Control of Blood Flow PDF

Life Sciences & Medicine Control of blood flow Dr Greg Knock (after PI Aaronson) Dpt. of Physiology PHYSIOLOGY AND ANATOMY OF SYSTEMS...

Life Sciences & Medicine Control of blood flow Dr Greg Knock (after PI Aaronson) Dpt. of Physiology PHYSIOLOGY AND ANATOMY OF SYSTEMS 4MBBS102/1B1  Learning Objectives After studying this lecture, you should be able to: Describe the mechanisms which regulate vascular tone, including the role of the autonomic nervous system, the endothelium and local metabolites Describe other local mechanisms regulating vascular tone: flow auto-regulation, and active/reactive hyperaemia Describe the important factors which control coronary blood flow and the effects of increased heart rate and coronary stenosis  Common diseases of the vasculature Hypertension Atherosclerosis Heart failure Kidney disease Coronary Vascular dementia heart disease Cerebral Stroke Retinopathy haemorrhage Excessive vasoconstriction contributes to hypertension Narrowing of arteries due to Many anti-hypertensive drugs are vasodilators plaque/thrombosis reduces blood flow  Regulation of vascular tone Adjustment of vascular tone maintains appropriate blood flow to tissues. 1. Cardiac output and arterial BP drives the blood through all the organs. 2. Appropriate dilatation/constriction of resistance vessels directs blood flow as needed. For example: Coronary arteries dilate during exercise to supply the heart with more blood (this lecture) Veins and arteries/arterioles in the lower extremities constrict to maintain central BP during orthostasis (Integrated CV responses lecture) Most vascular beds constrict during haemorrhage to maintain blood flow to the brain and heart (Integrated CV responses lecture) Tubuloglomerular feedback in the kidney adjusts afferent arteriolar resistance to stabilise glomerular pressure (sem B renal lectures) Vascular tone is the result of a balance between constricting and dilating influences Under both central and local control Adventitia (P1-P2) r 4 Tissue metabolites Flow = Smooth muscle (local) 8VL Endothelium Blood-borne hormones * adrenaline constricts Constriction (Adrenaline*, most arteries but NO angiotensin II) Direct dilation dilates those in heart and skeletal muscle Flow Indirect dilation Pressure/stretch Sympathetic nerves (noradrenaline) Central Local hormones control  (1) The endothelium: Nitric oxide The endothelium releases a substance which relaxes the surrounding smooth muscle. This was initially termed endothelium derived relaxing factor (EDRF). Furchgott & Zawadzki (1980) In 1987, EDRF was identified as the gas nitric oxide (NO) NO release is stimulated by bradykinin, ATP, histamine, CO2, acetylcholine. NO is also released by blood flow, thus it acts tonically to reduce BP. The endothelium also releases prostacyclin (PGI2) which inhibits platelet aggregation, and endothelin (a vasoconstrictor at ETA receptors). Endothelin tends to be released by a different set of stimuli (e.g. Ang 2, thrombin), often associated with pathological conditions.  Mechanism of nitric oxide release Vasodilating substances, eg bradykinin, histamine shear forces (flow) + L-arginine [Ca2+]i eNOS Endothelium + NO Smooth Muscle  NO - mediated vasorelaxation NO (from endothelium) SERCA + GC Ca2+ PMCA K+ K+ GTP channel + cGMP + GC = guanylate cyclase PDE SERCA = sarco/ endoplasmic reticulum Ca2+ ATPase Ca2+ desensitisation GMP PMCA = plasma VGCC membrane hyperpolarisation membrane Ca2+ ATPase PDE = phosphodiesterase Ca2+ cGMP activates protein kinase G NO strongly enhances resting blood flow blood flow restored eNOS inhibitor Blocks NO production blood flow falls Applying substrate restores NO production (2) The endothelium: endothelium-derived hyperpolarisation (EDH) Vasodilating substances, EDH may be more important eg bradykinin, histamine than NO in arterioles and shear forces (flow) may be upregulated if the NO system is impaired [Ca2+]i + Endothelium + releases hyperpolarisation gap EETs, H2O2 junctions K+ Smooth Muscle hyperpolarisation  Oxidative stress causes endothelial dysfunction Cardiovascular diseases are associated with inflammation leading to oxidative stress – the overproduction of reactive oxygen species NADPH oxidase superoxide hydrogen peroxide O2.- H2O2 mitochondria Superoxide reacts with nitric oxide to form peroxynitrite, thus preventing nitric oxide- mediated vasodilatation. Oxidative stress therefore tends to interfere with the ability of blood vessels to dilate.  (3) Autonomic nerves Smooth muscle cells in red SNS nerve fibres in green Sympathetic nerves cause vasoconstriction, especially in splanchnic, renal, cutaneous, and muscle vascular beds. Mainly noradrenaline via a1 receptors Important in redistribution of blood flow and for raising total peripheral resistance (TPR) to raise MAP Parasympathetic nerves causes vasodilatation in salivary glands, pancreas, intestinal mucosa, penis Mainly acetylcholine via muscarinic receptors The PNS regulates blood flow to these organs, but its activation has no effect on TPR since it affects so few vascular beds  (4) Circulating hormones Dehydration Posterior pituitary Anti-diuretic hormone (vasopressin) Kidney Renin/Angiotensin vasoconstriction SNS Angiotensin II raises TPR in response to reduced blood volume activation Adrenaline ANP lowers TPR in response to increased blood volume Adrenal gland Atria ANP vasodilatation  Noradrenaline vs Adrenaline Under normal (at rest) conditions, noradrenaline is Noradrenaline Adrenaline more important than circulating adrenaline in mediating the effects of the SNS on the cardiovascular system. The hormone adrenaline is b1 a1 b2 secreted by the adrenal medulla. This is increased during stressful situations: fight or flight, ↑HR, cardiac Vasoconstriction vasodilatation in hypotension & hypoglycaemia. Contractility in most vascular beds skeletal muscle, heart Blood levels rise 5-fold Via cAMP Via IP3/DAG Via cAMP  (5) Local blood flow control: myogenic contraction Important in vascular beds that need to maintain relatively constant blood flow (cerebral, renal) Increased perfusion Rat cerebral artery pressure Increased stretch of smooth muscle Depolarisation and opening of VGCC [Ca2+]i and contraction Nimodipine = VGCC antagonist EGTA = Ca2+ chelator  G-protein Myogenic contraction Vasoconstrictor agonists coupled involves stretch receptors activated cation + channels rho kinase Stretch + PIP2 Ca2+ sensitisation Na+, Ca2+ phospholipase C + DAG + IP3 RGC + sarcoplasmic Na + reticulum + SAC Ca2+ Na+ Membrane VGCC depolarisation + Details in ‘Smooth Ca2+ muscle function’ gap junction lecture  (6) Local blood flow control: metabolic paracrine control Important in vascular beds that need to increase blood flow to meet local metabolic demand (skeletal and cardiac muscle) During exercise, muscle O2 and ATP consumption is increased Muscle metabolite production increases Metabolites cause vasodilatation of nearby arterioles The increase in blood flow is This vasodilatation washes away the metabolites proportional to the increased and delivers more O2 metabolic demand = ACTIVE HYPERAEMIA  Tissue metabolites act directly on the vascular smooth muscle Metabolising cell ↑ metabolism K channels + K+ + ↑CO2 + H2O Adenosine ATP H2CO3 ↑[K+]o + ↓O2 ↑H2O2 H+ + HCO3- A2 receptor + + inhibits Na pump + K+ channels 2K+ Ca2+ 3Na+ ↑cAMP Voltage-gated Hyperpolarisation Ca2+ channel Hyperpolarisation Smooth muscle Vasodilatation  Mechanism of active hyperaemia in skeletal muscle >START HERE< Increased work being done by muscle Activation of sympathetic nervous Increased consumption of fuel and O2 system + Accumulation of CO2 and H+ in the muscle Negative feedback More adrenaline arteriolar vasodilation in the muscle released into Feed-fo circulation r w ard Acting on b2 Increased blood flow to the muscle receptors More O2 and fuel delivered to muscle + Acid and CO2 removed more quickly Reactive Hyperaemia in Skeletal Muscle Blood flow in leg muscle during static exercise Periods of compression Compensation for periods of loss of blood flow Periods of muscle contraction of increasing Muscle arterial pressure duration During contraction, blood vessels are (mm Hg) compressed and blood flow ceases After each period of compression, blood flow Muscle blood flow is increased above resting level (ml/min) (dotted line) Extent of increase is proportional to the duration of the compression Time (min)  Flow Autoregulation ‘Flow auto-regulation’ is when a tissue can regulate its own blood flow Aim: To maintain tissue blood flow despite changing cardiac output or MAP Flow auto-regulation has two complimentary mechanisms: Present in kidneys, and heart at rest Metabolic control - increases flow in response to metabolite accumulation ‘Myogenic’ control - reduces flow in response to increased pressure The relative importance of metabolic compared to myogenic Especially important regulation of arterial tone increases as resistance vessel diameter in the brain decreases. Special Requirements of the Cerebral Circulation Brain metabolic demand remains relatively constant, even during intense physical activity Not enough blood Too much blood flow, neurons flow, vessels could become starved of rupture – cerebral O2 and quickly die haemorrhage Thus cerebral blood flow must remain relatively constant, despite changes elsewhere in the body How is this achieved? Flow Auto-regulation  Cerebral blood flow is tightly controlled by flow auto-regulation Cerebral arterioles respond to changes Flow = P/R in perfusion pressure (pressure within the blood vessels) Flow = P/R immediate Blood Flow (L/min/Kg) increase CO/MAP Haemorrhage Flow = P/R in flow increased Constriction  Perfusion  Perfusion pressure pressure Arterioles Arterioles constrict in dilate in response response Relaxation Flow brought Flow brought back back down to up to normal immediate fall in flow P3 P1 P2 normal if P falls Perfusion pressure (mm Hg)  >START HERE< Mechanism of cerebral flow autoregulation cardiac output and/or MAP increased Cerebral blood flow Increased Cerebral perfusion pressure more than needed increased Negative feedback CO2 washed away faster Circumferential stretch of arterioles than it is produced myogenic Opposite would occur if CO2 in CO/MAP were reduced metabolic Cerebral arteriolar (E.g. after blood loss) blood constriction Brain blood flow remains Cerebral blood flow decreased back to normal level matched to metabolic demand in the brain  Matching blood flow to metabolic demand in the coronary circulation An increase in cardiac work requires a proportionate Distribution of increase in cardiac muscle blood flow blood flow at rest Heavy Exercise etc. 8% Coronary blood flow (ml/min/Kg) skin 8% liver and 800 ml/min gut 25% (splanchnic) skeletal muscle 20% kidneys 20% Moderate exercise 4% 400 ml/min art brain 15% he O2 consumption (ml/min/Kg) 4% of 5000ml/min At rest = 200 ml/min 200 ml/min Structural and functional adaptations of the coronary circulation  High capillary density: ~ 1 capillary/myocyte  Flow autoregulation at rest + strong active hyperaemia when needed  Adrenaline is a coronary vasodilator via b2 receptors.  Left ventricular myocardium is only perfused during diastole because intramyocardial arterioles are compressed during LV RV systole.  It is vulnerable to ischaemia if coronary flow is reduced when: Heart rate is increased (diastole shortens more than systole) Coronary arteries are narrowed by stenosis Diastolic pressure falls (eg. due to aortic stiffening)  Formation of coronary collaterals promoted by ischaemia  Mechanism of active hyperaemia in cardiac muscle Resting metabolic Increased metabolic demand demand Increased cardiac output Resting cardiac output Increased cardiac muscle work High level of contractile tone Increased O2 consumption in coronary + arterioles Increased metabolite production (flow auto- Negative feedback regulation) K+ From adenosine ↑CO2 Activation of repeated cardiac sympathetic nervous from ATP muscle Acid Flow system metabolism repolarisations maintained at 4% of cardiac Coronary arteriolar dilation (during diastole) output Adrenaline Acting on b2 receptors Increased flow in cardiac muscle  Coronary blood flow varies during the cardiac cycle It is at its peak During It briefly rises Blood can only flow when there is a during early isovolumetric during the pressure difference (P1-P2, DP) diastole when contraction, ejection phase myocardium is coronary blood in line with most relaxed, flow falls to zero aortic DP is at its lowest during systole when (or even briefly pressure aortic pressure is left ventricular arterioles are compressed still high and DP reverses) is high And at its highest during diastole 100 120 Aortic pressure 80 mmHg (ml/min) DP Left coronary 40 blood flow LV Pressure 0 0 systole diastole systole diastole This becomes a major problem when heart rate is greatly increased HR ~3-fold Therefore, diastole Therefore, higher shorter perfusion time shorter… Heavy exercise: CO increased 4-fold Mean Coronary Cardiac Output Heart Rate Diastole Perfusion time flow L/min ml/min beats/min sec secs/min REST 5.0 200 70 0.5 35 EXERCIS 20 800 180 0.13 23 E …and yet mean coronary blood flow is still increased 4-fold, in line with cardiac output Due to accumulated metabolites causing enhanced vasodilation during the shortened diastole. There is a very large coronary flow reserve.  Right ventricular blood flow continues throughout the cardiac cycle 120 DP remains substantive throughout the Aortic pressure 80 cardiac cycle because RV pressure is so much lower than LV pressure mmHg 2 3 4 40 1 RV Pressure During systole, aortic pressure rises more 0 systole diastole than RV pressure, so DP actually increases during systole 80 Right coronary Compression of vessels in the wall of the RV (ml/min) blood flow is negligible Blood flow is maintained 0 systole diastole Stenosis impairs coronary blood flow – compensation by flow autoregulation FLOW = DP /R Vasodilatory autoregulation compensates for increased resistance caused by stenosis, but Healthy coronary artery Stenotic coronary artery only up to a point resistance ≤ 50% stenosis coronary flow reserve plaque 70% ia lic n o ra tab ilati stenosis pe e d hy o m aso em o Flow et mv Du imu ≥90% Microvasculature ax stenosis M pressure dilates in response DP DP Large DP – strong flow Stenosis reduces DP 40 mM Hg DP through microvasculature (and therefore flow) Chronic stenosis causes endothelial dysfunction, through the impairing microvascular vasodilatation Prolonged ischaemia causes the development of intra-arterial collaterals between coronary arteries Right coronary artery Left anterior descending coronary artery ↑ collateral Traupe T et al. Circulation. 2010;122:1210-1220 flow Copyright © American Heart Association, Inc. All rights reserved.  Summary Vascular tone is a function of vascular smooth muscle cell contraction/relaxation, which is controlled by multiple factors; these include ANS activity, hormones, blood flow, internal pressure, metabolites, and autacoids, in particular those released by the vascular endothelium. This combination of central and local influences allows the body to control the BP and regional vascular resistances in such way as to supply a flow of blood to all of the organs which matches their metabolic needs and allows for renal regulation of the body fluid balance and composition. The vascular endothelium regulates vascular tone via NO, EDH and others. Endothelial dysfunction, often associated with oxidative stress, tends to increase vascular tone, and makes an important contribution to cardiovascular disease. Flow autoregulation, the ability of arteries to maintain a constant blood flow over a wide range of pressures, is mediated by the myogenic response and metabolite washout. Metabolic hyperaemia allows tissues to regulate their own blood supply. Coronary blood flow to the left ventricle occurs mainly during diastole due to a fall in the driving force for flow and compression of the coronary branches which penetrate the ventricular wall Under resting conditions, coronary blood flow is heavily autoregulated. When cardiac work increases blood flow to the heart can increase greatly as a result of metabolic hyperaemia, which is especially pronounced in coronary arteries and arterioles with a diameter of