Cardiovascular System CVS

Physiology of Muscle contraction

• Muscle is assembly of contractile + elastic elements.

• Each crossbridge generate force > tendon > move bone

Inital length of muscle cell (preload)

• Actin are firmly anchored at the ends by Z disks. Myosin tugging on thin filaments draws the Z disks closer together > shortening it > muscle contraction

• Skeletal muscles rests at a length optimal for crossbridging - cardiac muscles rests at point less than this > increasing preload (stretching) > increase force (Starling’s law)

The main function is transport - heat, water and electrolytes between the blood and external environment. It transports:

• O2 and CO2 from lungs to all cells

• Metabolic waste from all cells to the kidneys

• Nutrients and water

• Metabolic processing to liver

• Immune cells and antibodies

• hormones

• Pulomonary artery carries blood away from the heart, pulonary vein carries towards it

• Output of the RV into pulmonary circulation = the output of LV into systemic circulation

• Vascular beds are in parellel arrangement > all receive blood with same level of oxygen (~13kpa)

• Systole - period of contraction and ejection (in both RV & LV).

• Diastole - period of relaxation and filling (60% of cardiac cycle)

> Pressure in the aorta is higher during systole, during diastole pressure is maintained by elastic recoil.

> Pulse pressure = diastolic BP - systolic

> Mean arterial pressure = [(SP-DP)/3] +DP

• Blood coming back to right heart is at very low pressure (0mmHg) > goes to lung (25 mmHg) then goes to LV > aorta at an increased pressure (90mmHg)

Cardiac Output (CO) is the volume of blood pumped/min. On average this is 5-6L/min.

CO = Stroke volume (70ml) x Heart rate (70bpm)

• SV - Volume ejected per contraction (ml)

• HR - Rate at which your heart beats (b/min)

-> Left CO = right CO

• As blood move through systemic circulation, pressure falls

  • it remains pulsatile in arteries & arterioles (greatest resistance > pressure drop) then it gets continuous & drops when it get to capillaries > venules > veins

• Pressure in arterial system is determined by:

  • Resistance to blood flow

  • Blood volume in arterial system

• Pressure = flow (cardiac output from LV) x resistance (e.g HTN)

• Arterial BP = CO x total peripheral resistance (TPR)

  • TPR (systemic vascular resistance - SVR) is the resistance to flow offered by all systemic vasculature (except pulmonary)

• Arterioles can change resistance by vasoconstriction (increases TPR > less flow) or vasodilation (decreases TPR > increase flow)

• Resistance is controlled by many factors - nerves, local factors & hormones

• Pulse pressure = SP - DP

• Mean arterial BP = [(SP-DP)/3]+DP —> [(120-80)/3] + 80 = 93mHg

• Describe the cardiac electrical conduction system

• Identify the currents underlying the shape of the SA node action potential

• Assess how autonomic nerves modify SAN activity & HR

• Identify the currents underlying the shape of the ventricular action potential

• Discuss & evaluate factors controlling cardiac conduction velocity and refractoriness

• Measures electrical activity of the heart

• Monitors extracellular field potential between 2 electrodes

• Represents the sum of depolarisation & repolarisation potential from all cardiac myocytes.

• P wave - atrial depolarisation

• QRS complex - ventricular depolarisation

• T wave - ventricular repolarisation

• R-R interval - used to calculate HR & ? irregular rhythms

• P-R interval - time from begining of atrial depolarisation > initiation of ventricular depolarisation. ?AVN delay

• QRS duration - total time of ventricular depolarisation. Helps to ? ventricular conduction issues

• QT interval - time from start of ventricular depolarisation to end of ventricular repolarisation. Help to ?prolongation of vetricular APs.

This system allows AP to travel through the heart

• SA node is the pacemaker - located at RA wall, where firing of spontanous APs begins

• AP spread throughout B/L atria > down to AV node - located at base of RA

• AP then conducted through Bundles of His > Purkinje fibres > spread from ventricular endocardium (inner) > epicardium (outer layer)

The cells of the heart differ in their ability to generate spontaneous APs.

• SAN and AVN myocytes can produce spontaneous APs

• Purkinje fibre cells have very slow spontaneous AP generation

• Atrial and ventricular cardiac myocytes cannot generate spontaneous APs.

-> SAN cells: highest rate of spontaneous AP generation (80-100/min) = drives the HR in healthy person

-> AVN cells: slower rate of spontaneous AP generation (40-60/min)

-> Purkinje fibres: slowest rate of spontaneous AP generation (20-40/min)

Sinoatrial Node

• Fires spontanous APs at frequency of 80-100/min

• Fastest of all cells = dictates HR = is the pacemaker

• Has no resting membrane potential as the MP of these cells are always drifting upwards towards the threshold > continous increase in potential (the pacemaker potential).

• SA node PMP starts at -60mV > becomes slowly more +ve > once reach threshold value > rapid depolarisation - MP peaks at +10mV.

• Rapid repolarisation follows back to -60mV

During pacemaker potential:

• Inward movement of Na+ via HCN channels (If)

• Inward movement of Ca2+ through T-type Ca channels

• Outward movement of K+ (low conductance)

• Overall, rate of Na+ & Ca2+ influx exceeds K+ efflux > MP raises towards threshold.

During depolarisation & repolarisation:

• Once threshold reached, L-type voltage gated Ca2+ channels open > rapid influx of Ca2+ > rapid depolarisation

• AP peaks at 10mV, voltage gated Ca2+ channel start to close > opening of voltage gated K+ channels > K+ efflux

• This causes MP to fall back to -60mV = repolarisation phase

Note: HCN = hyperpolarisation-activated cyclic nucleotide-gated

SA node is innervatd by ANS:

• Parasympathetic neurones carried in the vagus nerve (CNX), release acetylcholine (ACh), acting to slow HR

• Sympathetic neurones carried in the cardiac sympathetic nerves, release noradrenaline (NA), acting to increase HR

-> The intrinsic rate of the SAN is 80-100 AP/min, however the heart rate is 60-70 bpm. This is due to constant vagal tone which slows down our heart rate.

Occurs by altering the slope of PM potential in SA node:

Increased parasympathetic activity (vagal):

• ACh is released > acts on M2 ACh receptors expressed on SAN cells

• This increases K+ efflux which reduces slope of pacemaker potential

• This means it takes longer to get to threshold, therefore decreasing frequency of APs, decreasing heart rate

• This is called a negative chronotropic effect

Increased sympathetic activity

• NA is released > binds to B1 adrenoreceptors on SAN cells

• This causes increase in Na+ and Ca2+ influx, elevating slope of pacemaker potential

• This means threshold is reached faster, increasing the frequency of APs, increasing heart rate

• Where adrenaline is circulating in the blood, this can also have the same effect on B1 adrenoreceptors.

• AVN is found at base of RA - capable of spontanous AP but the pacemaker potential is less steep = takes longer to reach threshold > slower rate of AP (40-60/min)

• Electrical conduction is slowest through the AVN. > causes a delay in AP reaching the ventricles, called the AV delay.

• AV delay is important as it ensures the atrial depolarised, contracted & ejected into the ventricles, before ventricle contraction occurs.

-> Ventricular myocytes have no pacemaker potential - instead have a stable resting MP (-80 to -90mV).

-> Stimulated by APs from AVN > AP and contraction. They do not fire their own APs = Do not contract spontanously

• Phase 0: Rapid depolarisation

  • From -80mV to +20mV due to inward movement of Na+ through fast voltage gated Na+ channels

• Phase 1: Partial repolarisation

  • Na+ channels inactivate

  • Opening of fast voltage gated K+ channels > to partial repolarisation

• Phase 2: Plateau

  • Voltage gated Ca2+ channels open > calcium influx

  • K+ efflux continues & equals Ca2+ influx > No change in overall membrane potential causing a plateau

• Phase 3: terminal repolarisation

  • Delayed rectifier voltage gated K+ channels open > greater K+ efflux, allowing for repolarisation down to resting membrane potential

• Phase 4: Reached resting membrane potential

Refractory period = time from initial depolarisation of the 1st action potential to the point at which 2nd AP can be stimulated.

• Absolute refractory period: Period of time where a new AP cannot be generated at all.

  • This is the depolarisation and plateau phases.

• Relative refractory period: an action potential can be stimulated in some cases (e.g. stronger stimulus).

  • During the terminal repolarisation phase until membrane potential returns to the resting value

• RP is determined by number of available & recovered (re-prime) volage gated Na+ channels.

• Length of RP under different conditions can be examined using 2 pulse protocol -

  • Voltage gated Na+ channels stimulated & current generated = P1

  • If these channels stimulated again too quickly, the 2nd current generated (P2) is smaller in magnitide than 1st one - due to insufficient amount of Na+ channel recoery.

  • But after sufficient time pass, new stimulus can generate current equal to the 1st one - because the RP has ended.

• Na+ channels recover faster at more -ve MP. = sooner the MP return to resting potential, the faster the Na+ channels can recover = RP is also dependent on AP duration!

  • Shorter AP > shorter RP.

• Cardiac myocytes in atria & ventricles are connected (electrically coupled) through membrane proteins at gap junction > allows passive movement of +ve ions (Na+ & Ca2+) between neighbour cells when there is a charge gradient (ie different charges in 2 cells)

  • Transmission via gap junction is the reason why transmission is fast in the heart

• AP in one cardiac myocyte (cell 1) > MP depolarise from -85mV > +20mV due to influx of Ca2+ & Na+

• This creates charge gradient between this cell & neighbouring resting cell (at -85mV) > flow of Na+ & Ca2+ ions through gap junction into cell 2 > becomes more +ve

• If this is enough to reach threshold potential of -60mV > AP in the cell 2 > opening of VG Na+ channels > continues to cell 3

Note: 1st pic, both cells at -ve RMP = no charge gradient = no movements of +ve ions. In the 2nd pic, cell one has +20mV charge > charge gradient so the +ve ions move down to cell 2

• Main factor is magnitude of the charge gradient between cells - this depends on the amplitude of AP generated in cells (APA = AP amplitude)

  • Higher APA = faster conduction velocity

• Normally, APA is ~ +20mV - his can vary in disease > arrythmia.

• Other factor that influences CV is expression & function of gap junctions - less expression > lower conduction velocity.

Conduction velocity is slowest at AV node (not get mixed up with the ability to generate their own APs - in that case the Purkinjee is the slowest).

Beta-blocker

• To calculate HR - 60s/RR = 60/0.4 = 150bpm = tachycardia

• Pheochromocytoma > excess adrenaline > acts on B1 adrenoceptors on the SA node > increase the steepness of the pacemaker current > high HR.

• Beta-blocker will reduce the steepness > reduce HR

PR and QRS prolongation

• Malformarion of the AVN & bundle of his > slow conduction between atria & ventricles and through the ventricles

• Slow AV conduction > prolonged PR.

• Depending on the severity, some P waves may not be followed by QRS or complete loss of association between P & QRS complexes

Prolonged late (phase 3) repolarisation

• Delayed rectified K+ channels are open during phase 3 > K+ efflux > the MP comes back to the resting potential

• A loss of function / mutation of that channel > prolongs the repolarisaiton > longer AP > increase the risk of ectopic beats & ventricular arrythmia

• hERG safety screening ensures that the the drugs dont affect these channels

• This will present in ECG as lengthening of QT

  • T wave represents ventricular repolarisation

  • QT = time from start of ventricular depolarisation to end of ventricular repolarisation.

  • Prolonged ventricular repolarisation therefore leads to prolonged QT interval. So this mutation > long QT syndrome

Shortens the ventricular refractory period

• The upstroke (amplitude) of the AP is usually determined by Na+ channels

• During the plateau phase - influx of Ca2+ = efflux of K+ so no overal net change

• Blockade of the L-type Ca2+ > reduced Ca2+ influx compared to K+ efflux > -ve MP is achieved earlier > faster return to RMP > shorter AP duration and faster Na+ channel recovery.

Ventricular conduction slowing

• Na channel blocker > prolonged refractory period

• Na channel controls the conduction velocity in the myocardiocytes - blocking the Na channel > reduce Na influx in phase 0 > reduce the depolarising current and reduce AP amplitude

  • E.g if Cell one is +20mV & cell 2 is -80mV the charge gradient > movement of ions through gap junction

  • If cell one is -10mV (due to blocked Na channel) and cell 2 is -80mV, the charge gradient is lower > slower spread of ions through gap junction so it takes longer for cell 2 to reach AP.

Note: the SA & AN node cells have no RMP and they usually have drifting potential towards the threshold - once it gets to the threshold, the Ca2+ cause the upstroke in the graph.

In the ventricular myocytes, which usually have RMP, its the Na+ chennels that cause the upstroke in the graph.

A: Right ventricle

• RV has much less pressure - mainly due to the fact that if doesn’t need to generate high pressure as it is pumping blood only to pulmonary system which is much lower resistant system (PV pressure is ~20mmHg) . So its build less musculature.

• LV on the other hand has much higher pressure as it need to pump blood agaist much higher systemic resistance.

B: The ventricle continue to contract untill it exceeds the pressure in the aorta causing the AV to open > blood pumped out into aorta. SO that the pressure in the LV can go up and down to allow valves to open and close

• Isometric contraction > pressure go up to open AV valve

• Isometric relaxation > pressure go down to allow MV to open

C: As ventricles relaxes and the pressure drops, the pressure in the atrium increases due to the venous return. Once the LV pressure goes below the the atrial pressure, the AV valve opens and the blood pours down to LV and at the end of the diastole, the atria contracts pushing last bit of the blood into the LV.

• Some one with AF at rest, around 110ml of blood pours into LV at the initial stage then the atrial contraction pushes about 10ml more into LV. At rest this doesnt matter as the 110ml is adequate stroke vol.

• However during exertion, the addition blood from atrial contraction does matter > symptomatic due to reduced SV.

Its the movement of blood out the heart into the great vessels due to the muscular activity of the heart.

• Arterial BP (ABP) = Cardiac output x total peripheral resistance (TPR)

  • Cardiac output = stroke vol (SV) x heart rate (HR)

  • SV = vol of blood ejected from the ventricles. So if any of the other components affected, SV will be affected

• Electrical activity > mechanical activity > pressure changes > volume changes = cardiac cycle

• Pressure changes in the aorta and LV can be measured using cardiac catheter.

• Echo can be used to assess volume and function of the heart

-> At resting HR of 70bpm, each cardiac cycle lasts 850ms.

-> Split into 2 phases:

• Diastole = ventricles relaxed > filling is mainly passive from atria.

  • Occupies 2/3rd of cardiac cycle (600ms)

  • When HR increases > duration of diastole is shortened

• Systole = ventrical contraction > pressure generation > blood ejected out.

  • Occupies 1/3rd of the cardiac cycle (250ms)

 5 principles key to understanding the cardiac cycle:

1. Pressure (P) will increase in a chamber when the muscle around it contracts. Thicker & stronger muscle (LV) > increase pressure. Muscle relaxation > reduced pressure.

2. Valves will open when there is a pressure gradient across them.

3. Blood flows down a pressure gradient, from an area of high pressure to an area of lower pressure

4. When valves are open, pressures in neighbouring chambers change together

5. When valves are closed, pressures in neighbouring chambers can be different (change independently)

Diastole = filling stage

• Both atria and ventricles relaxed

• Pressure in atria is > than ventricle > AV (mitral) valve open

• Aortic valve closed aortic pressure is > ventricular pressure

• Pulmonar vein pressure > atrial > ventricle = blood flow into LV

• The flow is passive, not require any muscle contraction

Atrial systole

• Atria depolarises and contracts > increase atrial pressure

• This contributes to ~5ml to ventricular filling (most of ventricular filling is passive)

  • Exercise > increase HR > more contribution from atria as it contracts harder.

Ventricular systole (isovolumetric contraction)

• Ventricular depolarisation > contraction > increase ventricular pressure.

• When ventricular pressure exceeds atrial pressure, atrioventricular valves close

• Aortic pressure is still higher than ventricular pressure so the AV remains closed

• Ventricular blood vol does not change as both A-V valve & AV remains closed = isovolumetric contraction

  • Purpose of this phase is to raise the LV pressure (~80mmHg) to open AV

  • In HTN, the aortic pressure is very high > LV pressure will have to be higher (~110mmHg) to open AV

After the Isovolumetric contraction phase, ventricles continue to contract > LV pressure exceeds the aortic pressure > opening of AV.

• Blood ejected from LV to aorta with high momentum & velocity

  • This is important as half way through, the aortic pressure exceeds LV pressure but due to high momentum of blood, the AV remains open as blood as high energy than aorta so it moves down energy gradient.

• During 2nd half of ejection phase, the force of LV contraction reduces > LV & aortic pressure also reduces

After the ventricular ejection, repolarisation > relaxation of the ventricular walls > reduced ventricular pressure

• As LV relaxes, pressure falls below that of aortic pressure + energy of blood leaving falls > causing AV to close

• The LV pressure still remains higher than atrial pressure so A-V valves remain closed.

• As both AV & A-V valves closed, no change in LV volume = ventricular isovolumetric relaxation

-> When LV pressure drops below atrial pressure, the A-V valve opens and the cycle repeat again. (note that while A-V valve were shut, the blood already started pouring into atria, so when the A-V valve open, the ventricle get filled rapidly)

-> The X-axis represents time (~800ms/ resting cardiac cycle)

-> The Y-axis shows a number of different variables:

The line in green shows ECG trace. This gives the landmarks of the cardiac cycle as the electrical activity precedes the mechanical activity of the heart:

• P-wave – atrial depolarisation > atrial contraction

• QRS complex – ventricular depolarisation which precedes ventricular contraction

• T-wave – ventricular repolarisation > ventricular relaxation.

The Y-axis as the top represents 3 different pressures

• Aortic pressure – varies between 80-120 mmHg

• Ventricular pressure – varies between 10-120 mmHg

• Atrial pressure – varies between 0-10 mmHg (much lower)

The changes in these pressures are important for the filling and emptying of the ventricle, represented in purple as the Left Ventricular (LV) volume (ml) has a large amount of variation:

• End diastolic volume ~ 120ml

• End systolic volume ~ 50ml. = there is still blood left in the heart at the end of systole. This reserve of blood allows for stroke volume to be increased if necessary.

Difference between these two volumes = stroke volume (70ml).

At the bottom of the Y-axis,> heart sounds, These occur when the valves of the heart shut:

• S1 – the closure of the AV valves (lub sound)

• S2 – the closure of the SL valves (dub sound)

Can be seen at the beginning & at the end of each line

On the Right:

• Mid-diastole (halfway filling) seen - atrial pressure (black) is > ventricular pressure (blue) = blood flow from atria to LV > LV vol increase (purple)

• Aortic pressure (red) is much greater than LV pressure but is falling as blood moves into systemic circulation

Left side

• Slight increase in atrial pressure due to depolarisation (P wave) & contraction. > simultanous pressure increase in neighbouring chamber (LV)

• Atrial contraction > 5ml into LV (seen as tiny peak in the LV vol

• QRS (1) = ventricular depolarisation

• Leads to LV contraction > LV pressure rise - when it exceeds atrial pressure (2), MV shuts > S1 (3)

• AV remains closed = ventricle is a closed chamber.

  • Rapid increase in pressure (4) with no vol change (5)

  • Isovolumetric contraction phase (6)

• Small peak in atrial pressure as A-V valve pressing back into atria (7)

• Diastolic pressure = lowest pressure in bloodstream during cardiac cycle immediately before AV opens (8)

• LV pressure exceeds aortic pressure (1 - blue line is above red line)

• AV opens > increase pressure in aorta & LV increases > blood flow into aorta

• LV vol falls as blood ejected out (2)

• Mid ejection, aortic pressure exceeds LV pressure (3) - ejection continues due to blood energy gradient

• End of ejection, aortic & LV pressure drops (4) > speed of ejection reduces > LV vol slopes (5)

• T wave = ventricular repolarisation > relaxation (1)

• As LV pressure drops below aortic pressure, AV closes generating 2nd HS S2 (2)

• Both AV & A-V valve closed = closed system - LV pressure dropping (3) with no change in LV vol (4) = isovolumetric relaxation (5)

• LV pressure drops below atrial pressure (6) > A-V valve opens > ventricullar filling commence

  • Atrial pressure steadily increases (6) during ejection & isovol relax as blood from pulmonary veins comes in

• LV pressure falls below atrial pressure (1)

• A-V valve opens (2) > rapid ventricular filling cause increase in LV vol (3)

• Cycle repeats again.

Normal timings of cardiac cycle:

-> Systole lasts 250ms (remains stable even when HR rises)

• Isovolumetric contraction = 50ms

• Ejection = 200ms

-> Diastole lasts 600ms

• Isovolumetric relaxation = 80ms

• Filling = 520ms. - this is the only phase where changes occur e.g length decreases in tachycadia.

  • Atrial depolarisation occurs earlier (shifting P wave to L before ventricular filling is compromised

  • Rapid passive filling occurs early in filling phase - any issues during this can be compensated by stronger atrial contraction stimulated by increased sympathetic activity to atria (topping-up more than just 5ml blood)

    • Ventricular filling wont be affect unless HR >180

  • HR changes seen as reduced distance between T & next P wave.

Right CO = Left CO to prevent blood accumulating in lungs & peripheral tissues

• Pulomonary vasular resistance on the right heart is low while the systemic vascular resistance on the left is high

• RV - as PVR is low, a lower pressure is needed to drive same CO + RV muscle doesn’t need to thick

• LV - as TPR is high, higher pressure is needed to dive same CO + LV muscle is thicker

• RA (0-4), RV (4-25), LA (0-8), LV (8-120), Pulm artery (10-25), aorta (80-120)

Qualitative changes in pressures are identical for L and R ventricule but the pulomanry, ventricular & atrial pressures are much lower on the right than left.

The heart and the blood vessels are continuous. They share similar histology, they both consist of 3 layers:

• Tunica Intima - innermost layer

  • Endocardium (epithelial lining of the heart)

• Tunica Media - middle layer

  • Myocardium (heart muscle)

• Tunica Externa (Adventitia) - outer layer

  • Epicardium (outer layer of the heart)

The endocardium includes the endothelium and subepithelial connective tissue.

• The endothelium is a simple squamous epithelium

• The subendothelial layer is deep to the endothelium, it is dense irregular connective tissue. It connects the endothelium to the myocardium

Myocardium consists of cardiac muscles which are:

• Striated - can see myofibrils

• Involuntary - myogenic under autonomic nervous system via SA node.

• Cells are elongated & branched with central nuclei

• Cells are tightly connected by intercalated discs which contains gap junctions, desmosomes & adhering junctions - together forms functional syncytium (= cells with multiple nuclei) and allows electrical & physical coupling

• Skeletal muscles are an example of true syntium while cardiac musles are ‘functional syntium’

• Cardiac & skeletal muscles differ in T-tubles:

  • Skeletal - ‘Triad’ = 1 T-tuble coupled to 2 SR

  • Cardiac - ‘Diad’ = 1 T-tuble coupled with 1 terminal cisterna of the sarcoplasmic reticulum

Epicardium is the outermost layer - also serves as innermost layer of pericardium (the serous visceral pericardium)

• Epicardium is separated from serous parietal pericardium by pericardial cavity containing pericardial fluid

• Its a collection of CT, contains many adipose cells + has blood vessels (CA) within it

• Its outermost layer functions as serous visceral pericaridum - aka mesothelium (a simple squamous epithelium)

Heart valve

• Formed by folds of endocardium, covered both sides by endothelium

• Enclosed within is Dense CT - this is fibroelastic to permit movement.

• Infective endocarditis = infection of the valve > damage & clot formation which can travel & cause stroke

There are 4 fibrous rings of dense irregular tissues with makes up fibrous core of the heart

• The rings surround the aortic, pulomanary, left & right AV canals.

• The rings separate the atria from ventricles & electrically insulate them allowing independent contraction - only exception is the opening through which fibres from AV conduction system pass.

• The cardiac skeleton provides structural support & serves as attachment site for myocardium & heart valves.

• Present in the sub-endocardial layer of the heart wall

• Fibres are modified cardiac myocytes - specialised for electrical conduction rather than contraction

• Stain differently to myocytes - have pale cytoplasm, larger than normal myocytes, have no intercalated discs, fewer myofibrils (mostly in the periphery of the cell) and possess more glycogen.

Structure varies throughout the body, but have common histological layers - 3 layers, continuous with that of the heart:

• Tunica Intima - inner layer, composed of endothelium on a basement membrane lying over subendothelial CT layer

• Tunica Media - middle muscular layer, has concentric layers of SM & elastin

• Tunica Adventitia - Outer layer, mainly collagen rich CT to give strength to vessel wall & anchor to surrounding structuers.

  • Thick = larger vessels needs their own bloody supply +/- their own lymphatics & nerves = known as Vasa vasorum.

  • Outer surface also has mesothelium

i. Artery

ii. A = Tunica media, B = Tunica adventitia

iii. A = smooth muscle, B = dense CT -collage

• Arteries have Internal and external elastic lamina

Elastic arteries - Major arteries immediately leaving heart e.g. aorta, carotid & pulmonary arteries

• When heart pumps, blood rush into these arteries so they must be able to expand to accept this pressure + able to recoil during diastole to maintain pressure

• Have very broad tunica media

• Many layers of elastic tissues known as lamina or fenestrations

• 2 specific layers of elastic tissues - internal & external elastic laminae

• Some smooth muscle cells present to maintain elastic tissue

  • All ageing arteries loose elastic tissue > increase resistance & BP

Muscular arteries - e.g femoral & coronary arteries

• Medium size compared to elastic arteries

• Lots of smooth muscle in the tunica media (~40 layers) - for vasoconstriction & dilation

• Don’t have many layers of elastic laminae, only internal & external lamina (defined border)

• Tunia adventitia may be much thicker than tunica media

Arterioles are small arteries with small lumen

• Regulate delivery of blood into capillaries

• 1-3 layers of smooth muscle in the tunica media.

• Vasoconstriction and vasodilation controls rate of blood flow into capillaries

• Larger arterioles contain an internal elastic lamina, there is no external elastic lamina

Capillaries

• Small vessels, connects arterioles to venules

• Lacks the 3 layers - only have single layer of endothelial cells (one part of tunica intima). No tunica media / externa

  • One cell layers > allows molecular exchange

• Have supportive pericytes - repair capillaries

Continuous

• Have no pores or gaps between endothelial cells, because they adhere together via tight junctions

• Sat upon a complete basement membrane.

• The endothelial cells contain pinocytic vesicles - collect substances from one side of the endothelial cell (e.g. blood) and deliver it to the other side (e.g. tissues).

Fenestrated

• Have pores (fenestrae) between endothelial cells - allow substances to diffuse between the blood and tissues

• Have Complete basement membrane

• Located in areas which require exchange of large quantities of substances e.g intestines, kidneys, pancreas and endocrine glands

Sinusoid (discontinuous)

• Have large gaps within the wall & a large diameter.

  • Make them more permeable to larger macromolecules

• The basement membrane is also discontinuous. These capillaries allow direct contact of the blood with tissues and exchange of large macromolecules.

• Found in specific organs including the liver, spleen and bone marrow.

Left curly one is a vein

• Venules & veins have smaller tunica media = have lesser muscular & elastic contents > lumen prone to collapse

• As their size increases, size of tunica externa increases

• Small to large veins have valves made of endothelial folds & fibroelastic CT - prevent backflow & ensure unidirectional

• During infection, WBCs can leave the blood through small post capillary venules.

• The largest vein - vena cava - has thick adventitia layer (for protection) + internal elastic lamina

• Lymph vessels are thin & close ended

• Have fenestrated endothelium

• They collect tissue fluids (lymph) and return it to blood

• Similar to vein - have valves & 3 layers (much thinner & less developed adventitia)

• Ageing > loss of elastic tissue within blood vessel walls. In contrast, the amount of collagen increases.

• Diseases can accelerate this process, e.g arteriosclerosis, atherosclerosis, Marfan’s syndrome, and Ehlers-Danlos syndrome.

  • In these conditions, elastin fibres are replaced by collagen.

Marfan’s syndome

• Genetic condition caused by mutation in fibrillin gene > reduced functional elastin fibres > reduced elastic recoil of vessels (mainly aorta)

• This lead to increase luminal diameters, wall weaknening > aneurysm & dissection or rupture

Arteriosclerosis

• Process of stiffening of arterial wall - increase in size of tunica intima (intimal proliferation - IP)

• Normally occurs with age but can be due to atherosclerotic plaque

Atherosclerosis

• Inflammatory response - Starts with thickening of intima

  • Damage due to DM, HTN, smoking

• Myointimal cells, SM, macrophages infiltrated with cholesterol (foam cells)

• Fatty streak > develops atherosclerotic plaque / atheroma > narrowing

• Occurs in CA > CAD > angina > MI due to reduced blood flow to myocytes due to narrowing of the lumen > reduce radius (flow is proportional to radius4).

• Unstable plaque > blood clot > embolism

Notes from the lecture:

• CO can be altered by altering either HR or SV (EDV - ESV)

• HR can be changed ONLY via SA node

• SV: Central venous pressure = pressure in the thoracic vena cava neart the RA which in fact is determined by venous return.

• Factors that increase the venous return are - valves in the vein, muscle contraction (exercise), breathing pattern, total blood volume.

• Veins are capacitance vessels = have high ability to hold on to blood vol & stretch > able to have large change in vol without great increase in pressure = high compliance. Arteries have high tone and low compliance.

• Increase sympathetic activity on the veins > constriction > increase venous return

• Increase venous return > increase central venous pressure > increase EDV > increase SV (=EDV-ESV)

• EDV = preload = how much tension is in the muscles at rest.

-> Cardiac output = volume of blood pumped by the heart in a given timeframe - measured in L/min

• CO = HR x SV (EDV-ESV)

• Any of these factors can be altered to improve CO to meed metabolic need. Changing electrical activity at the SA node is the OLNLY way HR can change.

-> SV is the vol of blood ejected by heart in every beat:

• SV = end diastolic Vol - end systolic Vol = ~70ml

-> Normally, some blood left in each ventricle after systole = ESV. By minusing this from EDV > SV

-> Heart receives sympathetic and parasympathetic input - these nerves adjust heart’s activity but do not initiate each beat - this is normally done by SA node

• Sympathetic nerve - arise from upper thoracic spinal cord > heart via cardiac nerves. Release noradrenaline > act on Beta-1 receptors > makes SA node fire faster, strengthens contraction and speed conduction through AV node

  • Note that the HR can be increased only via SA node

• Parasympathetic nerve - travel in vagus nerve > release ACh > act on M2 receptor in SA & AV node > slows HR & AV conduction. Little effect on ventricular contraction

-> Chronotrophy = effect on HR

• Sympathetic stimulation > increase HR (+ve chronotropy)

• Vagal stimulation > decreases HR (-ve chronotropy)

-> Inotropy = effect on force of contraction

• Sympathetic increases it (+ve)

• Parasympathetic have modest -ve direct effect - mainly in atria

-> sympathetic = faster and stronger; parasympathetic = slower, with little direct effect on ventricular strength.

PSNS - pregalion (vagus nerve) cell body is in the brain stem and the post ganglionic is in the heart.

• Intrinsic HR = rate the SA node produces without autonomic input - ~100bpm

• Resting HR is usually lower due to vagus nerve activity at rest (vagal tone predominates)

• Vagus nerve > ACh > M2 receptors on SA node > slows the pacemaker cells > takes longer to reach the threshold for next beat.

  • This ‘vagal brake’ usually outweighs sympathetic stimulation at rest

-> Venous return = vol of blood returning to RA/min. Usually matches the CO & depends on the pressure gradient pushing blood towards the heart

-> Venous return ≈ (mean systemic filling pressure − right atrial pressure) ÷ resistance to venous return

-> Main influences are:

• Blood vol & venous return - More circulating blood or venous constriction > increase pressure that drives blood back to heart. Veins can change their tone to shift blood into circulation

• RA pressure - high RA pressure > fall in pressure gradient for return. Vice versa if RA pressure reduces

• Skeletal muscle pump - muscle contractio > squeeze nearby vein. One-way valve directs blood towards the heart

• Breathing (resp pump) - inspiration > pressure in chest falls + abdominal pressure rises - favours blood flow from abdominal vein to chest.

• Sympathetic activity - venoconstriction > reduce vol in the vein & increase pressure driving blood centrally

• Gravity & pressure - Gravity > blood pooling in LL > temporary reduce central venous return. Muscle activity & vasoconstriction counter this

By increasing contractility (+ve chronotropy)

• Since SV = EDV - ESV, if EDV stays constant, SV rises when heart ejects more blood > ESV falls.

• Sympathetic stimulation > B1 receptors > increase Ca2+ availability in the cardiac muscles > stronger contraction > ventricle empties more

Increased preload

• Preload = stretch of ventricular muscle just before it contracts (by EDV).

• Increase preload > ventricle fills more > fibres stretch more > stronger contraction (Starling mech) > ejects more blood (inc SV)

Increased afterload

• Afterload = load the ventricle must overcome to eject blood e.g. for LV its aortic pressure & sytemic vascular resistance

• When afterload arise > ventricle generate more pressure before it eject. Usually ejects less blood (ESV increases & SV reduces). If higher afterload persists (chronic), ventricles adapt by thickening

In short: more preload usually increases SV; more afterload usually decreases SV, assuming other factors stay the same

EF = % of blood in a ventricle at the end of flling that is ejected with each beat:

• EF = SV / EDV x100%

Example, if EDV is 120 mL and ESV is 50 mL, then SV is 70 mL and EF is about 58%. SV =EDV-ESV

1. Influx of Ca2+ via L-type calcium channels > activation of connected Ryanodine receptor (RyR) on sarcoplasmic reticulum membrane

2. This cause release of Ca2+ stored within SR = calcium induced calcium release (increase Ca2+ sensitivity)

3. Ca2+ able to bind to troponin C present within an inhibitory complex on actin filament

   • This normally blocks the myocin binding sites & prevent cross-bridge formation - involves the tropomyosin which directly blocks the binding site.

4. Ca2+ binding to trop C > conformational change > removes troponin inhibitory complex out of the way, allowing myosin head binding to actin > cross-bridge formation > muscle contraction

5. Force of contraction is correlated to no of cross-bridges

6. After the contraction, Ca2+ returns to SR via SERCA (sarco-endoplasmic reticulum calcium ATPase) and phospholamban proteins which regulates SERCA.

7. Some excess Ca2+ is exchanged for 3Na+ via Na/Ca exchanger

-> Increase force of contraction can be done by either:

• Increasing intracellular Ca2+ or by increasing the Ca2+ sensitivity of the contractile apparatus (troponin complex > more corss-bridges)

SV = volume of blood ejected by RV / LV per heart beat (equal). It depends on force of contraction

• The Frank–Starling law = stretching cardiac muscle (increase sarcomere length) before contraction increases the force of contraction

• Increase venous return to the heart > increased ventricular EDV.

• The ventricular muscle fibers are stretched further, so they contract more forcefully and eject a greater volume of blood. = Stroke volume (SV) increases.

• Proposed explanations include increased sensitivity of troponin C to calcium and changes in how actin and myosin interact. Excessive stretching can reduce stroke volume

• Firstly, an increase in venous return (increases CVP) to right side > increase filling of the RV, raising its EDV.

• By Starling mechanism, the RV contracts more forcefully and its stroke volume increases.

• The additional blood then passes through the pulmonary circulation, increasing filling of the LV.

• The left ventricular EDV and SV subsequently rise as well.

• Over time, the RV & LV must pump roughly equal volumes.

• Starling’s law ensures that any change to right SV is ultimately matched by left SV & vice versa.

• If RV output persistently exceeds LV output, blood can accumulate in the pulmonary circulation.

• If LV output exceeds right ventricular output, blood can accumulate in the systemic venous circulation.

1. Blood volume: A larger circulating volume > increase venous return & ventricular filling > raising EDV & SV. Dehydration or haemorrhage > reduce blood volume, venous return, and SV.

2. Skeletal muscle pump: When skeletal muscles contract, they compress veins. Venous valves help direct blood toward the heart and limit backflow. Mainly important in the legs, where blood must travel against gravity.

3. Respiratory pump: Inspiration > thoracic pressure falls while abdominal pressure rises as the diaphragm contracts and flattens. This pressure difference helps drive blood from abdominal veins toward the thorax, increasing venous return.

4. Venous tone: Sympathetic stimulation can constrict veins > reduce compliance. This reduces their capacity to store blood, shifting blood toward the heart and increasing venous return.

5. Gravity and posture: Lying down distributes venous blood more evenly. On standing, gravity > blood to pool in the legs, reducing CVP and venous return > lower SV

Note- prolonged standing / immobility > compromised skeletal pump > reduced venous return > reduced SV & fall in BP > faint

Atrial contraction

• Important during tachycardia where passive filling phase is short.

• Atrial contraction can be increased by sympathetic nerovous system > counter the reduced passive filling.

Heart rate

• Extreme tachycardia (HR >180) > reduced rapid passive filling phase of ventricles - this cannot be countered by atrial contraction

• On standing, gravity causes more blood to pool in the veins of the lower limbs. = Less blood returns to the right side of the heart, reducing CVP, ventricular filling, and EDV. Stroke volume may fall as a result.

• Movement helps counter this effect: contracting leg muscles squeeze veins and, venous valves, move blood toward the heart.

• During Prolonged immobility (e.g standing still), muscle pump is less active. Venous return & SV can decrease, > lowering BP > fainting

• ESV = vol of left over blood in the ventricle post systole.

• One way to increase SV is to reduce ESV by increasing the force of contraction - e.g by increasing intracellular Ca2+ - this is done by SNS activity

• Adrenaline and noradrenaline can stimulate β₁ receptors on cardiac muscle cells.

• These receptors activate a Gs signalling pathway, increasing intracellular cyclic AMP and protein kinase A (PKA) activity.

• PKA phosphorylates L-type calcium channels, > increase calcium entry into the cell during excitation.

• This promotes further calcium release from the SR.

• Hence more cross-bridge formation between actin and myosin, > a stronger contraction.

• This helps the ventricle eject more blood, reducing end-systolic volume (ESV). Since SV = EDV − ESV, a lower ESV increases SV if EDV is unchanged

-> Afterload = resistance the ventricle must overcome to eject blood.

-> For the LV, it is mainly aortic pressure and systemic vascular resistance

-> For the RV, it is related to pulmonary resistance and pulmonary artery pressure.

-> High afterload > difficult ejection.

-> For a given contractility and preload, more blood remains in the ventricle after contraction

-> so ESV rises and stroke volume falls.

-> The higher ESV can lead to a higher EDV on the next beat.

-> This extra filling stretches the muscle and may increase contraction strength (Frank–Starling mechanism), partly compensating for the increased afterload.

-> If the LV must pump against high afterload over a long period, e.g HTN, its wall may thicken (LVH).

-> This can be harmful, esp when the heart already has a CAD, and may increase the risk of angina or myocardial infarction

• Atrial contraction adds blood to the ventricles near the end of filling.

• Its contribution becomes more important at higher HR, when the time available for passive ventricular filling is shortened.

• A stronger atrial contraction, by sympathetic activity, may help maintain ventricular filling.

• At extremely high HR (> 180bpm) the rapid passive filling phase can be shortened so much that atrial contraction cannot fully compensate. EDV may then fall, reducing stroke volume

• Directly by influencing rate of action potential generation, or force of contraction

  • E.g Class I (Lidocaine, Flecainide), Class II (B-blocker), class III (amiodarone, sotalol), class IV (verapamil). Non classified (adenosine, digoxin

• Indirectly by affecting blood vessels, blood volume and composition, and renal function which all indirectly affect the heart.

Arrhythmia = disturbance in the normal rhythm of the heart.

• It can originate from atria, ventricles, or junctional tissue around the AV node or bundle of His

Atrial fibrillation = atrial depolarisation is rapid and disorganised > insufficient emptying > prone to clots.

• The atria do not contract effectively, and the ventricles receive irregular impulses through the AV node.

• AF is also a supraventricular rhythm, but is distinguished by its irregularity.

SVT = fast rhythm (regular) arising above the ventricles, commonly in the atria or around the AV node.

Arrhythmias can be associated with coronary artery disease, thyroid disease, or hypertension; with certain drugs; with electrolyte disturbances; or with congenital factors

The Four phases:

• Phase 0—rapid depolarisation: When threshold reaches > Voltage-gated Na+ channels open > large influx of Na+

• Phase 1—partial repolarisation: V-G Na+ channels inactivate and a small amount of K⁺ leaves the cell.

• Phase 2—plateau: L-type Ca2+ channels (slow VG CC) open and Ca²⁺ enters, helping maintain the plateau.

• Phase 3— Terminal repolarisation: Ca2+ channels inactivate and delayed rectifier K⁺ channels allow K⁺ efflux, returning the membrane potential toward its resting level.

• Phase 4—gradual pacemaker depolarisation: In pacemaker cells, such as those sinoatrial (SA/AV) node, a net influx of +ve ions (Ca2+ & Na+) against small K+ efflux > gradually brings the cell toward threshold. This phase is steepest in the SA node

  • Ca2+ influx is via V-G T-type (short) Ca2+ channel

  • The funny current (Na+ influx) (If) through HCN Na+ channels. The funny current is activated by hyperpolarisation

The phase 4 description applies to pacemaker cells; working cardiac muscle (myocytes) have a stable resting phase instead of spontaneous gradual depolarisation.

-> Class I drugs block voltage-gated Na⁺ channels.

-> Their block is use-dependent: they bind more to channels that are opening and inactivating frequently.

-> This tends to affect rapidly firing tachy-arrhythmic tissue > slows the rate of depolarisation.

-> Class I drugs divided into three subtypes (low yield):

• Class Ib - e.g. lidocaine, rapidly associates & dissociates from channels > blocks premature heartbeats. It has mild effect on depolarisation.

• Class Ic - e.g. flecainide, dissociates & associates slowly > significantly slows depolarisation > reduce amplitute of AP.

• Class Ia - e.g. quinidine, speed of Asso / Disso with channel is between that of Ib and Ic > moderately reduce amplitude of AP & rate of depolarisation. They also prolongs repolarisation phase > prolongs AP.

• Class II drugs are beta blockers e.g. Metoprolol

• β-adrenoceptor antagonists > reduce HR by blocking +ve chronotropic effect of the sympathetic nervous system that normally speeds the SA node.

• This slows the rate of gradual pacemaker depolarisation

• Also prolong the refractory period and slow conduction through the AV node.

• This can limit how many rapid atrial impulses reach the ventricles.

• Class III drugs - E.g. Amiodarone and sotalol

• Block K⁺ channels involved in repolarisation e.g outward delayed rectifier.

• Repolarisation takes longer, so the action potential and refractory period are prolonged.

• Sotalol also blocks beta receptors, so it has both Class II and Class III actions.

• Amiodarone contains iodine and can affect thyroid function, so thyroid status needs monitoring.

  • Can lead to thyrotoxicosis, hypo/ hyperthyroidism

• Class IV drugs - e.g. verapamil,

• Block voltage-gated calcium channels, especially L-type channels (also the T-type).

• Lead to reduce rate of depolarisation & slows conduction velocity

• The AV node depends on calcium entry for depolarisation and conduction, so these drugs slow AV nodal conduction & can prolong its refractory period > can induce AV block.

• Can limit the passage of rapid atrial impulses to ventricles.

• Can also reduce the force of contraction by reducing Ca2+ entry into cardiac muscle cells > shortens plateau phase.

• These drugs are specific to heart ONLY as other tissues have different types of Ca2+ channel

Adenosine

• Acts on A₁ receptors in the SA and AV nodes.

• Receptor activation > opens K+ channels > cells more -ve > hyperpolarisation > reduce the rate at which PM potential raise towards the threshold (negative chronotrophic effect)

• Thus, slowing pacemaker depolarisation > reduced rate of AP generation.

• Also slows AV nodal conduction and prolongs the refractory period.

• Can be given intravenously to terminate certain SVTs.

• Caffeine blocks adenosine receptors, opposing adenosine’s slowing effect

Digoxin

• a cardiac glycoside, is mainly a positive inotrope, but it can also increase vagal activity.

• This slows AV nodal conduction and can help control the ventricular contraction rate in atrial fibrillation.

Side Effects

• Arrythmia - Antiarrhythmic drugs can sometimes worsen it if the drug or dose is unsuitable.

• By changing ion movement and the timing of cardiac electrical activity, a drug can promote abnormal rhythms.

• Negative inotropic action - Drug may reduce force of contraction of cardiac myocytes - e.g. by reducing calcium entry into cardiac muscle cells.

Drug choice

• Depends on the type and cause of the arrhythmia, other health conditions, and possible drug interactions (e.g amiodarone contraindicated in thyroid issue).

• Beta blockers (AF), verapamil (pSVT), flecainide (AF), amiodarone (SVT, WPWS), and adenosine (SVT)

Inotropy = force of cardiac muscle contraction.

• Positive inotropic drugs increase this force; negative inotropic drugs decrease it.

• +ve inotropic drugs used in conditions where heart muscle is not contracting in sufficient force e.g

  • Anaphylaxis - overwhelming immune response which cause autoimmune damage to organs

  • HF - CO is insufficient to meet metabolic needs

Excitation contraction coupling

• When a cardiac muscle cell is electrically stimulated, L-type calcium channels open and Ca²⁺ enters the cell.

• This Ca2+ activates ryanodine receptors on the sarcoplasmic reticulum, releasing stored Ca²⁺ into cytosol.

• Calcium binds to troponin C > cause conformational change > releases tropomyosin from myosin head binding site > allowing myosin to bind to actin and form cross-bridges. The cross-bridges generate contraction.

• Positively inotropic drugs increase intracellular [Ca2+] while negatively inotropic drugs reduce it.

• In general, more calcium available during excitation > more cross-bridges to form > increases contraction force.

• The 3 main types of positive inotropic drugs are:

  • Sympathomimetics e.g Adrenaline, dobutamine

  • Cardiac glycosides e.g digoxin

  • Phosphodiesterase inhibitors

• Sympathomimetics such as adrenaline, dobutamine, and dopamine stimulate β₁ receptors on cardiac muscle cells.

  • Mimic the effects of SNS - +vely inotropic

• These receptors activate a Gs-protein pathway, increasing cAMP and activating PKA.

• PKA phosphorylates L-type calcium channels, > more calcium influx during excitation.

• This increases Ca2+ release from the sarcoplasmic reticulum > more cross-bridge formation, and strengthens contraction.

• These drugs therefore have a positive inotropic effect.

• Cardiac glycosides partially inhibit the Na⁺/K⁺ pump in cardiac myocytes.

• Normally, this pump moves 3Na⁺ out of the cell and 2K⁺ into it. When the pump is inhibited, intracellular Na⁺ rises.

• The Na⁺/Ca²⁺ exchanger normally uses the Na⁺ gradient to move Ca²⁺ In/out of the cell depending on Conc gradient.

  • At rest, extracellular Na+ is > than intracellular -> Ca2+ moves out of the cell

• When intracellular Na⁺ rises, this gradient is reduced, so less Ca²⁺ efflux.

• More calcium is retained in the cell and stored in the sarcoplasmic reticulum > higher intracellular Ca2+ during excitation-contraction coupling.

• On subsequent excitation, more calcium is available to support contraction, increasing contractile force

• Used in HF patients with arrythmia

Side effects

• Arrhythmias - due to blockade of Na/K pump & reduced activity of Na/Ca exchanger > more +ve ions build up inside cells > membrane potential gets more +ve > approaches threshold value > spotaneous AP generation

• Nneurological symptoms - Digoxin is able to cross blood-brain barriers > ionic imbalance > Sx such as confusion, dizziness, fatigue, or delirium

• GI symptoms - Na/K pumps is also present in GI smooth muscles > Sx such as nausea, vomiting, and diarrhoea.

• Gynaecomastia - Digoxin contains steroid ring structure which is similar to oestrogen. When the drug is metablised, its components can act on oestrogen receptors on breast tissue > elargement

• Some diuretics increase potassium loss, causing hypokalaemia.

• Digoxin binds to Na⁺/K⁺ pump at the K+ binding site: when serum K+ is low, there is less competition with digoxin for pump binding.

• Digoxin’s effect therefore increases > depletion in intracellular K+ > raising the risk of toxicity >low Na+, low Cl- & arrhythmias.

• Potassium-sparing diuretics may reduce potassium loss, but some e.g. spironolactone, can inhibit renal excretion of digoxin > toxicity

• Phosphodiesterase normally breaks down cAMP.

• PDE-3 inhibitors - e.g milrinone and enoximone, slow that breakdown, allowing cAMP levels to remain higher.

• More cAMP supports PKA activity and phosphorylation of L-type Ca2+ channels, increasing calcium entry and contraction force.

• These drugs can also increase cardiac myocyte excitability > spontaneous AP > contribute to arrhythmias.

• Used mainly for acute heart failure, with chronic use associated with reduced survival

Drugs used to reduce HR that might be useful to counter the effect of HF such as pulmonary congestion:

• Beta blockers, e.g. metoprolol, reduce the sympathetic stimulation of the SA node. This slows pacemaker depolarisation and lowers heart rate.

• Ivabradine blocks HCN channels in pacemaker cells. These channels contribute to the funny current (If), which helps the pacemaker potential rise during phase 4.

  • Blocking them slows that rise, so it takes longer for the cell to reach threshold and generate the next action potential > slows HR

• Diuretics - reduce circulating blood volume by increasing fluid excretion. This can reduce fluid accumulation and congestion, but potassium loss can cause hypokalaemia and increase the risk of digoxin toxicity.

• Vasodilators - widen blood vessels > reduce vascular resistance > reduce the load the heart pumps against.

• ACE inhibitors - reduce formation of angiotensin II (by angiotensin-converting enzmes), a hormone that promotes vasoconstriction > lowers vascular resistance & BP

  • ACE inhibitors can also affect fluid balance through the renin–angiotensin system - have diuretic effect as it normally promotes ADH release by pituitary gland.