Lecture 5 Microcirculation

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*We will do lots of therapy on microcirculation.
*We will do lots of therapy on microcirculation.
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===Objectives===
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*Lots of them
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===Rat===
===Rat===

Revision as of 02:58, 24 October 2013


  • Prof loves this material.
  • We will do lots of therapy on microcirculation.

FIUXHR I really enjoy the article.Really thank you! Want more.

Contents

Rat

  • All the color is due to Hb so you can see how much microvessel there is.

Images

  • Very small.

Slingback shoes

  • Diabetic pt wearing slingbacks.
  • Blister occurs because of compression of microvessels.
  • Tissue dies.
  • Skin graft needed.

Overview

  • Energy of pressure is disipated in return for flow in the microvessels
  • Typical cap pressure is around 20-25 mmHg.
  • Pressures drop off even more in venules.
  • 20% of resting blood volume in arteries.
  • 5-10% in microvessels.
  • 75% in veins.
  • Blood doesn't stay in microvessels very long.
    • circulation time in organs is fast: 1-2 seconds.
    • In the heart, in the coronary vessels to the venous system = 2-3 seconds.
    • Gut is a little slower because vasculature is more complicated.
  • Exchange takes place in arterioles, caps, and venules.
  • Lymphatic system is required to clear leaked plasma proteins and water to the blood again.

Image

  • Arteriole are smaller than venules
    • Can be smaller because the pressure is higher.

Synthesis

  • Endothelial cells, with smooth muscle and connective tissue.
  • Smooth muscles change muscle diameter.

Image

  • Smooth musc of vessels are constantly changing; called vasomotion.
  • Leukocytes have to squeeze through capilaries.
    • Once through they are a little activated, so they sometimes stick to the wall around them.

Capillaries

  • Endothelial tube with a bm and some parasites.
  • Most species have cap diameters smaller than rbc diameter.
    • Must bend.
  • Venules
    • Same as arterioles but bigger.
    • Vascular smooth muscle cells are less developed b/c pressure is lower.
    • Leak larger molecules easily.
      • Important for things liek albumin and globulins and WBCs (diapedes).

Vascular smooth

  • If you lower the pressure in a vessel, the vessel will relax to get bigger.
    • You don't even need flow to make this happen, just pressure.
  • If you let the pressure come up, the vessel will constrict.
  • So thre is some sensing of the tension in its wall.
  • The brain is really good at this, thus we can bend over without fainting.
  • Vessel gets smaller and increases resistance as the pressure goes up.

Mechanisms

  • The more stretch there is, the lower the membrane potential.
  • Normally smooth muscle sits at around -40 mV.
  • If you take the tension out of the membrane, the cell hyperpolarizes.
    • Hyperpolarized cells will have Ca go down because voltage gated channels won't open because the voltage won't be met. Also there are ca pumps moving ca out (as is the case in any state).
  • When stretched, Ca goes up.
    • First the membrane potential changes and then the ca goes up.
  • You don't have to have endothelial cells by the smooth muscle cells to get this to work.
    • So this is inherent to the smooth muscle cells.

Possible cellular mechanisms...

  • We think:...
  • Smooth muscle cell cytoskeleton is anchored to ecm by integrins
  • When cell or ecm moves, there is tension on the integrins.
  • When this happens,
    • TRP channels might open up and let Ca come in and activate the cell.
    • Na may leak in to depolarize the cell which would cause Ca channels to open.
  • We know, though, that the cell has to be attached to its environment and that Na channels and Ca channels are involved.
  • We also know that Ca goes up and the cell reacts.
  • Ultimately we turn on Phospholipase C.
    • This might be activated by Ca going up
    • This mibht be activated simply by stretching of membrane.
  • PLC chews up lipis and rleases diacylglycerol DAG.
  • DAG turns on PKC
  • PKC turns on everything that has to do with contraction
    • Ca gets released from SR
    • Membrane ca channels open
    • M and a get expressed
  • IP3 is also made (wht DAG)
    • It slows reuptake of Ca
  • Medical importance:
    • Routine hypertension treatment is blocking of Ca channels.
    • This is effectively shutting down the smooth muscle reaction in microvessels to there is less constriction.
    • These also decrease contractility in the heart.

Flow chart of mechanisms

  • Myogenic response is very fast and reacts to tension before stretch even occurs.
  • Myogenic response can be surpressed and this is important when we need more blood flow, like when running or injured.

Flow chart 2

  • If we lost our sympathetic nervous control, it would be hard to sit in a chair:
    • BP would drop
    • HR would go up
    • Heart contractility would plunge
  • Sympathetic can raise vascular resistance.
  • Skeletal muscle is barely alive when not in use; gets very little blood flow.

Image

  • Sympathetic nerves put NE on arteriole and it constricts quickly.
  • Only delivered at several locations; gap jxns communicate down the vessel.

Flow

ACE inhibitors

  • Capsopril, blocks ACE to angiotensin I cannot be converted to angiotensin II.
  • This means we reduce constriction, reduce resistance, reduce bp, reduce water retention, reduce stroke volume, increase venous pressure.
  • Angiotensin II activates PKC in smooth muscles.
  • Angiotensin II also destroys bradykinin (a potent vasodilator).
    • So vascular resistance goes down.
    • More bradykinin is floating around.


  • stopped here on 01/21/11 at 12PM.
  • started here on 01/24/11 at 11AM.


  • Angiotensin is a hormone-like agent that helps activate smooth muscle in vasculature.

Endothelial dependent regulation

  • NO is important.
  • It is a potent vasodilator.
  • Car engines produce it, too, thus we have the catalytic converter.
    • It is toxic so we have to convert it so something slightl less bad.
  • If NO is blocked, vascular resistance goes up by 20-25%.
  • We must have helathy epithelial cells to have neough NO.
  • We have to have arginine.
    • We can make our own, but it may be that adding arg to the diet of unhealthy people can help them lower their blood pressure.
  • Arginine reactins with eNOS (epithelial nitric oxid synthase) to generate NO.
  • Then NO goes to the smooth muscle cell to increase cGMP to relax the muscle cell.

Muscle video

  • This time our micropipette releases ach.
  • There is very rapid dilation.
  • This is an example of hyperpolarization.

Endothelial cell and OS

  • eNOS lives int he calveoli (little pits) of endothelial cells.
  • Ca up, eNOS fxn up, NO up,
  • What an cause Ca to go up:
    • shear stress (mechanical)
    • NaCl hyperosmolarity (kidney, SI when eating)
      • Na comes into the cell, gets exchanged for Ca, intracellular Ca is up.
    • One more

Actions of NO on vascular smooth muscle cells

  • NO goes to smooth muscle cell
  • REacts with soluble guanyly cyclase
  • Makes cGMP
  • cGMP Inactivates smooth msucle:
    • Blocks PLC (DAG and IP3 decreased, Ca+ influx decreased)
    • Stimulates ca channels (increases ca efflux)
    • Activates Phospholambam (turns on SR transproter so ca is moved into SR)
    • Blocks inositol triphosphate ...
  • Ca levels drop in the smooth muscle cytoplasm

Turning on eNOS

  • We are adding more and more activations.
  • Bradykinin
    • Routinely in the blood
    • Released by sweat glands, mast cells
    • Potent increaser of eNOS activity
  • Ach
    • Broken down very quickly
    • Activates PLC turns on a little DAG
      • At low levels DAG turns on eNOS
      • At high concentrations, DAG turns off eNOS
  • Norepinephrine
    • Turns on eNOS, a little
  • Serotonin
    • Invloved in clotting vai paracrine activity
    • Turns on eNOS 
*Missed one here
  • EDRF (endtothelial derived relaxing factor)
    • Toxic
    • No one believed this was a blood pressure reducing medicine.
    • Very potent
    • Pts with bad lipids have sick endothelial cells that make less NO, so the smooth muscle cells near them start dividing.
      • This can result in foam cells that generate plaques.
      • We don't want smooth muscle cells to proliferate.
  • Low oxygen
    • Increases NO
  • Flow drag
  • Potassium


  • NO effects:
    • Scavages oxygen radicals; combines with radicals to make nitride (pretty safe) and nitrate (very safe)
      • Sometimes NO + radical = oxynitrite, a very dangerous radical.
    • Decreases attachment sites for platelets and leukoctyes on vessels.

Measuring NO

  • "this is just for fun"
  • Measuring NO by an arteriole

Image

NO suppression

  • Oxygen radical damage of endothelial cells can decrease NO production.
  • Sources of oxygen radicals:
    • Upon allergic resonse, there is lots of oxygen radicals from inflammatory response.
    • Trauma
    • Hyperglycemia
      • This leads to excessive PKC activation because of high lipid levels
    • Poor diet with lots of oxidized lipids

Viagra

  • Inhibit the supression of PKC to decrease DAG.

Potassium channels

  • Usually when a potassium channel is turned on it makes the vessel dialate.
    • K flows outward.
    • This makes the cell hyperpolarized.
  • Cells can also communicate with each other so neighbors may become hyperpolarized, too.

Complicated version

  • Green is vascular smooth muscle
  • There are gap jxns between endothelial cells and the vascular smooth muscle cells.
    • So they share membrane electrical states.
  • When one opens thier K channel, both end up hyperpolarized.
  • Hyperpolarized enodthelial cells tend to leak ca (whereas msucle cells don't).
    • So ca in endothelial cells have ca increase so NO is made, so smooth muscle cells relax more.
    • So this increases relaxation.

Relaxation stimuli

  • If K goes up in ECF, (from 3 to 5 or 8 mM) there is dilation; at 10mM or higher causes constriction.
    • These are called potassium sensitive potassium channels: KIR.
    • As muscles are used and release K upon working, K of ECF goes up and surrounding vessels dilate.
    • This occurs in the brain, too.
  • A drop in ATP in endo or sm cells can open an ATP sensitive K channel. some will argue that when you have less ATP, you have more ADP and the K channel is ADP sensitive.
    • This is a way for a cell to monitor it's metabolism.
    • When you have low ATP or high ADP you need mnore oxygen.
  • BK channels
    • These are k channels that are sensitive to ?
    • As Ca leaks in BK channels open to let K out.
    • These prevent the cell from overcontracting.
  • Three good ways to close the K channels: nor-e, angiotensin, and PKC

Example

Prostaglandin

  • There are two categories: vasodilators and vasoconstrictors.
  • How do they work?
    • Flow through the vessels causes activatino of phospholipase A to rlease aa form the cell membranes
  • Got a bit lost here.

Very potent supppression of prostaglandin synthesis...

  • Vioxx shows that prostaglandins are import

Vaoscontricting prostaglandins

  • Thromboxane is most important.
    • Comes out when tissue is traumatized.
    • Most released pgs are constrictors
  • Hyperglycemia and oxygen radical damage can release these prostaglandins, too.
  • We can give cyclooxygenase activity following injury may be useful.
    • Broken leg example

Endothelin

  • This is a very potent vasoconstrictor.
  • Body makes very small amounts (femtomolar).
  • AKA end of the line
  • Found at high concentration when things are really bad.
  • It starts inactive and gets cut into activated form.
  • Activates PLC to increase DAG and IP3
  • Also activates PKC
  • Released b/c of:
    • Injury: TFG beta,, IL I, TNF, Thrombin
      • All of these hurt cells
      • Thrombin is the major cause
      • must be clipped to become active
    • Angiotensin II and vasopressin
    • Mechanical stimulation
      • Extreme vibration injury
  • Good way to reduce blood flow in an injury to stop blood loss.
  • Low physiological release of endothelin is minorly helpful because it releases NO.

Manifestations of microvascular control

  • In the 40s, we started workingon animals.
  • We coined "autregulation of blood flow".
  • We saw that if you clamp of some artery and an organ's bp would drop but then would raise again.
    • Like clamping hepatic artery, goes down, then goes up in liver.
  • So an organ has an intrinsic ability to regulate it's own blood flow.
  • Sympathetics can screw with this ability.
    • Though, brain and heart override this.

Flow chart

Reactive hyperemia

  • Example: standup after stting for a bit and there is large blood flow to the butt


  • stopped here on 01/24/11 at 12PM.
  • started here on 01/25/11 at 11AM.


Functional hyperemia

  • We have to be able to increase or decrease our oxygen supply to parts of the body as we ask them to do what they do more or less.
    • this is one reason to have a CV system it is called functional hyperemia.
    • nice term for increasing blood flow when we need an organ to do what it does.
    • eat: gi blood flow increases
    • run: muscle blood flow increases
  • Functional hyperemia in the brain:
    • close your eyes, blood flow in occiptal cortex goes down 10-20% because you're not processing
    • when you speak, the area of the brain for speech increases blood flow
    • Not a lot of change in the brain in general, though.
  • Most organs can change blood flow huge-time.
  • Oxygen delivery depends on oxygen extraction, too.
  • So we can change both the oxygen extraction and the blood flow if we want to change the amount of oxygen an organ receives.
  • Blood oxygen content is pretty much constant
    • Unless lungs, air, or blood are borked.
  • Oxygen extraction in muscle can double or tripple.
    • Same with gut.
  • Heart and brain, at rest, already extract up to 75% of the oxygen in the blood, though, so flow will be more important when increasing supply.
  • Heart can increase oxygen about 5 times, but skeletal muscle can increase 20 to 40 times!

Major characteristics of regional...

Probabe mechanisms involved inc coronary vascular regulation

  • Knocking out NO, not much goes wrong in mammals.
  • When adenosine is given, it causes vasodilation.
    • It also lowers their contractility
    • Its an amino acid
    • It increases glucose metabolism
  • Prostaglandins aren't super important in the short term, but may be impt in the long run.
    • Aspirin blocks.
  • Sympathetics also control coronary vasculature
    • Norepi will dilate the arteries.
    • Epi from the adrenal medulla causes arteries and arterioles to dialate
  • Blocking beta receptors
    • These must calm the cardiac muscle without inhibiting the smooth muscle.

Cerebral vasculature

  • Many vessels, richly innervated by sympathetics.
  • Mostly ignores the sympathetics.
    • However, when damaged, the vasculature will deteriorate
      • Stroke, poor permeability regulation
  • To increase oxygen to blood, you have to increase blood flow.
    • Venous blood has low oxygen saturation.
  • Sympathetics have little constrictor effect on cerebral vessels
  • Very responsive to dioxide, oxygen, and pH
    • NO is increased in this situation.
    • Brain has two forms of eNOS; they both respond to these three regulatory mechanisms
  • Has myogenic control
  • How does blood pressure change the resistance of the vessels?
  • BBB

Small intestine

  • Approximately 20% of cardiac output and 20% of resting oxygen consumption
  • Blood flow and oxygen use can increase 80-100% during digestion
  • Resting resistance dominated by sympathetic nervous system
  • Absorptive hyperemia mechanisms
    • Sodium hyperosmolarity to form nitric oxide is dominant mechanism
    • Oxygen depletion in mucosal layer related to about 20% of absorptive hyperemia


  • stopped taking notes about 5 slides back.


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