The Circulation - part 2 - Adelina Vlad, MD Ph

Transcription

1 The Circulation - part 2 - Adelina Vlad, MD Ph

2 Physical Characteristics of the Vascular System Aggregate Cross-Sectional Area (cm 2 ) Distribution of blood Mean linear velocity of blood flow is inversely proportional to aggregate vascular cross-sectional area: - 21 cm/s in the aorta cm/s in the capillaries, under resting conditions - 14 cm/s in venae cavae

3 Pressures Along the Vascular System High pressure zone: contracting LV systemic arterioles Low pressure zone: systemic capillaries right heart pulmonary circulation left atrium LV in relaxed state LV Average pressure 17 mm Hg 0 mm Hg Average pressure 7 mm Hg Pulsatile Mean value: 100 mmhg Pulsatile Mean value: 16 mmhg RV Normal blood pressures in the different portions of the circulatory system when a person is lying in the horizontal position

4 Structure Function Relationship (elastic fibers dominance) (collagen fibers dominance)

5 Allow blood return to the heart Systemic Veins By contracting or enlarging their lumen, veins can adjust the amount of blood returned to the heart and influence the cardiac output (Frank-Starling mechanism) store or mobilize large amounts of blood in accordance to the physiologic needs

6 Veins are compliant structures, with low resistance and large capacitance they can accommodate important amounts of blood for a tiny increase in pressure Total cross-section area of veins is larger than similar degrees of arborisation in the arterial system, therefore blood advances with a much lower velocity through the veins Pressure in the venous bed decreases from periphery towards atria, generating a pressure gradient that allows blood to return from tissues to the heart venous return is favored by an increase of pressure in the periphery and a lowering of pressure on the way to the heart

7 Central Venous Pressure = The pressure in the right atrium, the endpoint of systemic venous return It is regulated by a balance between the ability of the heart to pump blood out of the right atrium and ventricle into the lungs the tendency for blood to flow from the peripheral veins into the right atrium

8 Central Venous Pressure Normal value: about 0 mm Hg; Can increase to mm Hg due to serious heart failure massive transfusion Can decrease to about mm Hg, which is the pressure in the chest cavity that surrounds the heart when the heart pumps with exceptional vigor when blood flow from the peripheral vessels to the heart is greatly depressed (severe hemorrhage)

9 Peripheral venous pressure is increased by: raise of RA pressure above +4 to +6 mm Hg (heart failure) blood begins to back up into the veins high intra-abdominal pressure (pregnancy, abdominal tumors, ascites) pressure in the legs veins must surpass intra-abdominal pressure hydrostatic pressure when there is a difference in height along the veins

10 Venous resistance Could be very low Large veins do usually offer some resistance to blood flow due to compression by the surrounding tissues: veins from the arms over the first rib intra-abdominal veins by different organs and by the intra-abdominal pressure neck veins often collapse under the push of the atmospheric pressure

11 Venous return can be increased by: Increased blood volume Decreased pressure toward the heart During inspiration By low pressures in the right atrium provided by a good RV performance Increased pheripheral venous pressure: increased large vessel tone throughout the body with resultant increased peripheral venous pressures dilatation of the arterioles which decreases the peripheral resistance and allows rapid flow of blood from the arteries into the veins The activity of the venous pump Changing body position from standing/sitting to horizontal or by rising the legs while lying down

12 Venous Valves and the Venous Pump Veins below the heart level are equipped with valves that allow blood to flow in only one direction towards the RA When veins below the heart are compressed by contracting muscles or pulsing arteries, due to the valves inside the veins the blood is pushed forward to the RA = venous pump or muscle pump the venous pressure in the feet of a walking adult is less than +20 mm Hg, whereas in the standing, immobile position it would be + 90 mm Hg Venous valve incompetence causes varicose veins

13 Estimation of Venous Pressure Clinical estimation - by simply observing the degree of distention of the peripheral veins: external jugular veins begin to protrude at + 10 mm Hg RA pressure Direct measurement of Peripheral venous pressure with a needle connected to a pressure recorder RA pressure with central venous catheters Zero height pressure reference level - near the level of the tricuspid valve - here the pressure is unaffected by changes of body posture because the heart acts as a feedback regulator of pressure

14 Reservoir Function of the Veins More than 60% of all the blood in the circulatory system is usually in the veins When circulating blood volume decreases, nervous reflexes determine the mobilization of blood from the reservoirs of the body venous reservoir can cover a loss of up to 20% of the total blood volume Specific blood reservoirs the venous sinuses of the spleen, 100 ml the venous sinuses of the liver, several hundreds ml the large abdominal veins, 300 ml the venous plexus beneath the skin, several hundreds ml

15 Limphatic System

16 Limphatic System Filtration at the arteriolar end of the capillary exceeds reabsorbtion at the venular end by 2 3 l/day this excess liquid together with proteins and other large molecules from the interstitium move into the lymphatics Limphatics arise at the interstitium as small thin-walled channels larger vessels the thoracic duct and the right lymph duct drain into the left and right subclavian veins Limphatics are absent from some tissues (myocardium, brain, bones...)

17 Structure of Limphatic Vessels Capillaries - closed ended channels with endothelial cells that are attached by anchoring filaments to the surrounding connective tissue - at the junctions of adjacent endothelial cells, the edge of one endothelial cell overlaps the edge of the adjacent cell forming a minute valve that opens to the interior of the lymphatic capillary Larger lymphatic vessels have walls similar to those of small veins (endothelium, smooth muscle) Lymphatic vessels are equipped with valves

18 Formation of Lymph Lymph as it first enters the terminal lymphatics has almost the same composition as the interstitial fluid; protein concentration of about 2 g/dl in most tissues, 6 g/dl in liver and 3-4 g/dl in intestines 3-5 g proteins/dl in the thoracic duct lymph Lymphatic system is also one of the major routes for absorption of nutrients from the gastrointestinal tract, especially for virtually all fats in food up to 1-2% fat in the thoracic duct lymph after a fatty meal Large particles such as bacteria can enter the lymph, but they are removed and destroyed as the lymph passes through the lymph nodes

19 Rate of Lymph Flow Averages 120 ml/hr or 2 to 3 liters per day Two primary factors determine lymph flow 1) the interstitial fluid pressure 2) the activity of the lymphatic pump The interstitial fluid pressure Increased interstitial fluid pressure increases lymph flow But only up to the maximum lymph flow rate (plateau) when the interstitial fluid pressure becomes greater than atmospheric pressure (0 mm Hg), the increasing tissue pressure also compresses the outside surfaces of the larger lymphatics, impeding lymph flow

20 Intrinsic pump Lymphatic Pump When a collecting lymphatic or larger lymph vessel becomes stretched with fluid, the smooth muscle in the wall of the vessel automatically contracts Each segment of the lymph vessel between successive valves functions as a separate automatic pump In the thoracic duct, this lymphatic pump can generate pressures as great as 50 to100 mm Hg External intermittent compression of the lymphatics Contraction of surrounding skeletal muscles and intestines Movement of the parts of the body Pulsations of arteries adjacent to the lymphatics Compression of the tissues by objects outside the body

21 Lymphatic capillary pump Terminal lymphatic capillaries are tethered to surrounding connective tissue by means of the anchoring filaments muscle contraction or swelled interstitium can deform them, making the openings between the endothelial cells more patent The lymphatic capillary endothelial cells also contain a few contractile actomyosin filaments

22 Roles of the Lymphatic System The lymphatic system plays a central role in controlling 1) the concentration of proteins in the interstitial fluids 2) the volume of interstitial fluid 3) the interstitial fluid pressure All these factors are linked to one another: Proteins leak from the capillaries into the interstitium increased interstitial colloid osmotic pressure increased volume of interstitial fluid increased interstitial fluid pressure increased limph flow wash-out of interstitial protein and liquid in excess = the return of protein and fluid by way of the lymphatic system balances exactly the rate of leakage of these into the interstitium from the blood capillaries = steady state

23 The Microcirculation

24 The Microcirculation Is the site of the most purposeful function of the circulation: delivery of nutrients to the tissues and removal of cell excreta Is defined as the blood vessels from the first-order arterioles to the first-order venule Principal components: 1 arteriole metarteriole (+/-) network of capillaries 1 venule

25 Structural Particulars Arterioles inner radius 5-25 mm Inner layer of endothelium Internal elastic lamina A single continuous layer of innervated VSMCs Metarterioles shorter than arterioles Similar structure to the arterioles except the VSCMs layer that is discontinuous and usually not innervated Precapillary sphincter small cuff of VSMCs, usually not innervated but very responsive to local stimuli Capillaries inner radius 2-5 mm Single layer of endothelial cells Basement membrane Pericytes in some tissues elongated, branched cells involved in exchange, growth and repair processes, local control of blood flow Venules inner radius 5-25 mm VSCMs layer is discontinuous, innervated May exchange some solutes across their wall

26 Metarteriolar Shunt

27 The Capillaries The walls of the capillaries are extremely thin and highly permeable The peripheral circulation of the whole body has about 10 billion capillaries with a total surface area estimated to be 500 to 700 square meters The capillaries are the principal site for exchange of respiratory gases water nutrients waste products Non-nutritional functions of the capillary flow: plasma filtration in the glomeruli of the kidney, temperature regulation in the skin, signalling (delivery of hormones) etc.

28 Endothelial Cells Have a smooth surface and are very thin ( nm) The cytoplasm is rich in endocytotic (pinocytotic) vesicles that sometimes form a transendothelial channel transcytosis of water and water-soluble compounds Some have fenestrations cylindrical conduits through the cell Separated by intercellular clefts (10 4 nm wide) May be linked to one another by tight junctions May present gaps nm wide between adjacent cells Vesicles, transendothelial channels, fenestrae, clefts and gaps are part of permeation across the endothelial cells

29 Types of Capillaries Based on their degree of leakiness, the capillaries can be Continuous capillary - the most common form of capillary; it has inter-endothelial junctions nm wide In the blood-brain barrier - capillaries without clefts and narrow tight junctions; they don t permit any paracelullar flow of hydrophilic solutes

30 Fenestrated capillary - the endothelial cells are thin and perforated with fenestrations Most often they surround epithelia (e.g., small intestine, exocrine glands) and are present in the glomerular tufts of the kidney Discontinuous capillary - in addition to fenestrae, these capillaries have large gaps - found in sinusoids (e.g., liver)

31 Flow of Blood in the Capillaries Is intermittent, turning on and off every few seconds or minutes due to vasomotion = intermitent contraction of the metarterioles and precapillary sphincters It is influenced mainly by O2 concentration in the surrounding interstitium The parameters of capillary circulation are expressed as average of the overall capillary activity in each capillary bed: average rate of blood flow average capillary pressure average rate of transfer of substances between the blood of the capillaries and the surrounding interstitial fluid

32 Capillary Exchange of Solutes The main mechanism for the transfer of solutes across capillaries is diffusion It is governed by: specific capillary permeability concentration gradient between capillary and interstitium for each solute

33 Fick s law: P X = D X /a, the permeability coefficient (cm/s), expresses the ease with which the solute crosses a capillary by diffusion

34 Lipophilic solutes (O2, CO2) can permeate all areas of the capillary membrane much faster rates of transport through the capillary membrane than the rates for hydrophilic solutes Hydrophilic solutes need special pathways for passing through the capillary wall Paracellular pathway - diffusion through water-filled pores (clefts, gaps, fenestrae) Transcytosis - endocytotic vesicles and transendothelial channels

35 Paracellular Pathway Hydrophilic solutes smaller than albumin can traverse the capillary wall by diffusion via a paracellular route: clefts, gaps, fenestrae Diffusion through water-filled capillary pores depends on the Size of the polar molecules: permeability coefficient P X falls as the molecular radius increases Location: P X increases towards the venular end of the capillary, where the clefts are wider and the fenestrae are more common than at its arteriolar end Electrical charge of small proteins or other macromolecules, a major determinant of their P X : negative charges in the diffusion path favor the transit of molecules with positive charge and impairs the passage of those with negative charge Solvent drag a dissolved solute can be carried by the convective movement of water; has a minor contribution

36 Transcytosis Is a second mechanism of macromolecular translocation through capillary, by means of endocytotic (pinocytotic) vesicles transendothelial channels formed by the endothelial cells Characteristics: It s not governed by the laws of diffusion Falls steeply with increases in molecular radius due to steric hindrance, a process called sieving Some of the macromolecular cargo may be processed during transcytosis (e.g., only a tiny part of the endocytosed ferritin is delivered to the opposite side of the cell) It s less prominent in brain capillaries lower permeability of the blood-brain barrier for macromolecules

37 Interstitium Spaces between cells are collectively called the interstitium Interstitium contains two major types of solid structures: collagen fiber bundles and proteoglycan filaments (98% hyaluronic acid and 2% protein) The interstitial fluid is derived by filtration and diffusion from the capillaries the same components as plasma but with much lower concentrations of proteins Most of it is entrapped within proteoglycan filaments tissue gel; diffusion through the gel occurs about 95 99% as rapidly as it does through free fluid Occasionally a tiny part is free (< 1%) free fluid rivulets and vesicles

38 Capillary Exchange of Water The pathways for fluid movement across capillary walls are both paracellular (clefts, fenestrae, gaps) and transcellular (aquaporin1 water channels) The main mechanism for fluid transfer across capillaries is convection (bulk water movement) and depends on hydrostatic and osmotic forces = Starling forces (1856)

39 Starling Forces 1) The capillary hydrostatic pressure (Pc) forces fluid outside the capillary 2) The interstitial fluid hydrostatic pressure (Pif) forces fluid outside the interstitium when is positive and attracts fluid into interstitium when is negative 3) The capillary plasma colloid osmotic pressure (Pp) caused by plasma proteins, keeps water inside the capillaries 4) The interstitial fluid colloid osmotic pressure (Pif) caused by interstitial protein and proteoglycans, keeps water into interstitium

40 The Net Filtration Pressure NFP, is the algebraic sum of hydrostatic and colloid osmotic forces acting across the capillary wall Arterial end DP DP If the NFP is positive net fluid outflow from the capillaries into the interstitium = filtration If the NFP is negative net fluid absorption from the interstitial spaces into the capillaries

41 Capillary Filtration Coefficient The rate of fluid filtration in a tissue is also determined by the number and size of the pores in each capillary as well as the number of capillaries in which blood is flowing the capacity of the capillary membranes to filter water for a given NFP is expressed as the capillary filtration coefficient (Kf) or hydraulic conductivity; unit measure: ml/min per mm Hg net filtration pressure The rate of capillary fluid filtration is therefore determined as Filtration = the volume flow of fluid across the capillary wall

42 Capillary Hydrostatic Pressure In the human skin Pc falls from 30 mm Hg at the arteriolar end to 10 mm Hg at the venular end of the capillary Pc depends on Precapillary resistance (Rpre) and postcapillary resistance (Rpost): usually Rpre > Rpost midcapillary pressure is not the mean value between arteriolar and venular pressures Arteriolar and venular pressures: Rpre > Rpost Pc follows venular pressure Pv more closely than arteriolar pressure Pa Location: high Pc in the glomerular capillaries of the kidney, retinal capillaries; low Pc in the pulmonary capillaries Time: the permanent fluctuation of the arteriolar diameter and tone of the precapillary sphincter lead to times of net filtration and other times of net absorbtion in individual capillaries Gravity: capillary beds bellow the level of the heart have a higher Pc than those above the level of the heart

43 EFFECT OF UPSTREAM AND DOWNSTREAM PRESSURE CHANGES ON CAPILLARY PRESSURE* P a (mm Hg) P c (mm Hg) P v (mm Hg) Control Increased arteriolar pressure Increased venular pressure *Constant R post /R pre =

44 Interstitial-Fluid Pressure Pif is sub-atmospheric (slightly negative) in loose tissues, averaging about - 3 mm Hg Pif is positive in encapsulated organs (kidney, muscle, eye etc.) and inside rigid enclosed compartments (bone marrow, brain); however, Pif in the parenchima is lower than pressures exerted by their encasements (kidney: capsular pressure = +13 mm Hg, Pif = + 6 mm Hg) the normal interstitial fluid pressure is several mm Hg negative with respect to the pressure that surrounds each tissue (capsular pressure, barometric pressure) The negative Pif is due to fluid removal by the lymphatic pump

45 Capillary Coloid Osmotic Pressure Molecules or ions that fail to pass through the pores of a semipermeable membrane exert osmotic pressure; water is attracted towards the compartment with a higher concentration of osmotic-active particles (and lower water concentration ) Proteins of the plasma and interstitial fluids do not readily pass through the capillary pores they are responsible for the osmotic pressures on the two sides of the capillary membrane = colloid osmotic or oncotic pressures Pp averages about 28 mm Hg 19 mm of this is caused by molecular effects of the dissolved protein and 9 mm by the Donnan effect - that is, extra osmotic pressure caused by sodium, potassium, and the other cations held in the plasma by the electro-negatively charged proteins

46 Types of Plasma Proteins and Pp Osmotic pressure is determined by the number of molecules dissolved in a fluid small proteins develop a higher P albumin is the most important protein for the capillary and tissue fluid dynamics

47 Interstitial Fluid Colloid Osmotic Pressure Small amounts of proteins do leak through the capillary wall into the interstitium ( g/day); most of them are removed by the lymph ( g/day); a tiny part is reabsorbed at the venular end of the capillary (5 g/day) Protein leakage varies greatly from tissue to tissue (higher in the liver: 4 to 6 g/dl, or intestines: 3 to 4 g/dl); the average Pif is about + 8 mm Hg Pif increases along the axis of the capillary because protein - free fluid is filtered at the arteriolar end of the capillary, decreasing protein concentration in the interstitium (lower Pif) protein-free fluid is reabsorbed at the venular end from the interstitium, increasing protein concentration in the interstitium (higher Pif)

48 Fluid Filtration at the Arterial End of the Capillary

49 Fluid Reabsorption at the Venular End of the Capillary

50 Net Filtration Pressure Along a Capillary DP DP

51 Starling Equilibrium for Capillary Exchange The amount of fluid filtering outward from the arterial ends of capillaries equals almost exactly the fluid returned to the circulation by absorption

52 The slight excess of filtration is called net filtration and it is the fluid that must be returned to the circulation through the lymphatics (2 ml/min for the entire body)

53 Interstitial Edema Edema (from the Greek oidema, for "swelling") is characterized by an excess of salt and water in the extracellular space, particularly in the interstitium Occurs due to alteration in Hydrostatic forces (high Pc due to immobile upright position, varicose veins, pulmonary hypertension, right heart inssuficiency etc.) Coloid osmotic forces (low plasma protein in nephrotic syndrome, pregnancy, protein malnutrition, liver disease etc.) Properties of the capillary wall (increased permeability due to inflammation, breakdown of the tight endothelial barrier of the cerebral vessels, ischemia reperfusion etc.) Lymphatic drainage (removal of lymph nodes for cancer surgery, lymph nodes obstructed by malignancy, external compression of limph vessels etc.)

54 Regulation of the Microcirculation Each tissue controls its own local blood flow in proportion to its metabolic needs Tissue metabolites regulate local blood flow in specific vascular beds independently of the systemic circulation regulation Can be: Short-termed (acute control) rapid changes in local vasodilation or vasoconstriction of the arterioles, metarterioles, and precapillary sphincters Long-termed slow changes in flow over a period of days, weeks, months increase or decrease in the physical sizes and numbers of tissue blood vessels (angiogenesis)

55 Acute Control Depends on local mechanisms mediated by metabolic factors endothelial factors autoregulatory processes The cardiac output is distributed among tissues in accordance to their instantaneous needs the work of the heart is spared by an optimized distribution of the blood flow

56 Blood Flow to Different Organs and Tissues Under Basal Conditions During heavy exercise, muscle metabolic activity can increase more than 60- fold and the blood flow as much as 20-fold (15,000 ml/min or 80 ml/min/100 g of muscle)

57 Role of Resistance in Precapillary Vessels Modulating the contractility of VSMCs in precapillary vessels is the main mechanism for adjusting capillary blood flow Capillary flow is roughly inversely proportional to R pre because the aggregate R cap is small, R post /R pre 0.3 R pre > R cap + R post R pre is the principal determinant of the overall resistance of the microcirculatory bed (Rtotal) R pre is determined by smooth-muscle tone in arterioles, metarterioles, and pre-capillary sphincters (R = 8hl /pr 4 )

58 Metabolic Control There are two basic theories for the regulation of local blood flow when either the rate of tissue metabolism changes or the availability of oxygen changes: Vasodilator theory Oxygen and nutrients lack theory

59 Vasodilator Theory The greater the rate of metabolism, the greater the rate of formation of vasodilator substances in the tissue cells Chemical factors act directly on the VSMCs LOCAL METABOLIC CHANGES THAT CAUSE VASODILATION IN THE SYSTEMIC CIRCULATION CHANGE PO 2 MECHANISM [ATP] i, adenosine release PCO 2 ph [lactic acid] o [ATP] i [Adenosine] o ph o ph o ph o Opens K ATP channels Activates purinergic receptors

60 Adenosine Formed by degradation of adenine nucleotides when ATP consumption exceeds cell capacity to resynthesize high energy phosphate compounds, due to - increased local metabolism - insufficient local blood flow - fall in blood po2 From tissue cells adenosine diffuses into VSMCs activates adenosine receptors K channels open hyperpolarization voltage-gated Ca++ channels close decreases [Ca2+]i vasodilatation increased O2 supply

61 Oxygen Lack Theory In the absence of adequate oxygen and possibly of some other nutrients (glucose, thiamine, niacin, riboflavin) blood vessels simply relax and naturally dilate oxygen and nutrients supply raises vasoconstriction periodic fluctuation of capillary blood fow (vasomotion) regulated by the level of oxygen and nutrients Acute local feedback control of blood flow

62 Endothelial Factors The vascular endothelium is the source of several important vasoactive compounds VASODILATORS Nitric oxide (NO) VASOCONSTRICTORS Endothelin (ET) Endothelium-derived hyperpolarizing factor (EDHF) Prostacyclin (PGI 2 ) Endothelium-derived constricting factor-1 (EDCF 1 ) Endothelium-derived constricting factor-2 (EDCF 2 ) Vasodilators release stimulated by shear-stress or in response to acetylcholine NO acts through a cgmp PKG pathway to decrease the interaction between actin and myosin (decreases MLC phosphorilation) as well as [Ca2+]i (SERCA activation) EDHF makes the membrane potential more negative Vasoconstrictors release: endothelins (ETs) long lasting and potent effect; increases [Ca2+]i

63 Autoregulation Despite large changes in arterial blood pressure the local blood flow is maintained within a narrow range In the physiological pressure range over which autoregulation occurs ( mm Hg), increases in pressure lead to increases in resistance (flow is maintained approx. constant) Autoregulation is an autonomous process Realized through myogenic and metabolic mechanisms

64 Autoregulation Myogenic control: the stretch of VSMCs induced by increased perfusion pressure triggers myogenic contraction (via membrane stretch receptors and increased Ca++ inflow) Metabolic control: the increase in PO2 (or decrease in PCO2, or increase in ph) that follows an increase in perfusion pressure triggers a metabolic vasoconstriction that brings the perfusion pressure back to lower levels Importance With an increase in perfusion pressure, autoregulation avoids a waste of perfusion in organs with an already sufficient flow With a decrease in perfusion pressure, autoregulation maintains capillary flow and capillary pressure very important for organs sensible to ischemia (heart, brain) or for organs that filter the blood (kidneys)

65 Long-Term Control In adults the size and shape of microcirculation remains rather constant Exceptions: wound healing, inflammation, tumor growth, endometrial vessels during the menstrual cycle, physical training, acclimatization to altitude Sustained hypoxia is followed by the expansion of the vascular bed by angiogenesis (= development of new vessels) and by arteriogenesis (= development of collateral circulation) AGENTS THAT AFFECT VASCULAR GROWTH PROMOTERS INHIBITORS Vascular endothelial growth factor (VEGF) Fibroblast growth factors (FGFs) Angiopoietin-1 (ANGPT1) Endostatin Angiostatin Angiopoietin-2 (ANGPT2)