 - Plateau 3 - Repolarisation 4 - Inactivation
What can mutations of K+ VGCs cause?
Long QT syndrome
What cause LQT3?
A mutation in the loop connecting domains III and IV of the cardiac Na+ VGC
What channels cause I(f)
HCN
What is the structure of HCN channels?
S1-6 structure
Voltage sensitive S4 segment
Selectivity pore between S5 and S6
What an important feature of HCN channels? (Adrenergic stimulation)
They are directly activated by cAMP as opposed to phosphorylation by PKA
cAMP binds to the C-terminus
When is the HCN channel open and when is it closed?
Opened on hyperpolarisation and closed on depolarisation
How does sympathetic stimulation affect the heart?
β1 receptor stimulation results in increase cAMP = increased I(Ca-L) and I(Ca-T) by phosphorylation of the α1subunit
In nodal tissue cAMP directly interacts with the HCN channel increasing I(f)
Also sensitisation of Ryanodine receptors = increase Ca2+ release
Phosphorylation of SERCA2 and phospholamban
Increased calcium sensitisation by phosphorylation of tropinin C
Delayed rectifiers are also enhanced = shorter AP
What effect does parasympathetic have on the heart?
ACh acts via the M2 receptor = decreased cAMP (Gi)
The potential at which I9f) is activated is shifted to a more negative level
Ca2+ currents are diminished
I(K-ACh) is stimulated, hyperpolarising the cells, making it more difficult to produce APs
Why are parasympathetic effects more chronotropic that ionotropic?
Because the M2 receptors are mainly found in the nodal tissue
What effect does cholera toxin have on the heart?
It mimics β1 stimulation through stimulation of the G-protein
What effect does forskolin have on the heart?
Mimics sympathetic action though stimulation of adenylyl cyclase
Forskolin?
Stimulates adenylyl cyclase
What is an ectopic pacemaker?
A pacemaker that isn’t the SAN (ectopic focus)
How can an MI cause dysrhythmias?
By damaging the conductive pathway of the heart and slowing the conduction velocity of the tissue = uneven spread of discharge
What is Wolff-Parkinson-White syndrome?
Congenital abnormal conducting fibres which accelerate the transmission of impulse from atria to ventricles
What can be the cause of dysrhythmias?
Infarct
Congenital abnormality in the conducting fibres (WPW syndrome)
Mutant ion channels
What is SADS?
Sudden Adult Death Syndrome
Draw a diagram to show the normal conductive pathway through the heart and the two types of dysrhythmias.
Normal
Inappropriate dysrhythmias and circus dysrhythmias
What is Vaughan Williams classification of anti-dysrhythmic based on?
Their effect on the cardiac AP
What are the classes of antidysrhythmic agents?
Class 1 - Block Na+ VGCs (subdivided by kinetics)
Class 2 - Sympathetic antagonists
Class 3 - Prolong AP (and thus refractory period)
Class 4 - Ca2+ channel blockers
Class I antidysrhythmic agents
Block Na+ VGCs
IA = Increased AP duration, intermediate ass/dis IB = Decreased AP duration, fast ass/dis IC = No effect on AP, slow ass/dis
Class II antidyrythmic agents
Sympathetic antagonists (beta-blockers)
Class III antidysrhythmic agents
Prolong AP and this refractory period
Class IV
Ca2+ channel blockers
Quinidine
Class IA anti-dysrhythmic agent
Increased AP duration, intermediate dis/ass
Procainamide
Na+ VGC blocker (use dependence as it is charged)
Class IA anti dysrhythmic agent
Intermediate ass/dis, increases AP duration
Lidocaine
Na+ VGC blocker
Local anaesthetic
Class IB antidysrhythmic agent
Fast ass/dis, decreased AP duration
Flecainamide
Na+ VGC blocker
Class IC antidysrhythmic agent
Very slow ass/dis, no effect on AP
Amlodarone
Class III antidysrhythmic agent
Unknown mechanism
Prolongs AP and thus refractory period
How do β-blockers work as antidysrhythmics?
In ischaemic heart disease cells are partly depolarised and therefore liable to inappropriate excitation
Beta blockers prevent their discharge by lowering their excitability
What limits the used of Class IV antidysrhythmic agents?
Ca2+ channel blockage can compromise the excitation-contraction coupling process
What are the main cause of heart failure?
MI Beta haemolytic streptococci Protozoal infection Dysrhythmias Systemic/pulmonary hypertension Heart valve insufficiencies Diabetes mellitus Anaemia Vitamin B1 deficiency
What are the four class of dyspnoea
Class I - Minimal dyspnoea
Class II - dyspnoea while walking on the flat
Class II - dyspnoea on getting in/out of bed
Class IV - dyspnoea whilst lying in bed
What are the drug types used to treat hypertension?
Diuretics ACE inhibitors Betablockers Alpha 1 antagonists Ca2+ chennel openers KCOs Centrally acting alpha a2/II agonists Other
How do cardiac glycosides work?
Inhibit the Na+/K+ ATPase thus reducing the activity of Na+/Ca2+ exchanger therefore increasing [Ca2+]i
Why are β-blockers used in the treatment of heart failure? Which beta blockers are used?
Because chronic adrenergic stimulation of the myocardium leads to desensitization making heart failure worse
Also sympathetic activity decreases hearts efficiency
β1 selective blockers eg bisoprolol and carvedol
What is the ratio of adrenoceptors in a normal heart? what is it in heart failure?
β1 β2 α1
Normal 70:20:10
Heart failure 50:25:25
Bisoprolol?
β1 selective agonist used in the treatment of chronic heart failure
Carvedilol?
β1 selective agonist used in the treatment of chronic heart failure
What effect does chronic sympathetic stimulation have on the heart?
Alters ratio of adrenoceptors through desensitization
Enhances apoptosis in cardiomyocytes
What are inodilators?
Phosphodiesterase inhibitors - therefore raise [cAMP]i and thus mimics the effects of beta adrenoceptors stimulation
Used in the treatment of heart failure
What is the property of PDE I and what is its inhibitor?
Ca2+/calmodulin dependent
Phenothiazines
What is the property of PDE II and what is its inhibitor?
cGMP-stimulated
No inhibitor
What is the property of PDE III and what is its inhibitor?
cGMP-inhibited
milrinone
What is the property of PDE IV and what is its inhibitor?
cAMP-specific
Rolipram
What is the property of PDE V and what is its inhibitor?
cGMP-specific
Dyhyrdopyridamole and sildenafil
Milrinone?
PDE type II inhibitor used in the treatment of heart failure
Inhibition of PDE leads to an increase in cAMP and vasodilation (decreases the afterload of the heart)
Dipyridamole?
PDE type V inhibitor
Methylxanthines
Eg caffiene
Non-selective PDE inhibitors and A1/2 antagonists
This leads to positive iontropic and chronotropic effects (and increased tendency to give dyrhythmias)
Levosimendan?
Calcium sensitiser used in the treatment of heart failure
Binds to tropinin 3 leading to more efficient binding
Draw the Intrinsic Pathway for clot formation
XII —> XIIa
XI —> XIa
IX —> IXa
\/ Xa
\/ Thrombin
Fibrinogen —> Fibrin
\/ <— XIII
Draw the extrinsic pathway for clot formation
VIIIa ---> VII
X ---> Xa
\/ Thrombin
Fibrinogen ---> Fibrin
\/ <---XIIIWhat is the pathway of clot lysis?
Plasminogen —–> Plasmin ——> Fibrinogen
\/ \/
————–> Fibrin
Streptokinase?
47kDa protein formed by haemolytic streptococci
Binds to plasminogen activator and causes generation of plasmin
Leads to degeneration of fibrin in clots (and breakdown of factor II, V and VII)
Anistreplase?
Clot lysis
Combination of plasminogen and anisoylated streptokinase
Streptokinase is inactive until the anisoyl groups is removed in the blood
More prolong activity that streptokinase
Alteplase?
Single chain human tissue plasminogen activator
Have greater activity bound to fibrin - localises their activity
Duteplase
Double chain human tissue plasminogen activator
Have greater activity bound to fibrin - localises their activity
Reteplase?
Human tissue plasminogen activator
Have greater activity bound to fibrin - localises their activity
Clopidogrel
Inhibits platelet aggregation by inhibiting binding of ADP to its receptor on platelets
Used with low dose aspirin
Eptifibatide
Cyclic heptapeptide inhibitor of glycoprotein IIb/IIIa receptor (aIII/b3 antagonist)
(receptor required for the fibrinogen bridging between platelets that causes aggregation)
Tirofaban
Non-peptide inhibitor of glycoprotein IIb/IIIa receptor (aIII/b3 antagonist)
(receptor required for the fibrinogen bridging between platelets that causes aggregation)
Used to prevent MI in patients with unstable angina
Abciximab
Monoclonal antibody that acts as an inhibitor of glycoprotein IIb/IIIa receptor (aIII/b3 antagonist)
Also binds to vitronectin (involved in cell adhesion)
(receptor required for the fibrinogen bridging between platelets that causes aggregation)
Heparin
Naturally occuring anticoagulant from basophils and mast cells
Binds to enzyme inhibitor antithrombin III (AT-III) causing a conformational change that exposes its active site
AT-III inactivates thrombin
Used in unstable angina, after MI and as a prophylactic to prevent DVT
Warfarin
Inhibits clotting
Inhibits the synthesis of clotting factors II, VII, IX and X and proteins C, S and Z
Dosing of warfarin is complicated as it interacts with many commonly used drug and chemicals
Dabigatran
Thrombin inhibitor
Used for patients with AF and one additional risk factor for stroke
Rivaroxaban
The first Xa inhibitor
Aminocaproic acid
Competitively inhibits plasminogen activation
Tranexamic acid
Analogue of aminocaproic acid
Competitively inhibits plasminogen activation
What is the role of the macula densa?
Detects levels of Na+ and Cl- and secretes local hormones to maintain GFR = auto-regulation
Where does renin come from? and what is its role?
Juxtaglomerular cells and leads to the production of angiotensin II
What happens to the arterioles if there is a fall in GFR?
Afferent dilates
PGI2 leads to constriction of efferent (and increased angiotensin II)
What does an increase in GFR lead to?
Increased Na+ in macula densa
Adenosine release
A1 receptor stimultion at afferent arteriole and juxtaglomerular cells
Decreased cAMP
Constriction of afferent arteriole and inhibition of renin
How do Loop diuretics work?
Act on Loop of Henle
Block Na+/K+/2Cl- co-transport in the luminal membrane in the thick ascending limb = increased Na+ excretion
Furosemide?
Loop diuretic (blocks Na+/K+/Cl- co-transport)
Also causes venodilation and thus reduces atrial filling pressure
Can lead to hypokalaemia, metabolic alkalosis, Ca2+ and Mg2+ loss and a reduction in uric acid excretion
How do thiazide diuretic work?
Block Na+/Cl- cotransporter in the thick ascending limb or distal tubule
Bind to Cl- site
Hydrocholorothiazide
Thiazide diuretic
Blocks Na+/Cl- cotransporter in the thick ascending limb or distal tubule
Binds to Cl- site
Also vasodilator effect
Bendroflumethiazide
Thiazide diuretic
Blocks Na+/Cl- cotransporter in the thick ascending limb or distal tubule
Binds to Cl- site
Also vasodilator effect
What are the side effects of thiazide diuretics?
Hypokaleamia
Metabolic acidosis
Increase Mg2+ secretion but decrease that of Ca2+
Uric acid excretion is also decreased
How do carbonic anhydrase inhibitors work?
Inhibit carbonic anhydrase
Net effect of CA is reabsorption of both Na+ and HCO3-
Therefore this is stopped by inhibition (no HCO3- for the Na+/HCO3- exchanger)
Needs 99% block to be effective
Acetazolamide?
Carbonic anhydrase inhibitor
Used to be a diuretic, now used to treat glaucoma
How do potassium sparring diuretics work?
They have different mechanisms but all interfere with Na+ absorption in the late distal tubule
Amiloride
Potassium sparring diuretic that prevents Na+ reabsorption by blocking apical Na+ channels
Triamterene
Potassium sparring diuretic that prevents Na+ reabsorption by blocking apical Na+ channels
Spironolactone?
Potassium sparring diuretic
Acts as an antagonist of the action of aldosterone
Canrenone
Potassium sparring diuretic
Acts as an antagonist of the action of aldosterone
Mannitol?
Osmotic diuretic
Filtered at the glomerulus and then not reabsorbed
Rapidly reduces intracranial pressure so is useful in cerebral oedema
What causes renin release? What acts to reduce it?
Reduction in the perfusion pressure at the kidney and by sympathetic nerve stimulation as the result of increased [cAMP]i
Adenosine, AMP and by negative feedback by angiotensin
How do ACE inhibitors work?
Prevents production of angiotensin II = no aldosterone secretion (no Na+/water retention)
Saralasin?
Angiotensin II peptide partial agonist
Losartan?
AT1 angiotensin II receptor antagonist (non peptide)
What is the role of AT2 receptors?
Vasodilation
Inhibition of cell proliferation
Present in the brain and during fetal development
Captopril
ACE inhibitor
Aliskiren?
Renin inhibitor
Enalapril?
ACE inhibitor
Which enzyme catalyses the conversion of angiotensin II to III
Aminopeptidase A
What are AT4 receptors?
Angiotensin IV receptors that are widely located
They are actually enzymes - insulin regulated aminopeptidases
Bradykinin?
Natriuretic agent and renal vasodilator
How is bradykinin involved in diuresis?
If high Na+ reaches the distal tubule then kallikrein is released to convert kinogen into bradykinin
Inhibits Na+ reabsorption (via B2 receptors in the collecting duct)
How does ANP work?
Released from the heart in response to atrial stretch
Acts via membrane bound GC to form cGMP
Leads to reduciton in BP by... Vasodilation Inhibition of noradrenaline secretion Stimulates diuresis and natriuresis by increasing GFR and inhibition of Na+ absorption Inhibits renin release
