VASCULAR SYSTEM - THE HEMODYNAMICS -

Transcription

1 VASCULAR SYSTEM - THE HEMODYNAMICS - Lecture 2 Dr. Ana-Maria Zagrean

2 Main function: -transport of nutrients -removal of cellular excreta Microcirculation Arterioles (highly muscular, their diameters can change manifold) Metarterioles/terminal arteriole (do not have a continuous muscular coat, but smooth muscle fibers encircle the vessel at intermittent points) Precapillary sphincters (smooth mm cell, local control of blood flow) Capillaries

3 Microcirculation Closed capillaries An artery branches 6-8 x until becoming arterioles; these are branching further 2-5 x towards capillaries.

4 Capillaries diameter = 4-9 mm, 10 billions, surface = m 2 Capillary no, distance capill-cells (20-30 µm)~ metabolic activity of the tissue pores in the capillary membranes: 1. intercellular cleft / gap: 6-7 nm, S~1/1000 of the total capillaries surface, allow the thermal motion of only small molecules 2. plasmalemmal / transcytosis vesicles = caveolae: role in endocytosis, transcytosis (coalesce to form vesicular channels/pores) 3. special types of pores: - large clefts in intestinal membranes, larger in liver capillaries (endothelial discontinuity...) - fenestrae in glomerular capillaries (20 to 100 nm), that appear to be sealed by a thin diaphragm, but they are permeable to larger molecules - no pores, but tight junctions, in brain capillaries (BBB) permeability is not uniform along the whole capillary: arterial end < venous end < venules (greater no of pores/clefts)

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6 Pores in the capillary membranes Exchange between blood & interstitial fluid takes place in the capillaries by diffusion, filtration, pinocytosis (transcytosis). (leaky junctions)

7 Types of capillaries, based on their degree of leakiness skeletal muscle small intestine, exocrine glands liver

8 Cerebral endothelium: Tight-junction epithelium & blood-brain barrier

9 Pericytes Capillary walls are closely associated with elongated, highly branched cells = pericytes Mesh-like outer layer between endothelium and interstitial fluid, more developed at the capillary venous end and venules level Functions: exchange, growth & repair processes, local control of blood flow at microcirculation level

10 Average function of the capillary system For the billions of capillaries which operate intermittently in response to the local conditions in the tissue, there are average rate of capillary blood flow average capillary pressure average rate of transfer of substances

11 Blood flow in the microcirculation Vasomotion = intermittent contraction/relaxation of the metarteriols and precapillary sphincters (5-10/min) - partly an intrinsic contractile behavior of the vascular smooth muscle -depends on local and humoral factors, mostly on O 2 conc. -influenced by sympathetic tone

12 Blood flow in the microcirculation Blood flows intermittently/randomly or it may oscillate rhythmically at different frequencies as determined by contraction and relaxation (vasomotion) of the precapillary vessels. Changes in transmural pressure = intravascular press. extravasc. press* affect the contractile state of the precapillary vessels: transmural pressure terminal arteriole/precapillary constriction CHANGES IN CAPILLARY DIAMETER ARE PASSIVE AND ARE CAUSED BY ALTERATIONS IN PRECAPILLARY AND POSTCAPILLARY RESISTANCE. Average velocity of capillary blood flow ~1 mm/sec (zero-several mm/sec). *Transmural pressure is essentially equal to intraluminal pressure because extravascular pressure is usually negligible.

13 Endothelium synthesize substances that affect the contractile state of the arterioles: 1. Endothelium-derived relaxing factor (EDRF) - nitric oxide (NO), vasodilator formed and released in response to stimulation of the endothelium by various agents (e.g., acetylcholine, ATP, serotonin, bradykinin, histamine, substance P); NO can also interfere with platelet aggregation. 2. Endothelium-derived hyperpolarizing factor (EDHF) - vasodilator 3. Prostacyclin, a vasodilator that also inhibits platelet adherence to the endothelium and platelet aggregation, aiding in the prevention of intravascular thrombosis 4. Endothelin, a powerful vasoconstrictor substance, released in large quantities in injured endothelium 5. Endothelium also synthesize: structural components: glycocalyx, basal lamina endothelial enzymes: Angiotensin-Converting Enzyme, carbonic anhydrase (lungs) thromboxane, von Willebrand factor (f VIII) adhesive molecules involved in cell migration during inflammation

14 Endothelium- and non-endothelium-mediated VASODILATION Prostacyclin (PGI 2 ) is formed from arachidonic acid (AA) by the action of cyclooxygenase (Cyc-Ox) and prostacyclin synthetase (PGI 2 Syn) in the endothelium and elicits relaxation of the adjacent vascular smooth muscle via increases in camp. Substances such as adenosine, H +, CO 2, and K + can arise in the parenchymal tissue and elicit vasodilation by direct action on the vascular smooth muscle.

15 Endothelium- and non-endothelium-mediated VASODILATION Stimulation of the endothelial cells with acetylcholine (Ach) results in the formation and release of an EDRF Nitric Oxide (NO). NO stimulates guanylyl cyclase (G Cyc) to increase cgmp in the vascular smooth muscle to produce relaxation. The vasodilator agent nitroprusside (NP) acts directly on the vascular smooth muscle.

16 Vasomotion is influenced by sympathetic tone Arterioles - A, before and B, after the microinjection of norepinephrine. Right inset - capillary with red cells during a period of complete closure of the feeding arteriole.

17 Angiogenesis creates new blood vessels Angiogenesis - growth, development, wound healing, inflammation, tumour growth - endurance exercise training, acclimatization to altitude Angiogenic factors: mitogens like VEGF, FGF Angiopoietins 1 & 2, role in postnatal angiogenic remodelling Plasma angiogenin increased in cancer, angiogenic effect Anti-angiogenic factors/cytokines: angiostatin and endostatin Therapeutic role: cancer AB against VEGF (Avastin) coronary artery disease/myocardial ischemia (FGF2)

18 Exchange of nutrients and other substances between the blood and interstitial fluid Diffusion back and forth continual mixing random movement Diffusion results from thermal motion of water molecules and dissolved substances What diffuses Lipid-soluble substances [through cell membrane]: O 2, CO 2 Water-soluble, non-lipid-soluble substances (through intercellular pores): H 2 O, Na +, Cl -, glucose Great velocity of thermal motion tremendous diffusion (rate of H 2 O diffusion through the capillary mb.= x the rate at which plasma itself flows linearly along the capillary) Diffusion depends on lipid-solubility, molecular size, molecular weight (MW), concentration difference between the two sides of the membrane.

19 Arterial end Blood capillary Venous end D I F F U S I O N Lymfatic capillary Diffusion between capillary and interstial fluid

20 Effect of molecular size on passage through the pores (paracellular) d intercell. cleft = 6-7 nm ~ 20 x d water < d plasma protein molecules (d=diameter) interstitial fluid contains almost the same constituents as plasma except for the proteins Capillary pores do not restrict the fast diffusion of water, NaCl, urea or glucose; they pass as much as they are available in the blood (flow limited transport) Minimal diffusion of molecules with MW > (diffusion limited transport). Water molecules transcellular movement through aquaporin 1 (AQP1), constitutively expressed in endothelial cells.

21 Relative permeability of muscle capillary pores to different-sized molecules Substance MW Permeability coefficient Water 18 1 NaCl 58,5 0,96 Urea 60 0,8 Glucose 180 0,6 Sucrose 342 0,4 Inulin ,2 Myoglobin ,03 Hemoglobin ,01 Albumin ,0001 Reflection coefficient - relative impediment to the passage of a substance through the capillary membrane = 0 for water = 1 for albumin Filterable solutes have reflection coefficients between 0 and 1.

22 Net rate of diffusion through the capillary membrane - net rate of diffusion is proportional to the concentration difference between the two sides of the membrane (e.g., concentration difference for O 2, CO 2, glucose) - O 2, CO 2 : lipid-soluble, readily pass through the endothelial wall possible diffusion shunt of gas around the capillaries, or directly between adjacent arterioles and venules diffusion of O 2 from the arterioles can decrease blood O 2 content at this level to about 80% of that in the aorta

23 Arterial end Blood capillary Venous end Interstitium Lymfatic capillary Interstitium: -solid structures (collagen fiber bundles, proteoglycan [PG] filaments) -interstitial fluid is derived by filtration and diffusion from the capillaries -interstitial/tissue gel : the interstitial fluid entrapped within the PG filaments mainly diffuses through the gel -free fluid vesicles in the interstitium: normally <1%, in edema

24 Arterial end Blood capillary Venous end D I F F U S I O N F I L T R A T I O N Lymfatic capillary Exchanges between capillary and interstial fluid (net transfer of fluid): capillary filtration/absorption - regulated by the hydrostatic pressure and effective osmotic pressure differences across the endothelium

25 Four primary forces determine fluid movement through the capillary membrane: Starling forces 1. Capillary pressure (Pc) hydrostatic pressure which tends to force fluid outward through the capillary mb. 2. Interstitial fluid pressure (Pif) hydrostatic pressure in the interstitial fluid which tends to force fluid outward(+)/inward(-) through the capillary mb. 3. Plasma colloid osmotic (oncotic) pressure (Pp) osmotic pressure caused by the plasma proteins, which tends to cause osmosis of fluid inward through the capillary mb. 4. Interstitial fluid colloid osmotic pressure (Pif) - osmotic pressure caused by the proteins in the interstitium, which tends to cause osmosis of fluid outward through the capillary membrane

26 Mean capillary (hydrostatic) pressure Mean capillary pressure measurement: - direct micropipette cannulation of the capillaries: 25mmHg - indirect functional measurement: 17mmHg Mean functional capillary pressure = 17,3 mmhg (nearer to the pressure in the venous end): - precapillary sphincters are closed during a large part of the vasomotion cycle - venous capillaries are several times as permeable as the arterial capillaries - there are far more venous capillaries then arterial ones.

27 Colloid osmotic pressure Only those molecules or ions that fail to pass through the pores of a semipermeable membrane exert osmotic pressure Proteins are the only significant dissolved constituents that do not readily penetrate the pores of the capillary membrane. Dissolved proteins of the plasma and interstitial fluids that are responsible for the osmotic pressure = colloid osmotic pressure or oncotic pressure (P). Pp = 28 mmhg 19 mmhg from dissolved proteins (80%-albumin, 20%-globulin) 9 mmhg from the cations associated with plasmatic proteins (Gibbs-Donnan effect) Pif = 8mmHg (protein concentration in interstitial fluid is 40% of that in plasma; also, no Gibbs-Donnan effect here)

28 Q f - fluid movement across the capillary wall k - filtration constant for the capillary membrane P c - capillary hydrostatic pressure (mm Hg) π i - interstitial fluid oncotic pressure (mm Hg) P i - interstitial fluid hydrostatic pressure (mm Hg) π p - plasma oncotic pressure (mm Hg) + for net filtration - for net absorption Net filtration occurs when the algebraic sum of the hydrostatic and osmotic pressures across the capillaries is positive, and net absorption occurs when the sum is negative.

29 Starling Equilibrium for Capillary Exchange Arterial end Venous end Pc=30 mmhg Pp =28 mmhg Pc=17,3mmHg Pp=28mmHg Pc=10 mmhg Pp=28 mmhg P outward =13mmHg Net outward force=0,3 P inward =7mmHg Pif = -3 mmhg Pif = 8 mmhg Pif = -3 mmhg Pif = 8 mmhg Pif = -3 mmhg Pif = 8 mmhg NET FILTRATION=2ml/min/entire body drained as LYMPH NET FILTRATION PRESSURE: outward inward net outward force ( ) 28 = =13 mmhg NET REABSORPTION PRESSURE: inward outward net inward force 28 -( ) =28 21= 7 mmhg

30 Fluid exchange at the capillary - Quick movement of fluid across the capillary endothelium - Filtration and absorption occur with very small imbalances of pressure across the capillary wall only about 2% of the plasma flowing through the vascular system is (net) filtered, and of this, about 85% is absorbed in the capillaries and venules. The remainder returns to the vascular system in the lymph, along with the albumin that escapes from the capillaries.

31 Lymphatic system Accessory rout for fluid drainage from interstitium (1/10 of the filtrated fluid, 2-3L/ day) together with proteins and macromolecules; act as an overflow mechanism ; its function is essential for survival. Lymphatic vessels in almost all tissues of the body (exception epidermis, brain, muscles endomysium and bones; here minute interstitial channels = prelymphatics). Terminal lymphatic vessels - close-end network of highly permeable lymph capillaries, anchored through fine filaments to the surrounding connective tissue

32 Lymphatic capillary

33 Lymphatic system Special structure of the lymphatic capillaries: - Endothelial cells (EC) with actomyosin filaments & anchoring filaments to the surrounding connective tissue (lymphatic capillary pump) - the edges of adjacent EC overlap in a minute valve, allowing an inward flap; the backflow in the lymphatic capillary closes the flap valves. Structure of lymphatic vessels: - valves along lymphatic vessels up to the point where they empty into the blood circulation; - smooth muscle that contracts in response to stretch system of pumps & valves (lymphatic pump)

34 Lymphatic system Juncture of subclavian vein and internal jugular vein Terminal lymphatic capillaries collecting lymphatic lymphatic vessels thoracic (left lymph) duct/right lymph duct

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36 Lymph composition - almost the same as interstitial fluid - proteins: 2 g/l in lymphatic capillaries 6 g/l in liver lymphatics 3-4 g/l in intestines lymphatics 2/3 3-5 g/l in thoracic duct - nutrients from GIT (1-2% fats after a fatty meal) - lipid-soluble vitamins (A, D, E, K) - lymphocytes - globulins synthesized in lymphatic nodes - clotting factors - microorganisms

37 Lymph flow - 2 ml/min = 120 ml/hour = 2-3 L/day - Interstitial fluid pressure Lymph flow < (-6) mmhg minim (-2) 0 mm Hg maxim (20 fold increase) >1,5 2 mm Hg maxim, constant - Factors that increase lymph flow: - intrinsic: Pc, Pp, Pif, permeability of the capillaries, lymphatic pump (valves & smooth mm.) - extrinsic: skeletal mm contraction, body movements, pulsations of arteries adjacent to the lymphatics, external compression of the tissues - Lymph flow increase 10- to 30-fold during exercise and decrease to almost zero during periods of rest

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40 Roles of the lymphatic system 1. Control the concentration of proteins in IF (prevent the increase in Pif); return the filtered proteins to the blood; 2. Control the volume of IF; 3. Control the pressure of IF (favours the fluid filtration into the interstitium and maintenance of lymph flow). 4. Lymph nodes filter the lymph and removes foreign particles such as bacteria

41 Blood flow through the venous system Blood flow converges in the venules and veins: Smallest venules: -similar to capillaries -thin exchange endothelium, little connective tissue - show a convergent pattern of flow Larger venules: -contain also smooth muscle -drain blood into larger veins Veins: -diameter, volume (hold more then 50% of the blood), -less elastic, more distensible tissue -lie closer to the surface of the body; venipuncture -below the heart there are veins with internal one-way valves -drain blood into venae cave RA (central venous pressure)

42 Blood flow through the venous system Valves create one-way flow in the veins below the heart Chronic excess venous press. venous valve incompetence varicose veins

43 Right atrial pressure - central venous pressure (CVP) - zero pressure reference level: tricuspid valve in a person standing/laying down, at which gravitational pressure factors caused by changes in body position usually do not affect the pressure measurement by more than 1-2 mmhg - CVP depends on: 1) ability of right heart to pump: normally, maintains a decreased CVP, favoring the venous return 2) venous return of the blood from the peripheral veins into the right atrium, directly depends on: - blood volume, - large vessel tone/peripheral venous pressures, - arterioles tone: their dilation decreases the peripheral resistance and allows rapid flow of blood from the arteries into the veins. - RA press.: normal ~ 0 mmhg = atmospheric press. around the body increases ~ mmhg under abnormal conditions (heart failure, massive blood transfusion, which increases blood volume/venous return). decreases up to -3-5 mmhg below atm. press. ~ intrathoracic pressure - when heart pumps with exceptional vigor blood volume decreases/severe hemorrhage.

44 Venous pressure in periphery Resistance to blood flow when large veins are distended is almost zero. Large veins that enter the thorax and the large abdominal veins are compressed at different points by the surrounding tissues blood flow impeded at these points small increase in resistance to blood flow at this level pressure in the more peripheral small veins in a person lying down is usually +4 to +6 mmhg greater than CVP. Compression points between peripheral veins and large central veins: - Rib collapse: in the arm veins, the pressure at the level of the first rib is usually about +6 mmhg because of compression of the subclavian vein as it passes in sharp angulation over this rib. -Atmospheric press. collapse: neck veins of a person standing upright collapse almost completely because of atmospheric pressure on the outside of the neck pressure in these veins remains at zero; also, any press. increase will increase blood flow, any press. decrease will rise the resistance - Abdominal pressure collapse: abdominal veins are often compressed by different organs and by the intra-abdominal pressure (+6 mmhg mmhg).

45 Compression points that tend to collapse the veins entering the thorax.

46 Peripheral venous pressure depends on: RA pressure: - >0 mmhg blood begins to back up in the large veins veins enlargement - rise at +4 to +6 mmhg (e.g., during heart failure) opening of the veins at the collapse points - >+6 mmhg rise in peripheral venous press. in the limbs and elsewhere. Intra-abdominal pressure: - normally up to +6 mm Hg, - can rise to +15 to +30 mmhg (pregnancy, large tumors, excessive fluid in the abdominal cavity/ascites) drainage of the blood from the legs only when the pressure in the veins rise above the abdominal pressure (e.g., if the intra-abdominal pressure is +20 mm Hg, the lowest possible pressure in the femoral veins is also +20 mm Hg). Gravitational/hydrostatic pressure -occurs in the vascular system because of weight of the blood in the vessels -! Also affects arterial pressure in the peripheral arteries and capillaries. In a standing person, for a MAP of 100 mmhg at the level of the heart, the arterial press in the feet is about 190 mmhg

47 Gravitational/hydrostatic pressure Gravitational/hydrostatic pressure occurs in the vascular system because of weight of the blood in the vessels (1 mmhg for each 13.6 millimeters). For a standing person: pressure in the RA remains ~ 0 mmhg (heart pumps any excess blood) pressure in the veins of the feet ~+90 mmhg if standing still at least 30 sec., <+20 mmhg if walking (venous/muscular pump) pressure between 0-90 mmhg at other levels of the body: +40 mmhg in the femoral a., +35 mmhg in the hands ( ) -10 mmhg in the sagittal sinus (hydrostatic suction between the top and the base of the noncollapsible skull cavity; risk of air embolism if sagittal sinus is opened during surgery). after standing still for min., blood volume decreases with 10-20% (fluid leakage, legs swell...)

48 Clinical estimation of venous pressure. -observing the degree of distention of the peripheral veins (neck veins): in sitting position, the neck veins are never distended in the normal quietly resting person, but distend when the RA pressure > +10 mm Hg. Direct measurement of venous pressure and RA pressure (CVP) -by inserting a catheter through the peripheral veins and into the right atrium (central venous catheter) to assess the heart pumping ability. Reference point for circulatory pressure measurement (located at/near the tricuspid valve).

49 Factors involved in venous return 1. Pressure gradient Central venous pressure: RA pressure Venous pressure in periphery: 2. Hydrostatic/gravitational pressure (1 mmhg for 13.6 mm) Body position Standing person: standing still or walking Heart activity: Aspiration pump together with the venous pump/muscle pump