Sem Physio 11 – Sem Physio 11 – Microcirculation; peripheral Microcirculation; peripheral

circulationcirculation

Prof. dr. Željko DujićProf. dr. Željko Dujić

Figure 16-2 Structure of the capillary wall. Note especially the intercellular cleft at the junction between adjacent endothelial cells; it is believed that most water-soluble substances diffuse through the capillary membrane along the clefts. Small membrane invaginations, called caveolae, are believed to play a role in transporting

macromolecules across the cell membrane. Caveolae contain caveolins, proteins which interact with cholesterol and polymerize to form the caveolae.

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Special types of pores in different Special types of pores in different capillariescapillaries

Brain – tight junctions, only small Brain – tight junctions, only small molecules such as H2O, O2 and CO2 flow molecules such as H2O, O2 and CO2 flow easier through Blood-Brain-Barrier (BBB)easier through Blood-Brain-Barrier (BBB)

Liver – even proteins can passLiver – even proteins can pass

Kidneys – fenestrated gromerular Kidneys – fenestrated gromerular endothelial cells endothelial cells

Vasomotion and it’s regulation Vasomotion and it’s regulation

Diffusibility through capillary membrane Diffusibility through capillary membrane (extremes water pearmeability = 1, and (extremes water pearmeability = 1, and albumins; permeability = 0)albumins; permeability = 0)

Figure 16-5 Fluid pressure and colloid osmotic pressure forces operate at the capillary membrane, tending to move fluid either outward or inward through the membrane pores.

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Capillary pressure – direct kanulation 25 Capillary pressure – direct kanulation 25 mmHg, “functional” capillary pressure 17 mmHg, “functional” capillary pressure 17 mmHg (isogravimetric method)mmHg (isogravimetric method)

Venous capillary side is more numerous Venous capillary side is more numerous and more permeable (leaky) than the and more permeable (leaky) than the arterial side, with vasomotion mean arterial side, with vasomotion mean capillary pressure is closer to the pressure capillary pressure is closer to the pressure on the venous side (10 mmHg)on the venous side (10 mmHg)

Micropipete measurement, implanted Micropipete measurement, implanted hollow capsules, cotton wickhollow capsules, cotton wick

Average value – 3 mmHgAverage value – 3 mmHg

Interstitial fluid pressure in tightly Interstitial fluid pressure in tightly encalpulated tissues (although positive still encalpulated tissues (although positive still negative in relation to capsular pressure)negative in relation to capsular pressure)

Plasma colloid osmotic pressure (28mmHg) – 19 mmHg Plasma colloid osmotic pressure (28mmHg) – 19 mmHg caused by dissolved protein and 9 mmHg by caused by dissolved protein and 9 mmHg by Donnan Donnan effecteffect and interstitial fluid colloid pressure (8 mmHg, due and interstitial fluid colloid pressure (8 mmHg, due to 30g/L protein concentration), importance of albumins to 30g/L protein concentration), importance of albumins

Net outward force (filtration) on the arterial side of Net outward force (filtration) on the arterial side of capillaries 13 mmHg and net inward (reapsorption) capillaries 13 mmHg and net inward (reapsorption) pressure of 7 mmHg on the venous side pressure of 7 mmHg on the venous side

Net outward pressure of 0.3 mmHgNet outward pressure of 0.3 mmHg

Filtration coefficient – very small in brain, high in liver Filtration coefficient – very small in brain, high in liver and GI (small intestines) and GI (small intestines)

Lymph channels in the body (exceptions Lymph channels in the body (exceptions brain, bone, endomysium of the muscle, brain, bone, endomysium of the muscle, superficial skin), lymph flow 2-3 L/day, superficial skin), lymph flow 2-3 L/day, lymph pump, reapsorption of fats, bacterial lymph pump, reapsorption of fats, bacterial inactivationinactivation

Lymph flow dependence on the relation Lymph flow dependence on the relation between interstitial fluid pressure and the between interstitial fluid pressure and the activity of lymph pumpactivity of lymph pump

Figure 16-7 Lymphatic system.

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Lymph pump, compression of lymph by Lymph pump, compression of lymph by surrounding tissue pressure (skeletal muscle surrounding tissue pressure (skeletal muscle contraction, arterial pulsation, movement of contraction, arterial pulsation, movement of limbs)limbs)

Lymph capillary pump – endotelial cells in Lymph capillary pump – endotelial cells in lymph capillaries contain contractile lymph capillaries contain contractile actomyosin filamentsactomyosin filaments

Central Venous Pressure (CVP) and lymph Central Venous Pressure (CVP) and lymph return to the right heart return to the right heart

Kidney (22% of resting CO), suprarenal gland, thyroid, Kidney (22% of resting CO), suprarenal gland, thyroid, liver (27% of CO), brain (14% of CO)liver (27% of CO), brain (14% of CO)

Active and reactive hyperemiaActive and reactive hyperemia

Lack of oxygen – high altitude, pneumonia, CO poisoning, Lack of oxygen – high altitude, pneumonia, CO poisoning, cianide poisoningcianide poisoning

Blood flow autoregulation: metabolic and myogenic Blood flow autoregulation: metabolic and myogenic theoriestheories

Metabolic theory – adenosine, H ions, K, CO2, histamineMetabolic theory – adenosine, H ions, K, CO2, histamine

Powerful autoregulation: kidney and brain Powerful autoregulation: kidney and brain

Figure 17-4 Effect of different levels of arterial pressure on blood flow through a muscle. The solid red curve shows the effect if the arterial pressure is raised over a period of a few minutes. The dashed green curve shows the effect if the arterial pressure is raised slowly over a period of many weeks.

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Endothelial relaxation factor: nitric oxide (NO), effect on Endothelial relaxation factor: nitric oxide (NO), effect on “upstream” resistance arteries in certain volume (volume “upstream” resistance arteries in certain volume (volume transmission), tangential shear stress of the endothelial transmission), tangential shear stress of the endothelial cells, fast inactivation (short term regulation)cells, fast inactivation (short term regulation)

Long term regulation of blood flow is much more Long term regulation of blood flow is much more complete than acute regulation (all acute mechanisms complete than acute regulation (all acute mechanisms fullfill only ¾ of tissue requirements)fullfill only ¾ of tissue requirements)

The role of oxygen (high altitude) and neoangiogenesis: The role of oxygen (high altitude) and neoangiogenesis: retrolental fibroplasia and increased tissue vascularity retrolental fibroplasia and increased tissue vascularity (plasticity, functional adaptations)(plasticity, functional adaptations)

Figure 17-5 Nitric oxide synthase (eNOS) enzyme in endothelial cells synthesizes nitric oxide (NO) from arginine and oxygen. NO activates soluble guanylate cyclases in vascular smooth muscle cells, resulting in conversion of cyclic guanosine triphosphate (cGTP) to cyclic guanosine monophosphate (cGMP) which ultimately causes the

blood vessels to relax.

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Nitric Oxide (NO)Function

VasodilatorVasodilator Inhibitor of vascular smooth muscle cell Inhibitor of vascular smooth muscle cell

proliferationproliferation Inhibitor of platelet adherence/aggregationInhibitor of platelet adherence/aggregation Inhibitor of leukocyte/endothelial interactionsInhibitor of leukocyte/endothelial interactions

Endothelin-1(ET-1) Peptide first sequenced in 1988Peptide first sequenced in 1988 Most potent vasoconstrictor in humansMost potent vasoconstrictor in humans

Maintenance of basal arterial vasomotor toneMaintenance of basal arterial vasomotor tone

Strong chemoattractant for circulating monocytes Strong chemoattractant for circulating monocytes and macrophage activation and macrophage activation “proatherogenic”“proatherogenic”

Endothelial Dysfunction

Imbalance of endothelium-derived relaxing Imbalance of endothelium-derived relaxing and contracting factorsand contracting factors

Atherosclerotic risk factors

Decreased NO bioavailabilityIncreased levels of ET-1

Vascular endothelial growth factor (VEGF), Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), angiogenin fibroblast growth factor (FGF), angiogenin – increase angiogenesis, steroid hormones – increase angiogenesis, steroid hormones have negative effect have negative effect

Vascularity is determined by a maximal Vascularity is determined by a maximal blood flow and not by the averageblood flow and not by the average

Colateral circulation – 60. year old human Colateral circulation – 60. year old human

Figure 17-6 Large increase in the number of capillaries (white dots) in a rat anterior tibialis muscle that was stimulated electrically to contract for short periods of time each day for 30 days (B), compared with the unstimulated muscle (A). The 30 days of intermittent electrical stimulation converted the predominantly fast twitch, glycolytic

anterior tibialis muscle to a predominantly slow twitch, oxidative muscle with increased numbers of capillaries and decreased fiber diameter as shown. (Photo courtesy Dr. Thomas Adair.)

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Humoral mediators: vasoconstrictors: epinephrine Humoral mediators: vasoconstrictors: epinephrine and norepinephrine (alpha i beta effect), and norepinephrine (alpha i beta effect), angiotensin II, vasopressin (physiologically only angiotensin II, vasopressin (physiologically only ADH), endothelinADH), endothelin

Vasodilators: bradykinin (alpha-2 globulin formed Vasodilators: bradykinin (alpha-2 globulin formed by liver, enzyme kalikrein, kalidin and bradykinin by liver, enzyme kalikrein, kalidin and bradykinin products, inaktivation by carboxypeptidase – the products, inaktivation by carboxypeptidase – the same enzyme activates AII) and inflammation, same enzyme activates AII) and inflammation, salivary glands, skin; histaminesalivary glands, skin; histamine

Increased calcium – vasocontrictionIncreased calcium – vasocontriction Increased potassium - vasodilatationIncreased potassium - vasodilatation Increased magnesium – strong vasodilatationIncreased magnesium – strong vasodilatation Acidosis – vasodilatation, small reduction Acidosis – vasodilatation, small reduction

vasoconstriction, larger reduction vasodilatationvasoconstriction, larger reduction vasodilatation Increased CO2 – vasodilatation, direct, indirect Increased CO2 – vasodilatation, direct, indirect

vasoconstriction due to increased central vasoconstriction due to increased central sympathetic activity (basal activity 1-2 Hz)sympathetic activity (basal activity 1-2 Hz)