Cardiovascular System-2

1. Cardiovascular System-2 Rahul Penumaka 26-02-2019

2. Lectures • Control of CVS 1 • Control of CVS 2 • CVS Mechanics • Microcirculation • Vascular Endothelium 1 • Vascular Endothelium 2

3. Before we begin… • Ask questions! • If you don’t understand something, say something • Listen • There will be chocolate 

4. Learning Objectives • Circulation: explain the physical principles, structure and function of the circulation • Flow: explain the physical principles, recall Poiseuille's equation, explain the effect of gravity, explain the control of capillary blood flow, and explain the concept of vascular capacitance and compliance • Blood pressure measurement: perform blood pressure measurement, explain the principles of using a sphygmanometer and intra-arterial blood pressure monitoring • Vascular endothelium: recall the structure and function of the vascular endothelium, and recall its role in inflammation • Vascular endothelium drugs: recall the mechanism of action of drugs including aspirin, nitrovasodilators, calcium channel blockers • Vascular Starling forces: explain solute transport and fluid transfer • Lymphatic system: explain structure and function • Law of Laplace (vascular): recall the Law of Laplace (vascular) and explain the relationship to blood flow • Sympathetic nervous system: recall the organisation and role of the sympathetic nervous system, and recall neurotransmitters acting within the sympathetic nervous system including receptors and effects • Renin-angiotensin-aldosterone system (RAAS): recall the organisation and role of the RAAS, and synthesis pathway of angiotensin II • Baroreceptors: explain the anatomy and function of baroreceptors • Cardiovascular stress: explain the response to standing, haemorrhage, exercise

5. Lectures • Control of CVS 1 • Control of CVS 2 • CVS Mechanics • Microcirculation • Vascular Endothelium 1 • Vascular Endothelium 2

6. Nernst and Goldman-Hodgkins-Katz equations • Both of these equations give us a general idea about resting membrane potential for a cell GHK is a bit more realistic because it takes into account the cell having different permeability

7. The Electrics of the Heart • The heart is a muscle, it is vital that it contracts • Contraction of myocytes is initiated by electical impulses, i.e action potential • Unlike skeletal muscle which requires neurons • The heart generates its own electrical stimulation (ITS ELECTRIC PROPERTIES ARE INTRINSIC) • In fact the heart can beat even when it is removed from the body

8. General Facts about Cardiac Action Potentials • They are LONG (200-300 ms) • The duration of A.P = duration of contraction • A slower contraction is better and more efficient • Absolute refractory period (ARP) = time during which no action potential can be initiated regardless of stimulus intensity • Relative refractory period = period after ARP where an AP can be elicited but only with stimulus strength larger than normal.

9. +50 WHY IS IT GOOD TO HAVE A LONG REFRACTORY PERIOD? Resting membrane potential 0 Absolute refractory period Membrane potential (mV) Relative refractory period -50 -100 0 300 200 100 Time (ms) As a result, the heart muscle cannot be tetanized (which could prevent it from beating)

10. Cardiac Action Potentials +50 0 Phase 1 Early repolarisation Membrane potential (mV) Phase 2 Plateau -50 Phase 3 Repolarisation -100 0 300 200 100 Time (ms) Phase 0 Upstroke Phase 4 Resting membrane potential

11. The Upstroke +50 0 • Like in neurons – opening of Na+ channels results in sodium rushing into the cell Membrane potential (mV) -50 -100 0 300 200 100 Time (ms) Phase 0 Upstroke

12. Early Repolarization +50 0 Phase 1 Early repolarisation • Sodium channels inactivate, so repolarization begins to occur • There is also brief increase in permeability to potassium causing the characteristic NOTCH of the cardiac action potential Membrane potential (mV) -50 -100 0 300 200 100 Time (ms)

13. Plateau +50 0 • There is an increase in Permeability to CALCIUM and these calcium channels remain open for a long time which is why they are called L-type Calcium Channels (L = long lasting)   • This influx of calcium just about balances the efflux of potassium thus keeping the membrane depolarised at the plateau value (around 0 mV)  Membrane potential (mV) Phase 2 Plateau -50 -100 0 300 200 100 Time (ms)

14. Repolarization +50 0 • Repolarization of the cardiac cell eventually occurs due to: • Inactivation of the L-type calcium channels • Activation of potassium channels (such as IK1) during repolarization • IK1 (Inward rectified potassium channel) is responsible for fully repolarizing the cell) Membrane potential (mV) -50 Phase 3 Repolarisation -100 0 300 200 100 Time (ms) Phase 4 Resting membrane potential

15. MAIN PERIOD OF REPOLARISATION +50 Phases of the action potential Resting membrane potential determined by K+ flowing out of cells 0 Membrane potential (mV) Upstroke determined by large increase in membrane to Na+ permeability Inhibited by dihydropyridine calcium channel antagonists (e.g. nifedipine) -50 -100 Ca2+ influx required to trigger Ca2+ release from intracellular stores – essential for contraction Ca2+ current (ICa) activates rapidly (within a few milliseconds) but the upstroke is more dependent on INa PNa 10 10 PCa Gradual activation of K+ currents (K+ moving outward) that balance, then overcome, inward flow of Ca2+ Relative permeability of K+ Relative permeability of Na+ & Ca2+ 1.0 1.0 PK1 Large K+ current (IK1) that is inactive during the plateau starts to flow once the cells have partially repolarised PTO IK1 is responsible for fully repolarising the cell 0.1 0.1 PK IK1 is large and flows during diastole. It stabilises the resting membrane potential reducing the risk of arrhythmias by requiring a large stimulus to excite the cells 0 300 200 100 Time (ms) 1-LSS-CVS-COND-01: Cellular electrical activity: explain membrane potential and changes in ionic permeability; draw action potentials for the ventricle and sino-atrial node; explain the role of the sino-atrial node and importance of refractory periods

16. SA Node • SA node cells do not have a stable resting membrane potential • Because, the IK1 channels (Which maintain stable potentials) are not present in SA nodal cells • If (pacemaker/funny currents) are really channels which open up to allow the cell to reach its threshold potential • Calcium influx causes the UPSTROKE in SA node cells • There is very little Sodium influx

17. The sinoatrial node – pacemaker Ventricular cell SA node cell Most channels exist in SA node – to some extent +40 +40 +20 +20 0 Exception is IK1 – no IK1 in SA node: Very little Na+ influx – upstroke produced by Ca2+ influx 0 -20 Membrane potential (mV) Membrane potential (mV) -20 -40 -40 -60 -60 -80 Also T-type Ca channels that activate at more negative potentials than L-type -80 -100 K+ -100 Time (ms) 0 300 200 100 Time (ms) K+ Na+ 0 Ca2+ Pacemaker current (If) present 400 1000 800 200 600 Ca2+ Na+ 1-LSS-CVS-COND-01: Cellular electrical activity: explain membrane potential and changes in ionic permeability; draw action potentials for the ventricle and sino-atrial node; explain the role of the sino-atrial node and importance of refractory periods

18. Pacemaker cells and heart rate Normal increased sympathetic stimulation increased parasympathetic stimulation 20 0 -20 Membrane potential (mV) -40 Threshold potential -60 0 400 1000 800 200 600 Time (ms) 1-LSS-CVS-COND-01: Cellular electrical activity: explain membrane potential and changes in ionic permeability; draw action potentials for the ventricle and sino-atrial node; explain the role of the sino-atrial node and importance of refractory periods

19. Modulating the intrinsic heart rate PNS innervation slows heart rate Paraympathetic nerve (Vagus) Cardioregulatory centre and vasomotor centres in Medulla Sympathetic nerves SNS innervation increases heart rate (chronotropy) and contractility (Inotropy) 1-LSS-CVS-COND-01: Cellular electrical activity: explain membrane potential and changes in ionic permeability; draw action potentials for the ventricle and sino-atrial node; explain the role of the sino-atrial node and importance of refractory periods

20. Cardiac conduction system Atrioventricular node Specialised cells to delay wave of excitation and insulate from superior ventricular myocardium Sinoatrial node Specialised cluster of autorhythmic cells Bundle of His Rapid conduction cells to transport an insulated wave of excitation Internodal fibres Rapid conduction tracts to stimulate atrial myocardium Ventricular fibres Propagate the impulse across the ventricular myocardium 1-LSS-CVS-COND-02: Cardiac conduction pathways: explain cardiac conduction pathways

21. Impulse propagation iNa iNa + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + iK1 iK1 iK1 Contractile cell Pacemaker cell Contractile cell Contractile cell Threshold Source Sink The propagation of the cardiac action potential is due to a combination of passive spread of current and the existence of a threshold which, once reached, causes the cell to generate its own action potential. Gap junctions greatlyreduce membrane resistance allowing current to easily leak from one cell to a neighbouring cell. 1-LSS-CVS-COND-01: Cellular electrical activity: explain membrane potential and changes in ionic permeability; draw action potentials for the ventricle and sino-atrial node; explain the role of the sino-atrial node and importance of refractory periods

22. SBA Which process is responsible for the plateau phase in a cardiac action potential? • Chlorine efflux • Sodium influx • Sodium efflux • Calcium influx • Calcium efflux

23. SBA Which process is responsible for the plateau phase in a cardiac action potential? • Chlorine efflux • Sodium influx • Sodium efflux • Calcium influx • Calcium efflux

24. Lectures • Control of CVS 1 • Control of CVS 2 • CVS Mechanics • Microcirculation • Vascular Endothelium 1 • Vascular Endothelium 2

25. LO: Circulation: explain the physical principles, structure and function of the circulation • Role of the Circulation: To transport blood around the body (and therefore, deliver O2 & nutrients, remove metabolites & CO2) • Heart (muscular pump)  generate pressure gradient • Vessels (network of tubes) • Arteries: Large & elastic • Capillaries: Numerous & Thin  For Exchange! • Maximum diffusion distance = 10 micrometer • Veins: Highly Compliant  act as a reservoir for blood volume • Blood pressure drives the flow of blood within the body

26. V I R LO: Flow: explain the physical principles • Think of the circulatory system as an electric circuit • In a normal circuit: A battery drives the flow of current through the circuit where it encounters resistance • Similarly, the difference in pressures drives the flow of blood through the body where it encounters resistance (in the form of vessels) Electrical Circuit (Ohm’s Law) V = I x R Fluid Circuit (Darcy’s Law) DP = Q x R

27. LO: Flow: explain the physical principles • We can restate the equation in more physiological terms • Reminder: Cardiac Output = SV (volume/beats) x HR(beats/minute) • Assumptions: • Blood flow is steady • Vessels are rigid • Negligible right atrial pressure DP = Q (FLOW) x R x Total Peripheral Resistance (TPR) Cardiac output (CO) MBP =

28. KEY POINT: Physiologically when regulating flow, the blood pressure is constant so resistance (of vessels) is what changes. • So…we can direct flow of blood to particular organs/vascular beds by changing the resistance to those areas (think vasodilation and vasoconstriction). DP = Q (FLOW) x R MBP = Cardiac output (CO) x Resistance (TPR)

29. LO: Flow: recall Poiseuille's equation Poiseuille’s equation can be used to describe resistance to blood flow in a vessel It depends on: Length of tube: We can’t change the length of our vessels Fluid (blood) viscosity: Not fixed, but usually constant Radius of the tube: This is variable and the main way we vary RESISTANCE KEY POINT: HALVING THE RADIUS DECREASES FLOW 16 TIMES

31. Regulation of Blood Flow • Regulation of blood flow is achieved in two main ways: • LOCAL MECHANISMS - specific to the smooth muscle of the blood vessels. • SYSTEMIC MECHANISMS – hormones/neurotransmitters are released that act on the smooth muscle of the blood vessels.

32. Local Mechanisms • Autoregulation: the intrinsic capacity to compensate for changes in perfusion pressure by changing vascular resistance • What does that mean? • Say perfusion pressure falls and there is NO local mechanism • Resistance is not changed • As a result flow of blood drop sharply because the pressure is not sufficient to DRIVE the blood to flow through the tight vessel • In reality, local mechanisms cause resistance to slowly decrease when pressure falls • This raises flow because despite the lower pressure it is easier for blood to move through the dilated vessel • Test it out with the equation above! • There are 2 theories behind this mechanism…

33. Theories on Autoregulation MYOGENIC THEORY METABOLIC THEORY When pressure drops and flow reduces the blood accumulates in the vessels In the blood are a bunch of metabolites which act on the vascular smooth muscle Thus, causing vasodilation When the flow increases again those metabolites are taken away by the blood • The smooth muscles themselves are sensitive to stretch • Say pressure drops the tension (or stretch) of the vessels fall • The smooth muscles senses this and vasodilates as a result to INCREASE FLOW

34. Hormones Local (endothelium-derived) Circulating (non-endothelium-derived) Nitric oxide (NO): potent vasodilator produced from arginine. NO diffuses into vascular smooth muscle cells. Kinins: hormones that bind to receptors on endothelial cells and stimulate NO synthesis – vasodilator effects Atrial natriuretic peptide (ANP): secreted from the atria in response to stretch – vasodilator effects to reduce BP Prostacylin: cardioprotective vasodilatorsynthesised from prostaglandin precursor (PGH2) – also has antiplatelet and anticoagulant effects Vasopressin (ADH): secreted from posterior pituitary in response to high blood osmolality. Binds to V1 receptors on smooth muscle to cause vasoconstriction Thromboxane A2 (TXA2): vasoconstrictorsynthesised from prostaglandin precursor (PGH2) – also heavily synthesized in platelets (amplify platelet activation) Noradrenaline/Adrenaline: secreted from adrenal gland and causes vasoconstriction Endothelins (ET): vasoconstrictors generated from the nucleus of endothelial cells – has minor vasodilator effects but principally a vasoconstrictor Angiotensin II: potent vasoconstrictor product from the renin-angiotensin-aldosterone axis. Also stimulates SNS activity and ADH secretion.

35. Design of the autonomic nervous system Post-ganglionic fibres Autonomic nervous system has two branches Parasympathetic arising from cranial part of spinal cord ACh ACh Target organ Parasympathetic ‘rest and digest’ Muscarinic receptor (M) Nicotinic Receptor (N) ACh Sympathetic arising from thoracic vertebra Target organ Sympathetic ‘fight or flight’ (N) Noradrenaline Sympathetic chain (paravertebral ganglia) SNS is important for controlling the circulation ACh Sympathetic arising from lumbar vertebra Target organ (N) Noradrenaline Pre-ganglionic fibres use ACh as their neurotransmitter PNS is important for controlling the heart rate Parasympathetic arising from sacral part of spinal cord ACh ACh PNS post ganglionic NT = ACh SNS post ganglionic NT = NA Target organ (N) (M) Pre-ganglionic fibres

36. Within the Autonomic nervous system there are 2 branches: SYMPATHETIC (fight or flight) and PARASYMPATHETIC (rest and digest) THE AUTONOMIC NERVOUS SYSTEM SYMPATHETIC PARASYMPATHETIC “Rest and digest” “Fight and flight”

37. Sympathetic Nervous System (SNS) • The SNS arises from the thoracolumbar part of the spinal cord (T1-L2). • Its short pre-gangliongic fibres synapse onto sympathetic ganglia located either side of the spinal cord. • From these ganglia, its long post-ganglionic fibres synapse onto effector organs.

38. The sympathetic nerve fibres are split into pre-synaptic and post-synaptic fibres. The pre-synaptic fibres are short and release acetylcholine The post-synaptic fibres are long and release noradrenaline (mostly) SCHEMATIC DIAGRAM OF THE AUTONOMIC NERVOUS SYSTEM Parasymp Cranial/sacral Effector organ ACh ACh ACh NA Effector organ ANS A (and NA) via bloodstream ACh Effector organ Sympathetic –thoracic/lumbar Adrenal medulla Effector organ e.g.sweat gland ACh ACh

39. Sympathetic control of vessel radius • All vessels EXCEPT capillaries, pre-capillary sphincters and metarterioles have sympathetic innervation • The heart also has sympathetic innervation • Distribution of these nerve fibers is variable • Noradrenaline binds to α1-adrenoceptors to cause smooth muscle contraction and vasoconstriction.

40. The Vasomotor Centre (VMC) • Bilateral structure within medulla & lower ⅓ of pons • 3 areas: • Vasoconstrictor (pressor) area • Vasodilator (depressor) area • Cardioregulatory inhibitory area • Influenced by higher brain centres • eg. Hypothalamus (ex. Or in.) • VMC transmits impulses to blood vessels Lateral portions influences HR & contractility Medial portion transmits via vagus nerve to heart  HR Credits: MM CVS2 Tutorial J.J Teh

41. Nervous control of blood vessel diameter Vasomotor centre • There is always some level of tonic activity to the vasculature • Activating or decreasing this tonic baseline leads to constriction/dilation • Generally there is NO PARASYMPATHETIC innervation to vascular system Pressor Depressor * - +

42. Cardiac innervation • The heart has dual innervation: Sympathetic and Parasympathetic • When the Parasympathetic nerves are stimulated HR DECREASES • When Sympathetic nerves are stimulated HR INCREASES • When both are cut, HR is at about 100 bpm • This shows that the Parasymapthetic nerves dominate heart rate control by usually keeping it lower (~70 bpm) HR beats/min Sympathetic nerves stimulated Parasympathetic nerves cut 120 90 normal 60 Sympathetic nerves cut 30 Parasympathetic nerves stimulated time

43. Strength of contraction • Sympathetic nerves can increase strength of contraction • They release noradrenaline which binds to adrenoceptors on the myocyte • This increases cAMP which in turn activates PKA • PKA phosphorylates L-type Ca channels, SR Ca release channels and Sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA) • Therefore, • Calcium influx increases • Calcium uptake into intracellular stores • KEY POINT: Sympathetic activation can increase heart rate AND force of contraction

44. Controlling force of contraction Noradrenaline β1 Ca2+ Ca2+ L-type Ca2+ channel SR Ca2+ release channel Sarcoplasmic reticulum Ca2+ influx increased ↑cAMP Ca2+ uptake into intracellular stores increased Ca2+ ATPase Protein kinase A Ca2+ Na+/Ca2+ exchanger Ca2+ release from intracellular stores increased Na+ 1-LSS-CVS-CONT-01: Sympathetic nervous system: recall the organisation and role of the sympathetic nervous system, and recall neurotransmitters acting within the sympathetic nervous system including receptors and effects

45. LO: Baroreceptors: explain the anatomy and function of baroreceptors • Remember, baroreceptors do whatever the blood pressure is doing • If blood pressure INCREASES then baroreceptor firing rate INCREASES • If blood pressure DECREASES then baroreceptor firing rate DECREASES • When baroreceptors fire they INCREASE parasympathetic activity and DECREASEsympathetic activity RECEPTOR Afferent nerve Parasymp. nerve Inhibitory interneurone HEART Tonic activity - ARTERIOLES AND VEINS Symp. nerve

46. SBA • What is the largest determinant of blood flow in vessels? • Mean Blood Pressure • Viscosity • Cardiac Output • Radius • Length

47. SBA • What is the largest determinant of flow in vessels? • Mean Blood Pressure • Viscosity • Cardiac Output • Radius • Length

48. Lectures • Control of CVS 1 • Control of CVS 2 • CVS Mechanics 3 • Microcirculation • Vascular Endothelium 1 • Vascular Endothelium 2

49. Types of Blood Flow High shear stress  GOOD  Laminar flow: Velocity of fluid is constant at every point, physiological Promotes endothelial survival Cell alignment in direction of flow Secrete molecules  Vasodilation and anticoagulation Turbulent flow: Velocity of fluid is not constant at every point – has whirlpool regions Low/Changes in shear stress on vessels  BAD  Promote endothelial proliferation and apoptosis + shape change + MORE Credits: MM CVS2 Tutorial J.J Teh

50. Shear Stress • Blood flows fastest in the center of the vessel • It’s slowest at the edges of the vessel • This is because of adhesion of the blood at the edge to the surface of the vessels • Shear rate = “velocity gradient” or the difference in velocity between two points (usually blood at the center and the edge of the vessel) • SHEAR STRESS = Shear rate X viscosity • Shear stress gives us an idea of the stress the blood flowing is placing on the walls of the vessels • KEY POINT: • Shear stress is HIGH in LAMINAR FLOW which is GOOD – endothelial survival • Shear stress is DISTURBED in TURBULENT FLOW which is BAD – endothelial proliferation, coagulation, platelet aggregation, atherosclerosis