Physiology LC14 Overview of Circulation PDF

OUTLINE I. INTRODUCTION II. PHYSICAL CHARACTERISTICS OF THE CIRCULATION III. BASIC PRINCIPLES OF CIRCULATORY FUNCTION IV. INTERRELATIONSHIPS OF PRESSURE, FLOW, AND RESISTANCE A. Blood Flow B. Blood P...

OUTLINE I. INTRODUCTION II. PHYSICAL CHARACTERISTICS OF THE CIRCULATION III. BASIC PRINCIPLES OF CIRCULATORY FUNCTION IV. INTERRELATIONSHIPS OF PRESSURE, FLOW, AND RESISTANCE A. Blood Flow B. Blood Pressure C. Resistance to Blood Flow D. Effects of Pressure on Vascular Resistance and Tissue Blood Flow V. CORONARY CIRCULATION A. Physiologic Anatomy of the Coronary Blood Supply B. Control of Coronary Blood Flow I. INTRODUCTION What does the Circulatory System do? - The function of the circulation is to serve the needs of the body tissues—to transport nutrients to the body tissues, to transport Figure 1. Distribution of blood (in percentage of total blood) in waste products away, to transport hormones from one part of the the different parts of the circulatory system. body to another and, in general, to maintain an appropriate environment in all the tissue fluids of the body for survival and - The low blood volume in the capillaries makes them do the most optimal function of the cells. important function of the circulation - diffusion of substances back and forth between the blood and the tissues. Circulate BLOOD throughout entire body for: Transport of oxygen to cells THE HEART AS A DOUBLE PUMP Transport of CO2 and other wastes away from cells The heart is actually two separate pumps: Transport of nutrients (glucose) to cells Right heart - pumps blood through the lungs Movement of immune system components (cells, antibodies) to Left heart - pumps blood through the systemic circulation fight infection Transport of endocrine gland secretions Regulates body temperature Helps stabilize pH and ionic concentration of body fluids COMPONENTS and FUNCTIONS Heart: pumps blood to maintain circulation Blood: vehicle that carries oxygen and nutrients essential to cell function Blood Vessels: ○ Arteries carry blood away from the heart ○ Veins carry blood back to the heart ○ Capillaries where diffusion happens II. PHYSICAL CHARACTERISTICS OF THE CIRCULATION The circulation, shown in Figure 1, is divided into the systemic circulation and Figure 2. The heart functions as a double pump that carries blood in the lungs the pulmonary circulation. and in the systemic circulation. Pulmonary Circulation: Eliminates carbon dioxide via the lungs and oxygenates FUNCTIONAL PARTS OF THE CIRCULATION the blood The cardiovascular system has three types of blood vessels: a. Arteries (and arterioles ) - carry blood away from the heart Systemic Circulation aka Greater Circulation or Peripheral Circulation: Delivers ○ Receive blood from ventricles oxygen to all body cells and carry away wastes ○ Take blood away from the heart ○ Usually carry oxygenated blood ○ Thickest vessel walls ○ Withstand greater blood pressure ○ Are very elastic b. Capillaries - where nutrient and gas exchange occur between the blood and the interstitial fluid ○ Smallest of blood vessels ○ Only one cell thick (epithelial cell) Page 1 of 8 [PHYSIOLOGY] 1.14 Overview of Circulation; Biophysics of Pressure, Flow, and Resistance; Coronary Circulation - Dr. Max Butardo ○ Walls are thin and have numerous minute capillary pores permeable to water and other small molecular substances ○ Connect arteries to veins ○ Bring oxygen and nutrients to cells ○ Removes CO2 , urea, and other wastes from cells ○ Where blood is under low pressure and moving slowly c. Veins (and venules) - carry blood toward the heart ○ Transport blood away from capillaries ○ Carry blood toward heart ○ Take blood to atria ○ Have valves ○ Thinner vessel walls with less smooth muscles than arteries ○ Can stretch a great deal ○ Have larger diameters ○ Usually carry deoxygenated blood ○ Serve as a major reservoir of extra blood Figure 4. Blood vessel layers: Tunica Intima, Tunica Media, and Tunica Externa CROSS SECTIONAL AREAS AND BLOOD FLOW DISTRIBUTION OF THE BLOOD VESSELS Table 1. Approximate total cross-sectional areas for the average human being Vessel Cross-Sectional Area (cm2) Aorta 2.5 Small Arteries 20 Arterioles 40 Capillaries 2500 Venules 250 Small veins 80 Venae cavae 8 Note particularly that the cross-sectional areas of the veins are much larger than those of the arteries, averaging about four times those of the corresponding arteries. This difference explains the large blood storage capacity of the venous system in comparison with the arterial system. Figure 3. Differences of the (A) Artery, (B) Arteriole, (C) Veins, and (D) Capillaries ANATOMY OF BLOOD VESSELS LAYERS: 1. TUNICA INTIMA: ○ Innermost layer ○ Endothelium: secrete substances, prevent platelet aggregation ○ Minimize friction 2. TUNICA MEDIA: ○ Middle layer ○ Circular Smooth Muscle: innervated by SNS ○ Vasoconstriction/dilation 3. TUNICA EXTERNA: ○ Outermost layer ○ CT w/ elastin and collagen ○ Strengthens, Anchors ○ Vascularized Figure 5. Blood flow distribution in the circulation in percentage. Page 2 of 8 [PHYSIOLOGY] 1.14 Overview of Circulation; Biophysics of Pressure, Flow, and Resistance; Coronary Circulation - Dr. Max Butardo 3. Arterial pressure regulation is generally independent of either local III. BASIC PRINCIPLES OF CIRCULATORY FUNCTION blood flow control or cardiac output control. Short term control during hypotension: a. increase the force of heart pumping b. cause contraction of the large venous reservoirs to provide more blood to the heart c. cause generalized constriction of most of the arterioles throughout the body so that more blood accumulates in the large arteries to increase the arterial pressure. Long term control: a. Kidney via pressure-controlling hormones and blood volume control IV. INTERRELATIONSHIPS OF PRESSURE, FLOW, AND RESISTANCE Blood flow through a blood vessel is determined by two factors: Figure 6. Normal blood pressures in the different portions of the circulatory system when a person is lying in the horizontal position. (1) Pressure difference of the blood between the two ends of the vessel, also sometimes called (“pressure gradient”) along the vessel, which - The low pressures of the pulmonary system are in accord with the needs of the is the force that pushes the blood through the vessel lungs because all that is required is to expose the blood in the pulmonary (2) The impediment to blood flow through the vessel, which is called capillaries to oxygen and other gasses in the pulmonary alveoli. vascular resistance NORMAL BLOOD PRESSURE IN DIFFERENT PORTIONS OF THE CIRCULATORY SYSTEM SYSTEMIC CIRCULATION ○ Aorta (mean pressure): 100 mmHg ○ Arterial pressure: Figure 7. Interrelationships of pressure, resistance, and blood systolic pressure: 120 mmHg flow. P1, pressure at the origin of the vessel; P2, pressure at the other diastolic pressure: 80 mmHg end of the vessel. Resistance occurs as a result of friction between the flowing ○ Vena Cavae : about 0 mmHg (As the blood flows through blood and the intravascular endothelium all along the inside of the vessel. the systemic circulation, its mean pressure falls progressively to about 0 mm Hg by the time it reaches the termination of the superior and inferior venae cavae Ohm’s Law - calculate the flow through the vessel where they empty into the right atrium of the heart.) ○ Capillaries: 35 mmHg (arteriolar end) 10 mmHg (venous ends) average “functional” pressure: about 17 mmHg Figure 8. Ohm’s Law PULMONARY CIRCULATION ○ Pulmonary artery (mean pressure): 7 mmHg F = blood flow, systolic pressure: 25 mmHg P = pressure difference (P 1 − P 2 ) between the two ends of the vessel diastolic pressure: 8 mmHg R = resistance. ○ Mean pulmonary capillary pressure: averages 7 mmHg Blood flow is directly proportional to the pressure difference but inversely The total blood flow through the lungs each minute is the same as through the proportional to the resistance systemic circulation. Note: it is the difference in pressure between the two ends of the vessel, not the absolute pressure in the vessel, that determines rate of flow BASIC PRINCIPLES OF CIRCULATORY FUNCTION 1. The rate of blood flow to each tissue of the body is almost always BLOOD FLOW precisely controlled in relation to the tissue need. = quantity of blood that passes a given point in the circulation in a When tissues are active → need increased supply of given period of time (in ml/min or L/min) nutrients and more blood flow — 20-30x the resting level! Overall blood flow in the total circulation of an adult person at rest Microvessels monitor tissue needs, such as the availability about 5000 ml/min of oxygen and other nutrients and the accumulation of Called the cardiac output = amount of blood pumped into the aorta carbon dioxide and other tissue waste products → control by the heart each minute. local blood flow by dilating or constricting them Also controlled by CNS and hormones Methods for Measuring Blood Flow: 2. The cardiac output is controlled mainly by the sum of all the local 1. Electromagnetic Flowmeter tissue flows. ○ When blood flows through the vessel, an electrical The heart acts as an automaton: voltage proportional to the rate of blood flow is generated ○ The heart responds automatically to increased between the two electrodes inflow of blood by pumping it immediately back into the arteries Page 3 of 8 [PHYSIOLOGY] 1.14 Overview of Circulation; Biophysics of Pressure, Flow, and Resistance; Coronary Circulation - Dr. Max Butardo TENDENCY FOR TURBULENT FLOW Reynold’s Number Figure 12. Reynolds number. Re = Reynolds’ number the measure of the tendency for turbulence to occur) ν = mean velocity of blood flow (in cm/sec) d = vessel diameter (in cm), ρ = density of blood η = viscosity (in poise). Figure 9. Flowmeter of the electromagnetic type, showing generation of an electrical voltage in a wire as it passes through an electromagnetic field (A); The tendency for turbulent flow increases in direct proportion to the velocity of generation of an electrical voltage in electrodes on a blood vessel when the blood flow, the diameter of the blood vessel, and the density of the blood and is vessel is placed in a strong magnetic field and blood flows through the vessel (B); inversely proportional to the viscosity of the blood and a modern electromagnetic flowmeter probe for chronic implantation around blood vessels (C). N and S refer to the magnet’s north and south poles. The Reynold’s number for flow in the vascular system normally rises to 200 to 400 in large arteries 2. Ultrasonic Doppler Flowmeter - some turbulence of flow at the branches of these vessels ○ A portion of the electronic apparatus determines the frequency difference between the transmitted wave and Conditions appropriate for turbulence: the reflected wave, thus determining the velocity of blood high velocity of blood flow flow pulsatile nature of the flow ○ Doppler effect. sudden change in vessel diameter large vessel diameter e.g.proximal aorta and pulmonary artery Blood Pressure - the force exerted by the blood against any unit area of the vessel wall Standard Units of Pressure: 1. millimeters of mercury (mm Hg) - Example: 50 mm Hg - the force exerted is sufficient to push a column of Figure 10. Ultrasonic Doppler flowmeter. mercury against gravity up to a level 50 millimeters high 2. centimeters of water (cm H2O) TYPES OF BLOOD FLOW - One millimeter of mercury pressure equals 1.36cm water pressure Laminar Flow or Streamlined Flow (opposite of turbulent flow) ○ steady rate through a long, smooth blood vessel, flows in Resistance - is the impediment to blood flow in a vessel streamlines ○ the velocity in the center is far greater than that toward the outer edges (PARABOLIC velocity profile) Turbulent Flow - Disorderly flow (blood flowing in all directions in the vessel and continually mixing within the vessel) due to: ○ the rate of blood flow becomes too great Figure 12. Formula for the resistance in the CGS (centimeters, grams, seconds) ○ passes by an obstruction in a vessel unit, which is used to express resistance ○ makes a sharp turn ○ passes over a rough surface ○ Form whorls in the blood called eddy currents must be calculated from measurements of blood flow and pressure difference between two points in the vessel blood vessels strongly constricted ○ total peripheral resistance rises to as high as 4 PRU vessels greatly dilated ○ the resistance can fall to as little as 0.2 PRU Systemic total peripheral resistance: - about 100/100, or 1 peripheral resistance unit (PRU) Total pulmonary vascular resistance: - about 0.14 PRU (about one seventh that in the systemic circulation) Conductance - a measure of the blood flow through a vessel for a given pressure Figure 11. A, Two fluids (one dyed red, and the other clear) before flow begins. difference (ml/sec/mmHg); the exact reciprocal of resistance B, The same fluids 1 second after flow begins. C, Turbulent flow, with elements of the fluid moving in a disorderly pattern. Figure 13. Conductance. Page 4 of 8 [PHYSIOLOGY] 1.14 Overview of Circulation; Biophysics of Pressure, Flow, and Resistance; Coronary Circulation - Dr. Max Butardo - Flow through each of the parallel vessels is determined by the pressure gradient and its own resistance (not the resistance of the other parallel blood - Increasing the resistance of any of the blood vessels increases the total vascular resistance Figure 18. Total resistance to blood flow Figure 14. A, Demonstration of the effect of vessel diameter on blood flow. B, Concentric rings of blood flowing at different velocities; the farther away from the vessel wall, the faster the flow. d, diameter; P, pressure difference between the two ends of the vessels. Very slight changes in diameter of a vessel can change its conductance tremendously! Figure 15. Conductance of the vessel increases in proportion to the fourth power of the diameter. Figure 19. Vascular resistances (R): A, in series and B, in parallel. Poiseuille’s Law Conductance in Parallel Vascular Circuits The total conductance (Ctotal) for blood flow is the sum of the conductance of each parallel pathway - Many parallel blood vessels make it easier for blood to flow through the circuit because each parallel vessel provides another pathway, or conductance, for blood flow - adding more blood vessels to a circuit reduces the total vascular Figure 16. Poiseuille’s Law resistance F = rate of blood flow ∆P = pressure difference between the ends of the vessel r = radius of the vessel Figure 20. Total conductance (Ctotal) for blood flow is the sum of the conductance l = length of the vessel of each parallel pathway η = viscosity of the blood Brain, kidney, muscle, gastrointestinal, skin, and coronary circulations: Note: the rate of blood flow is directly proportional to the fourth power of the arranged in parallel radius of the vessel each tissue contributes to the overall conductance of the systemic - makes it possible for the arterioles, responding with only small circulation changes in diameter to nervous signals or local tissue chemical blood flow through each tissue is a fraction of the total blood flow signals, either to turn off almost completely the blood flow to the (cardiac output) tissue or at the other extreme to cause a vast increase in flow determined by the resistance (the reciprocal of conductance) for blood flow in the tissue, as well as the pressure gradient Vascular Resistance in Series Vascular Circuits The arteries, arterioles, capillaries, venules, and veins are collectively arranged EFFECT OF BLOOD VISCOSITY in series: The greater the viscosity, the less the flow in a vessel. Furthermore, the viscosity - flow through each blood vessel is the same and the total resistance of normal blood is about three times as great as the viscosity of water to blood flow (Rtotal) is equal to the sum of the resistances of each vessel Hematocrit - proportion of the blood that is red blood cells - men (average) = 42 - women (average) = 38 These values vary tremendously, depending on whether the person has anemia, Figure 17. (Rtotal) is equal to the sum of the resistances of each vessel the degree of bodily activity, and the altitude at which the person resides. Vascular Resistance in Parallel Vascular Circuits Hematocrit is determined by centrifuging blood in a calibrated tube, as shown in Blood vessels branch extensively to form parallel circuits that supply blood to Figure 21. The calibration allows direct reading of the percentage of cells. the many organs and tissues of the body: - Far greater amounts of blood will flow through this parallel system than through any of the individual blood vessels (the total resistance is far less than the resistance of any single blood vessel) - Permits each tissue to regulate its own blood flow (independent of flow to other tissues) Page 5 of 8 [PHYSIOLOGY] 1.14 Overview of Circulation; Biophysics of Pressure, Flow, and Resistance; Coronary Circulation - Dr. Max Butardo Figure 23. Effect of changes in arterial pressure over a period of several minutes on blood flow in a tissue such as skeletal muscle. Note that between pressure of 70 and 175 mm Hg, blood flow is “autoregulated.” The blue line shows the effect Figure 21. Hematocrits in a healthy (normal) person and in patients with anemia of sympathetic nerve stimulation or vasoconstriction by hormones such as and polycythemia. The numbers refer to the percentage of the blood composed norepinephrine, angiotensin II, vasopressin, or endothelin on this relationship. of red blood cells. Reduced tissue blood flow is rarely maintained for more than a few hours because of the activation of local autoregulatory mechanisms that eventually return blood flow toward normal. Pressure Flow in Passive Vascular Beds Increased arterial pressure: - increases the force that pushes blood through the vessels - distends the elastic vessels - decreasing vascular resistance Decreased arterial pressure (passive blood vessels): - increases resistance - the elastic vessels gradually collapse due to reduced distending pressure When pressure falls below a critical level, called the critical closing pressure, flow ceases as the blood vessels are completely collapsed. Figure 22. Effect of hematocrit on blood viscosity (water viscosity = 1). Blood Flow “Autoregulation” - The ability of each tissue to adjust its vascular resistance and to maintain normal blood flow during changes in arterial pressure between approximately 70 and 175 mm Hg Increase in arterial pressure: - initiates compensatory increases in vascular resistance Reductions in arterial pressure: - vascular resistance is promptly reduced - blood flow is maintained Changes in blood flow can be caused by: Strong sympathetic stimulation ○ Constricts the blood vessels Figure 24. Effect of arterial pressure on blood flow through a passive blood Hormonal vasoconstrictors vessel at different degrees of vascular tone caused by increased or decreased ○ Norepinephrine, angiotensin II, vasopressin, or endothelin sympathetic stimulation of the vessel. Inhibition of sympathetic activity: - Dilates the vessels and increase the blood flow (2x or more) Sympathetic stimulation: - Constrict the vessels blood; flow decreases to as low as zero for a few seconds despite high arterial pressure V. CORONARY CIRCULATION - Although blood fills the chambers of the heart, the muscle tissue of the heart is so thick that it requires coronary blood vessels to deliver blood deep into the myocardium. - The coronary circulation consists of the blood vessels that supply blood to, and remove blood from the heart muscle itself Page 6 of 8 [PHYSIOLOGY] 1.14 Overview of Circulation; Biophysics of Pressure, Flow, and Resistance; Coronary Circulation - Dr. Max Butardo - The vessels that supply blood high in oxygen to the myocardium are known as coronary arteries. Physiologic Anatomy of the Coronary Blood Supply The two main coronary arteries have openings immediately above the aortic valve at the beginning of the aorta where the pressures are highest Arteries 1. LCA: Left Main Coronary Artery - supplies the anterior and left lateral portions of the left ventricle LAD: left anterior descending coronary artery LCC: left circumflex coronary artery 2. RCA: Right Coronary Artery - supplies the right ventricle and posterior part of left ventricle (in 80-90%) Figure 27. Cardiac Veins NORMAL CORONARY BLOOD FLOW At rest: - Average: 70 ml/min/100g heart weight - About 225 ml/min - About 4-5% of the total cardiac output During exercise: - Increases its cardiac output 4-7x - The coronary blood flow increases 3-4x Phasic Changes in Coronary Blood Flow During Systole and Diastole Effect of Cardiac Muscle Compression SYSTOLE: coronary capillary blood flow falls to a low value - strong compression of muscle around the vessels DIASTOLE: blood flows rapidly to the myocardium Figure 25. Coronary Arteries - the cardiac muscle relaxes and no longer obstructs blood flow Figure 28. Phasic flow of blood through the coronary capillaries of the human left ventricle during cardiac systole and diastole (as extrapolated from measured flows in dogs). Figure 26. Coronary arteries and the parts of the heart they supply. Epicardial Versus Subendocardial Coronary Blood Flow — Effect of Veins and Sinuses Intramyocardial Pressure 1. Coronary Sinus - Returns blood from left ventricle into the right atrium (75% of the total coronary blood flow) - Great, middle, small cardiac veins 2. Anterior cardiac veins: - Drains the right ventricle and flow directly into the right atrium 3. Thebesian veins - Drain small amount of blood which empty directly into all chambers of the heart 4. Cardiac veins Figure 29. Diagram of the epicardial, intramuscular, and subendocardial - Drains blood from heart muscle coronary vasculature. SYSTOLE - blood flow through the subendocardial plexus of the left ventricle, where the intramuscular coronary vessels are compressed greatly by ventricular muscle contraction, tends to be reduced. Extra vessels of the subendocardial plexus normally compensate for this. Page 7 of 8 [PHYSIOLOGY] 1.14 Overview of Circulation; Biophysics of Pressure, Flow, and Resistance; Coronary Circulation - Dr. Max Butardo CONTROL OF CORONARY BLOOD FLOW forms large amounts of lactic acid (cause of cardiac pain in cardiac ischemia) Local Muscle Metabolism Is the Primary Controller of Coronary Flow - regulated mostly by local arteriolar vasodilation In severe coronary ischemia: - in response to the nutritional needs of cardiac muscle ATP degrades first to adenosine diphosphate → adenosine monophosphate → adenosine → dilation of the coronary arterioles during coronary hypoxia Need for increased cardiac contraction → the rate of coronary blood flow also increases Decreased heart activity → decreased coronary flow TEST YOUR KNOWLEDGE Almost identical to that occurring in many other tissues of the body, especially in 1. Which among the following blood vessels has a valve? the skeletal muscles a. Capillary b. Vein Oxygen Demand as a Major Factor in Local Coronary Blood Flow Regulation c. Artery d. Arterioles Blood flow - regulated in proportion to the need for oxygen 2. This type of circulation eliminates carbon dioxide via the lungs and Increased oxygen consumption → causes coronary dilation oxygenates the blood. a. Peripheral Circulation ADENOSINE - great vasodilator property b. Greater Circulation - A product of ATP degradation during very low concentrations of c. Pulmonary Circulation oxygen in muscles cells d. Systemic Circulation Other VASODILATORS: 3. What’s the cross-sectional area of a small artery in an average human being? - include adenosine phosphate compounds, potassium ions, hydrogen a. 20 ions, carbon dioxide, prostaglandins, and nitric oxide b. 80 c. 2.5 Nervous Control of Coronary Blood Flow - AUTONOMIC NERVOUS SYSTEM d. 40 4. The exact reciprocal of resistance is called _______________. Sympathetic stimulation: releases norepinephrine and epinephrine a. Density increases both heart rate and heart contractility b. Viscosity increases the rate of metabolism of the heart c. Blood flow sets off local blood flow regulatory mechanisms → dilating the d. Conductance coronary vessels → the blood flow increases 5. What do you call the force exerted by the blood against any unit area of the Vagal stimulation: release of acetylcholine vessel wall? slows the heart and has a slight depressive effect on heart a. Density contractility b. Viscosity decrease cardiac oxygen consumption c. Blood flow constrict the coronary arteries d. Conductance 6. Decreased arterial pressure ____________________. Direct Effects of Nervous Stimuli on the Coronary Vasculature a. increases the force that pushes blood through the vessels b. increases resistance Parasympathetic (vagal) nerve fibers to the coronary system: is NOT very great c. distends the elastic vessels Acetylcholine - direct effect to dilate the coronary arteries d. decreases vascular resistance 7. During exercise, the cardiac output of an individual increases by __________. Sympathetic innervation of the coronary vessels: More extensive! a. 2-3 times Norepinephrine and epinephrine - either vascular constrictor or b. 8-10 times dilator effects c. 2-5 times depending on the presence or absence of constrictor or dilator d. 4-7 times receptors in the blood vessel walls 8. Vagal stimulation causes the release of ______________. a. Epinephrine only Constrictor receptors = alpha receptors (more in epicardial coronary vessels) b. Acetylcholine only Dilator receptors = beta receptors (more in intramuscular arteries) c. Both Norepinephrine and Epinephrine Both exist in the coronary vessels d. Norepinephrine only cause slight overall coronary constriction or dilation, but usually 9. Which of the following is NOT TRUE about arterioles? constriction. a. Can stretch a great deal b. Thickest vessel walls In some people, the alpha vasoconstrictor effects seem to be disproportionately c. Withstand greater blood pressure severe, and these people can have vasospastic myocardial ischemia during d. Are very elastic periods of excess sympathetic drive, often with resultant anginal pain. 10. It is the amount of blood pumped into the aorta by the heart each minute. a. Viscosity Special Features of Cardiac Muscle Metabolism b. Blood pressure c. Cardiac output Resting conditions: d. Conductance cardiac muscle normally consumes fatty acids to supply most of its energy Answer: 1. B. 2.C. 3. A. 4. D. 5. C. 6. B 7. D. 8. B 9. A. 10. C. instead of carbohydrates (about 70 percent of the energy is derived from fatty acids) References: Anaerobic or ischemic conditions: Guyton and Hall Medical Physiology 14th Edition, John E. Hall & Michael anaerobic glycolysis E. Hall, 2021 consumes tremendous quantities of the blood glucose Butardo, M. PPT Page 8 of 8