Physio Neural Reg of Arterial BP/Microvascular Circulation (18/19)

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  1. Lecture 18 - Neural Regulation of Arterial Blood Pressure
  2. What is the major system involved in the neural regulation of arterial blood pressure?
    • the reflex pathway, composed of:
    • sensor: baroreceptors
    • integrator: CNS (medulla)
    • effector: heart & blood vessels
  3. Baroreceptors
    • bare nerve endings mainly in the outer elastic lamina of the aortic arch & carotid bifurcation
    • areas in which they're concentrated are called sinuses
    • respond to distortion (changes in BP) by changing their firing frequency
    • when arteries are stretched → firing frequency ↑
    • they project via sensory (afferent) nerves IX & X to the medulla for CNS integration
  4. Baroreceptor Action Potentials
    • baroreceptors have a range within which they're effective: when mean arterial pressure (MAP) is between 75-125 mmHg
    • within that range adaptation can occur during systole & firing decreases
    • if MAP rises too high, b.receptors will not cease firing - there's no attenuation/adaptation & signals occur rapidly throughout a beat (no longer useful)
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  5. How does pulse pressure affect the baroreceptor firing rate?
    the greater the pulse pressure, the more frequently b.receptors fire (greater frequency w/ higher pulse pressures)
  6. What happens to sympathetic nerve impulse frequency as carotid sinus nerve impulse frequency increases?
    • carotid sinus nerve impulse = baroreceptors
    • as their frequency increases, sympathetic nerve impulse frequency decreases
    • sympathetic nerve impulses to the heart increase heart rate & contractility (SNS stimulation), so if baroreceptor firing increases, indicating an increase in BP, SNS stimulation should be down regulated (lower the BP)
  7. Measuring Blood Pressure Indirectly
    • measured using a brachial artery
    • the artery is blocked: when the artery 1st opens that corresponds to systolic BP; when the artery is almost completely open that corresponds to diastolic BP
    • progression:
    • no sound → systolic (1st sound heard) → Korotkoff's sounds → diastolic (sound disappears)
  8. Korotkoff Sounds
    turbulent flow through partially opened artery
  9. Coronary Circulation
    • the circulation of blood in the blood vessels of the heart muscle (myocardium)
    • coronary arteries are the vessels that deliver O2-rich blood to the myocardium
  10. What must there be for cardiac muscle to function properly?
    balance between oxygen demand & oxygen supply
  11. What is oxygen supply dependent upon?
    • 1. oxygen content of blood (dependent largely on amount of hemoglobin in blood)
    • 2. coronary blood flow
  12. What is oxygen demand dependent upon?
    • 1. heart rate
    • 2. ventricular wall stress: the force acting on
    • myocardial fibers that causes them to want to push outward (↑ ventricular wall stress → O2 demand ↑)
    • 3. inotropic state/contractility (a positive ionotropic effect → ↑ O2 demand)
  13. What is the only means of increasing O2 delivery to myocardium?
    • by increasing coronary flow
    • this is b/c even at rest there is maximal extraction of O2 by the myocardium
    • O2 delivery is “flow limited” at rest
    • if you need to supply more O2 to the heart it can't extract more, so really the only way to do that is to supply more coronary flow
  14. Skeletal v. Cardiac Musce: O2 Debt
    • unlike skeletal muscle, cardiac muscle never rests & so cannot let high energy phosphate get depleted
    • skeletal muscle can deplete high energy phosphate stores & replenish them later when resting
  15. When does coronary circulation primarily occur?
    • diastole (NOT systole) b/c the openings of coronary arteries are obscured when the aortic valve is open (aka during systole)
    • during diastole when the valve is closed, maximum perfusion occurs
    • a condition that reduces diastolic pressure can impair coronary flow (eg. aortic regurgitation)
  16. Ventricular Enlargement Effects
    • leads to inefficiency

    • a greater ventricular radius means that for a given intraventricular pressure, wall tension (tendency to expand) becomes greater (Law of LaPlace)

    • at a large radius it takes more muscle force & thus more O2 consumption to generate a given stroke volume

    • an increased preload or an increase EDV means that beat has an increased O2 demand that a normal one wouldn't

    • • whenever you generate more muscle force, there's a HIGHER O2 demand
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  17. The larger the ventricular radius, the ____ energy it must expend to develop a given amount of pressure & contraction during systole.
    the larger the ventricular radius, the MORE energy it must expend
  18. Myocardial Work
    • Work = Force * Distance
    • or = Pressure * Volume
    • or = Pressure * Volume per beat x beats per min
    • pressure: afterload (arterial pressure)
    • volume/beat: stroke volume
    • beats per min: heart rate
  19. What happens when O2 demand is greater than supply?
    pain develops
  20. What is the primary way coronary vessel (cardiac artery) blood flow is regulated?
    • by chemical vasodilators (NOT neuronally)
    • in the intact myocardium, release of adenosine (+ other vasodilators such as NO) produces coronary vasodilation
    • sypathetic adrenergic α receptors are present on coronary arteries & arterioles & play a role in vasoConstriction
  21. Coronary “Steal”
    • nitrate vasodilator drugs such as as nitroglycerine are vasodilators: they mimic the effect of NO released from endothelial cells & RELAX vascular smooth muscle
    • in patients with coronary ATH this may dilate healthy segments of the coronary supply “stealing” blood flow from atherosclerotic segments
  22. What is an additional beneficial effect of nitrate vasodilator?
    • they reduce preload (venous return) by relaxation of venous smooth muscle
    • reduction in preload leads to reduced O2 demand since cardiac work is reduced
  23. Lecture 19 - Microvascular Circulation
  24. Continuous Capillaries
    • endothelial cells provide an uninterrupted lining, that only allow smaller molecules (H2O, ions) to diffuse through tight junctions
    • locations: fat, muscle, nervous system
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  25. Fenestrated Capillaries
    • have pores in the endothelial cells that allow small molecules & limited amounts of protein to diffuse
    • locations: intestinal villi, endocrine glands, kidney glomeruli
    • *in endocrine glands facilitate transport of hormones from parenchyma to sites of action
  26. Discontinuous Capillaries
    • type of fenestrated capillaries that have larger openings in the endothelium that allow red & white blood cells + various serum proteins to pass aided by a discontinuous basal lamina
    • locations: live, bone marrow, spleen
    • function to "refurbish" worn out cells (i.e. in liver)
  27. Angiogenesis
    the formation/budding of new blood vessels from a pre-existing vasculature (typically comes from a venular structure)
  28. Vasculogenesis
    the DE NOVO formation of new blood vessels from angioblastic precursor cells (committed stem cells) during development & adult life
  29. What must happen for unstable vessels produced early on from vasculogenesis or angiogenesis to survive?
    they have to recruit mural cells - including microvascular pericytes (in capillaries & venules) - otherwise they'll die (microvascular regression)
  30. Steps in Microvascular remodeling
    • 1. Growth factor production/release (VEGF)
    • 2. Endothelial activation
    • 3. Altered permeability
    • 4. Matrix remodeling
    • 5. Pericyte recruitment/withdrawal
    • 6. Endothelial migration
    • 7. Cell division behind migrating sprout
    • 8. Lumen formation
    • 9. Sprout connection & initiation of blood flow
    • (migration in the front, proliferation in the back)
  31. Vascular Endothelial Growth Factor (VEGF)
    • critically important survival agent that regulates endothelial proliferation
    • usually not produced by endothelial cells but by neighboring cells (eg. macrophages, astrocytes)
  32. Where might angiogenesis NORMALLY take place during adult life?
    • female reproductive system
    • skeletal muscle (in response to exercise)
    • cardiac muscle (in response to training)
    • during wound healing
  33. Where might angiogenesis pathologically take place during adult life?
    • in response to ATH (intimal hyperplasia)
    • tumor progression (wound healing?)
    • diabetic retinopathy
    • age-related macular degeneration
    • post-MI
    • post-ischemic insult (eg. stroke)
    • (blood vessel proliferation that shouldn't be happening)
  34. Angiogenic "Switch"
    • typifies the transformation of a quiescent capillary bed → one that is actively growing (eg. during wound healing or tumor-induced angiogenesis)
    • there are unknown signaling pathways switched on or off that yield an actively growing endothelial cell population
    • *a disease ISN'T clinically detectable unless a growing tumor has a vascular supply; once switch takes place it's possible for a cancer to metastasize
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  35. Tumor Dormancy Hypotheses
    • 1. Immune Surveillance
    • 2. Hormonal withdrawal in hormone-dependent cancers
    • 3. Unfavorable growth conditions imposed by ectopic microenvironment
    • 4. Inhibition of angiogenesis
  36. What is the difference between a dormant tumor vs. stable disease?
    • Dormant Tumor = MICROscopic-sized tumor not expanding its mass
    • Stable disease = MACROscopic-sized tumor not expanding its mass
  37. What experimental effect does the presence of a primary tumor have on metastasis of the disease (nude mouse experiment)?
    • a mouse w/ an intact primary tumor has markedly less metastasis than a mouse who's primary tumor has been removed → immediately see that the number of distal lesions increases
    • suggests that the presence of a primary tumor itself has a NEGATIVE influence on the ability of a tumor population to spread/metastasize
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  38. Plasminogen
    • liver product precursor to plasmin (goes on to enact fibrinolysis)
    • however can cleave in a unique way that instead gives rise to angiostatin - an angiogenesis inhibitor
    • sometimes that unique cleavage is accomplished by overactive proteases around b/c of a tumor
    • in this way a tumor (by causing the upregulation of proteases which cleave plasminogen into angiostatin) might actually prevent angiogenesis & subsequently tumor metastasis
  39. Endostatin
    • a naturally-occurring cleavage products emergent from collagen XVIII (18) that also serve as an anti-angiogenic agent
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  40. Diabetic Retinopathy
    • non-proliferative diabetic retinopathy (NPDR): usually asymptomatic; may happen in conjunction w/ narrowing or blocked retinal BVs (retinal ischemia)
    • proliferative diabetic retinopathy (PDR): a 2nd stage of the disease during which abnormal new blood vessels (neovascularisation) form at the back of the eye - can burst/bleed & blur vision, b/c the new BVs are weak
  41. Age-related Macular Degeneration
    wet form: blood vessels (choroidal endothelial cells) grow up from the choroid behind the retina & the retina can become detached
  42. Endothelial-Pericyte Interactions
    mechanical deformation of endothelial cells by pericytes is enough to take a quiescent endothelial cell & PUSH it into the growth cycle & activate it angiogenically
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Physio Neural Reg of Arterial BP/Microvascular Circulation (18/19)
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