THE MICROCIRCULATION

THE MICROCIRCULATION

CAPILLARY FILTRATION AND RESORPTION: STARLING PRINCIPLE FOR CAPILLARY EXCHANGE:

• Filtration: Blood leaving capillary and entering organ. Net flow outward.
  • P_c, capillary hydrostatic pressure contributes to this outflow.
  • PI_i, interstitial oncotic pressure contributes to this outflow. It is the oncotic (osmotic) pressure created by insoluble proteins in the interstitial space.
  
  
  
• Absorption: Blood leaving organ and entering capillary. Net flow into capillary.
  • P_i, interstitial hydrostatic pressure, does not contribute to absorption under normal circumstances. It is ~ 0.
  • PI_p, capillary oncotic pressure, is the primary contributor to resorption. This is the osmotic pressure created by insoluble proteins in the blood.
• sigma, REFLECTION COEFFICIENT: It is equal to the percentage of proteins that are impermeable to the capillary membrane, i.e. a value between 0 and 1.
  • sigma = 1: Proteins are totally impermeable; all of them are "reflected" off the membrane, thus oncotic pressure has the greatest influence possible on net filtration.
  • sigma = 0: Proteins are completely permeable, hence no proteins are impermeable and oncotic pressures become zero.
    • Low reflection coefficient affects resorption but not so much filtration, since the capillary oncotic pressure is the only significant force for resorption.
    • RESULT: Edema.
• Lymphatics: Under normal circumstances, filtration is greater than absorption. Thus more blood is being deposited in organ systems than is being taken up. The difference is put back into the blood through the lymphatic system.
  • The entire blood circulation is turned around through the lymphatic system every 24 hrs.
• Capillary Hydrostatic Pressure:
  • R_a = arterial resistance is normally much larger than venous resistance. We can usually safely ignore venous resistance in the calculation.
  • P_v = venous pressure
  • P_a = mean arterial pressure
• INFLUENCES ON FILTRATION:

• ARTERIOLAR RESISTANCE: Note that local(arteriolar) changes to vascular tone have an exact opposite effect as systemic (large artery) changes.
  • All things constant, increased arterial resistance ------> lower capillary hydrostatic pressure + lower filtration
  • Vasoconstriction or dilation at the level of the arterioles does not affect MABP.
  • Arteriolar Vasoconstriction ------> ------> lower filtration rate.
  • Arteriolar Vasodilation ------>------> higher filtration rate.
• VENOUS PRESSURE: Increased Venous Pressure ------> Higher Capillary Hydrostatic Pressure ------> Increased Net Filtration, because of the hydrostatic pressure equation:
  • The capillary pressure must increase in order to achieve filtration in face of the increased venous pressure.
• ONCOTIC PRESSURE: Negative nitrogen balance or protein malnutrition (kwashiorkor) will lead to low plasma albumin ------> low plasma oncotic pressure ------> low or no resorption, which means high net rate of filtration ------> edema, ascites

CAPILLARY PERMEABILITY:

• Three types of capillaries, each having different levels of permeability:
  • Continuous: Tight Junctions, as in brain, thymus, retina.
  • Fenestrated: Little diaphragms where diffusion can take place, having somewhat higher permeability. GI-Tract.
  • Discontinuous: Liver sinusoids, complete discontinuities in the system.
• Endothelial Cells: When endothelial cells contract, the spaces between them increase ------> higher capillary permeability.
  • Mast Cell Degranulation leads to release of Histamine and Platelet-Activating Factor (PAF).
  • This makes the endothelial cell release Calcium from the SR ------> actin-myosin contraction of endothelial cell makes the cell change shape ------> more spaces between the cells.
• Anaphylactic Shock: High capillary permeability leads to low blood pressure. We can't just give them fluids to increase blood volume, because the fluids leak right out again.

EDEMA: It can occur from a lot of sources, such as no resorption. Consequences of edema:

• Impair Exchange of Metabolites: It leads to bigger spaces (longer distance) between capillaries and the tissues ------> diffusion becomes impossible.
• THE EDEMA POSITIVE-FEEDBACK CYCLE: Edema can compress venules ------> higher venous return ------> higher CVP ------> higher hydrostatic pressure and filtration rate ------> even more edema.

LYMPHATIC BLOCKAGE: If you block lymphatics, then interstitial fluid along with interstitial proteins will rise ------> increase interstitial oncotic pressure ------> more filtration ------> massive edema.

VASCULAR SMOOTH MUSCLE: Anything that increases intracellular Ca⁺² concentration will increase contractility of vascular muscle.

• VASCULAR CONTRACTION:
  • Mechanism of Contraction, briefly:
    • Calcium binds to Calmodulin
    • The Ca⁺²-Calmodulin Complex then binds to Myosin Light-Chain Kinase
    • This results in myosin being free to interact with actin.
  • Vascular Tone: The overall rate of cross bridging is much slower than in vascular smooth muscle. There is always a baseline level of activity = vascular tone.
  • Norepinephrine will cause vascular contraction by increasing Ca⁺² in smooth muscle, via three pathways:
    • NorE can directly open Ca⁺²-Channels
    • NorE can bind to alpha1-Receptors to active the alpha-Adrenergic Pathway (DAG/IP₃) ------> higher intracellular Ca⁺²
    • Voltage-Gated Ca⁺² Channels can further open, in response to the above two.
• VASCULAR RELAXATION: Anything that decreases Ca⁺² concentration will cause relaxation.
  • Epinephrine in the blood causes vascular relaxation.
    • Epi binds beta2-Receptors to activate beta-Adrenergic Pathway ------> higher levels of cAMP which results in decreased Ca⁺² in cytosol.
      • cAMP will facilitate pumping of Ca⁺² back into SR.
  • ATP: Low levels of ATP will cause vascular relaxation locally, which should allow greater blood flow, greater perfusion, and hence more ATP to deprived tissue.
    • ATP-Dependent K⁺-Channels open in response to LOW ATP.
    • This leads to Hyperpolarization ------> Vascular Relaxation ------> greater blood flow to area.
  • NO causes relaxation, covered later.
• VASOMOTION: Spontaneous action potentials can cause a cyclic change in vascular tone.
  • Addition of NorEpi increases the rate of firing of those action potentials ------> more vascular tone.
  • However, action potentials are not always required to cause sustained contraction.

ENDOTHELIAL-DERIVED FACTORS: Nitric Oxide

• EXPT: Acetylcholine's (i.e. parasympathetic) effect on vessels depends on the presence of the endothelial cells.
  • Add Ach to vessel with endothelial cells intact ------> relaxation.
  • Add Ach to vessel with endothelial cells removed ------> actually leads to contraction!
• Process of NO-Mediated Vascular Relaxation:
  • Ach binds to endothelial cell.
  • Ca⁺² channels open and Ca⁺² pours into endothelium.
  • This makes the endothelial cell produce NO from Arginine, by up-regulating synthesis of the enzyme Constitutive NO-Synthase.
  • Endothelium makes NO which diffuses to the underlying vascular smooth muscle.
  • NO then activates Guanylyl Cyclase, which produces cGMP ------> leads to Ca⁺² sequestration and vascular relaxation.
• L-Nitroarginine Methyl Ester (L-NAME): Inhibits NO-Synthase, blocking production of NO ------> arteriolar constriction ------> lower blood flow to region.
• ISCHEMIA-REPERFUSION: The danger in reperfusing ischemic tissue is that massive influx of O₂ can lead to oxidative free radicals which damage endothelial cells. The free radicals have two bad effects:
  • They react with NO, leading to vasoconstriction and reduced perfusion of the area.
  • They directly damage the endothelial membrane leading to increased vascular permeability which isn't good (it can lower blood pressure, etc.)
• SEPSIS: Causes vesicle to become less sensitive to vasoconstriction. Phenylephrine has a lesser effect on septic vessels.
  • It leads to higher NO via Inducible NO-Synthase. This is not the same enzyme as constitutive NO-Synthase.
  • The number of vasoconstrictive alpha-Receptors is decreased.
  • Basal Ca⁺² levels are reduced or Ca⁺²-channels don't open properly.
• ADHESION MOLECULES: NO protectively prevents expression of adhesion molecules, so that leucocytes don't stick to vessel wall, which can lead to microvascular injury.
  • Hence we can't use L-NAME as a treatment for Sepsis -- we need the NO to prevent sticking of blood cells, even if vasodilation is an undesired effect.
  • What we need is a drug that blocks only Inducible NO-Synthase (made during sepsis) and not constitutive NO-Synthase. We don't have that (yet).

ENDOTHELIN-1: Vasoconstrictive agent produced by endothelial cells.

• SLOW-RESPONSE: Endothelin is not stored in vesicles. It is synthesized de novo. Thus it is a slow (long-term) response.
  • SYNTHESES: Preproendothelin ------> Big Endothelin ------> Endothelin. Multi step synthesis adds to slow response.
• EFFECT: Endothelin causes sustained vasoconstriction. The effect lasts long! It causes increased levels of Ca⁺² and thus increased vascular tone.
  • It acts via alpha-adrenergic pathway (PIP/DAG ------> Ca⁺²)
  • It also acts directly on Ca⁺²-Channels.
• ISCHEMIA REPERFUSION: Endothelin is bad! It can be released along with inflammatory mediators to cause further vasoconstriction when we want vasodilation.

LOCAL REGULATION OF BLOOD FLOW:

• 
• We control local blood flow by changing local resistance.
• Three factors can change local resistance:
  • Endothelial-Derived Factors
  • Mechanical Stretch of the vessel itself
  • Intrinsic Factors = locally derived metabolites
• Organ-Distribution of Blood Flow: Highest perfusion rates are in liver, kidney, and skeletal muscle.
  • Kidneys have the highest Perfusion Index: The ratio of perfusion to organ size. It measures the relative amount of blood that different organs get per organ mass.
• OXYGEN UPTAKE:
  • To increase Oxygen Uptake by tissues, you can therefore increase one of two things. Most organs increase O₂-uptake by a combo of both things.
    • Increase O₂ extraction. This is how the KIDNEYS primarily get more oxygen.
    • Increase blood flow. This is how the HEART primarily gets more oxygen. The heart can't increase O₂-extraction because it is already extracting about the maximum amount possible.
  • O₂-Extraction = Arterial PO₂ - Venous PO₂
    • Oxygen is extracted by simple diffusion.
    • To increase oxygen extraction, increase the surface area of capillaries exposed to tissue.
      • Heart-Muscle has a high basal capillary concentration than skeletal muscle. Thus it has higher oxygen extraction.
    • Pre-Capillary Sphincters can be dilated to perfuse more capillaries in the capillary bed.
  • Specific Organs:
    • HEART: It has a high oxygen extraction, so the only way to increase O₂ uptake is to increase blood flow.
    • KIDNEY: It has a lower oxygen extraction. It can actually increase O₂ extraction to increase O₂-Uptake.

AUTOREGULATION:

• Mechanism: Keep constant flow and capillary pressure (i.e. filtration) in the face of changing systemic pressures.
  • Lower local pressure ------> Vasodilate ------> lower resistance ------> maintain higher flow and higher capillary pressure.
  • Higher local pressure ------> Vasoconstrict ------> higher resistance ------> maintain lower flow and lower capillary pressure
• Tissues: Autoregulation works particularly in the kidney, heart, and brain.
• Limits: Autoregulation only works in a limited range of pressures. Vessels won't change diameter past their minimum and maximum.

MYOGENIC RESPONSE: Sudden stretch of vascular wall can lead to vasoconstriction to counteract the higher blood-volume. Works in conjunction with the metabolic response to maintain blood flow.

• There are two types of arterioles:
  • One produces Action Potentials to have rhythmic vasoconstriction (vasomotion)
  • The other type does not produce action potentials.
  • Both types are still subject to the myogenic response.
• Mechanism:
  • AP-Capable Arterioles: Stretch ------> increased frequency of AP-firing ------> higher vascular tone.
  • AP-Incapable Arterioles: Stretch ------> depolarization of vascular smooth muscle ------> Ca⁺² influx and higher vascular tone.

METABOLIC RESPONSES: Works in conjunction with the Myogenic Response to maintain blood flow.

• METABOLIC HYPOTHESIS: Vasodilator Metabolites are made locally in response to hypoxia and poor blood flow, in order to increase blood flow. The metabolites are then washed away when blood flow increases again, disposing of their effect.
• HYPOXIA: Hypoxia leads to a decrease in intracellular ATP, which ultimately leads to vasodilation.
  • K⁺-ATP CHANNELS: They kick K⁺ out of the cell in exchange for bringing ATP in. They open in response to low ATP levels.
  • Hypoxia ------> low intracellular ATP ------> Open K⁺-ATP Channels ------> K⁺ pours out of cell ------> membrane hyperpolarizes ------> smooth muscle relaxation.
  • PROSTACYCLIN (PGI₂): Prostacyclin may be released by endothelial cells in response to hypoxia ------> potent vasodilation in a paracrine manner no neighboring smooth muscle.
• ACIDOSIS: Acidosis in smooth muscle directly causes hyperpolarization of smooth muscle membrane ------> vasodilation.
  • Acidosis means CO₂ levels in tissue are high.
  • CO₂ <====> H₂CO₃ <====> H⁺ + HCO₃^-
• ADENOSINE: Adenosine is an indicator that the target tissue is out of ATP (as opposed to the smooth muscle itself).
  • Adenosine is membrane-soluble while ATP, ADP, and AMP are not. So when the compounds gets down to the Adenosine level, it can then leave the cell to affect the neighboring smooth muscle.
  • Adenosine is a potent vasodilator.
• AUTOCOIDS: Histamine, Bradykinin, Serotonin, Prostaglandins, Leukotrienes.
• POTASSIUM: Potassium regulation is especially important in the brain and in skeletal muscle.
  • SMALL AMOUNTS OF K⁺
    • In both tissues, extracellular K⁺ concentration goes up because of repeated firing of action potentials.
    • This results in release of vasodilator-factors (NO, PGI₂) and in membrane hyperpolarization of vascular smooth muscle.
  • HUGE (PHARMACOLOGICAL) INCREASE IN K⁺ ------> depolarization of muscle membrane ------> vasoconstriction.
• INTERSTITIAL OSMOLARITY:

ACTIVE HYPEREMIA: Blood flow changes in proportion to changes in metabolic activity of the organ. Occurs in Skeletal Muscle.

• Lactic Acidosis in skeletal muscle ------> Vasodilation of vasculature.
• In Active Hyperemia, the metabolic activity of the target tissue (i.e. skeletal muscle) is changing, and that's what causing the vasodilation.

REACTIVE HYPEREMIA: The short-term increase in flow following temporary ischemia to a region.

• Both myogenic and metabolic effects are playing a role in causing the vasodilation.
• In reactive hyperemia, the metabolic activity of the target tissue does not change, whereas in active hyperemia, it does.

REGIONAL CIRCULATIONS:

• CEREBRAL CIRCULATION:
  • Cerebrospinal Fluid: Normally has a lower protein content than blood.
  • Cerebral Vasculatures have very poor sympathetic innervation. Hence in the Cushing Reflex, massive sympathetics don't cause constriction of vessels in the cerebrum (which they shouldn't!)
  • Regulation of Flow: It is primarily K⁺-Mediated. We can get higher extracellular K⁺ and vascular hyperpolarization by two sources:
    • Firing of neurons without repolarization.
    • K⁺-ATPase kicks out K⁺ in exchange for ATP, at low intracellular ATP levels.
  • The brain is very sensitive to changes in PCO₂, but not so much to changes in PO₂.
• CORONARY CIRCULATION: Regulated almost entirely by local factors.
  • Increase cardiac work ------> increased coronary blood flow.
  • SYSTOLE: Coronary blood flow decreases, as the vessels are squeezed as the myocardium contracts.
    • There may even be some retrograde flow of blood during systole.
  • DIASTOLE: Coronary blood flow increases.