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Autonomic Nervous System and Hemodynamics dr shabeel pn
Two or “Three” Subdivisions of the Nervous System Innervates skeletal muscle smooth muscle cardiac muscle secretory glands...
Principles of Neural Science , 3 rd  Ed. Kandel et al., p. 762 Synaptic Connectivity – Voluntary vs Autonomic Nerves skele...
Synaptic Transmission in Autonomic Ganglia Preganglionic neurons release acetylcholine http://www.pasteur.fr/recherche/ban...
Subdivisions of the Autonomic Nervous System Primary Neurotransmitter Sympathetic Parasympathetic
Cell body in spinal cord autonomic ganglion Focus on this synapse
Subdivisions of the Autonomic Nervous System Primary Neurotransmitter norepinephrine epinephrine (~20%) acetylcholine Rece...
Rockman et al., (2002) Nature 415:206-212 G-Protein Coupled Receptors
Principles of Neural Science , 3 rd  Ed.  Kandel et al., p. 768 Time Course of Post-Synaptic Potentials nicotinic AChR mus...
A Brief Digression on Parts of the Brain Berne and Levy,  Physiology  3 rd  Ed. p. 94-95 <ul><li>4 parts of the brain </li...
Berne and Levy,  Physiology  3 rd  Ed. p. 96 A Brief Digression on Parts of the Brain – Part 2
Principles of Neural Science , 3 rd  Ed. Kandel et al., p. 763 Sympathetic Parasympathetic thoracic lumbar sacral brainste...
Principles of Neural Science , 3 rd  Ed. Kandel et al., p. 772 Opposing Effects of Sympathetic and Parasympathetic Stimula...
Goodman and Gilman’s The Pharmacological Basis of Therapeutics 9 th  Ed. p. 110-111 Summary of  Effector Organ Responses t...
Goodman and Gilman’s The Pharmacological Basis of Therapeutics 9 th  Ed. p. 110-111 Summary of  Effector Organ Responses t...
Hemodynamics or  Why Blood Flows and What Determines How Much Laminar vs Turbulent Flow Relation of Pressure, Flow and Res...
Laminar vs Turbulent Flow Berne and Levy,  Physiology  3 rd  Ed. p. 447
Difference Between  Flow  and  Velocity Flow is a measure of volume per unit time Velocity is a measure of distance per se...
Relationship Between  Velocity  and Pressure Pressure is a form of potential energy.  Differences in pressure are the driv...
Relationship Between  Pressure ,  Flow  and  Resistance Similar to Ohm’s Law  I = for electricity  V R or  V = IR  P  = ...
Resistance to Fluid Flow The preceding discussion ignored resistance to flow in order to focus on some basic concepts.  Re...
Origin of Resistance in Laminar Flow resistance arises due to  1) interactions between the moving fluid and the stationary...
} r l length viscosity radius Q Determinants of Resistance in Laminar Flow – Poiseuille’s Law R = 8    l    r 4 <ul><li>...
Some Implications of Poiseuille’s Law If   P is constant, flow is very sensitive to tube radius 8    l    r 4 (  P) = ...
Path of Blood Flow in the Circulatory System Heart (left ventricle) aorta arteries arterioles capillaries venules veins ve...
West,  Physiological Basis of Medical Practice  11 th  Ed. p. 120 Blood Vessel Diameter and Blood Velocity
A Brief Digression on the Cardiac Pump Cycle Each pump cycle is subdivided into two times 1) Diastole – filling, no forwar...
The heart is the pump that keeps the fluid circulating. The heart is a pulsatile, intermittent pump.  During each pump cyc...
What Can the Body Regulate to Alter Blood Flow and Specific Tissue Perfusion?  P = Mean Arterial Pressure – Mean Venous P...
Arterioles are Heavily Innervated Radius Controlled by Autonomic Nervous System and Local Factors In most arterial beds sy...
Katzung,  Basic and Clinical Pharmacology , 2001, p. 123  -Adrenergic Receptor Signal Transduction Pathways
West,  Physiological Basis of Medical Practice  11 th  Ed. p. 121 Autonomic Nervous System Regulates Distribution of Blood...
Vaso-Vagal Episodes – Neural Control Lying down > stand up quickly > briefly feel lightheaded Failure of the venoconstrict...
Local Factors in the Control of Arteriolar Resistance endothelial derived relaxing factor (EDRF) – nitric oxide (NO) endot...
hypoxia Other Local Factors in the Control of Arteriolar Resistance arteriolar vasodilation increased tissue perfusion
Determinants of Arterial Blood Pressure and Flow 1) Heart – Cardiac Output 2) Vascular Resistance 3) Vascular Volume (Capa...
Factor #1: Heart – Cardiac Output Blood Pressure = (Blood Flow)*(Total Peripheral Resistance) BP = Q * TPR venous return a...
West,  Physiological Basis of Medical Practice  11 th  Ed. p. 120 Arterial blood pressure – systole vs diastole Perfusion ...
Fractional Drop in Pressure Total Peripheral Resistance = R artery  + R arteriole  + R capillary  + R venule  + R vein  P...
Factor #3: Vascular Volume - Capacitance CNS control arterial volume by regulating vessel diameter venous volume by regula...
 
 
<ul><li>The Contractile Event of Smooth Muscle  </li></ul><ul><li>A scheme for smooth muscle contraction is shown on next ...
Bárány, K. and Bárány, M. (1996). Myosin light chains. In   Biochemistry of Smooth Muscle Contraction  (M. Bárány , Ed.), ...
http://www.neuro.wustl.edu/neuromuscular/pathol/diagrams/smmusccont.htm Smooth Muscle Contraction: A More Complicated View
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Autonomic Nervous System and Hemodynamics

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Autonomic Nervous System and Hemodynamics

  1. 1. Autonomic Nervous System and Hemodynamics dr shabeel pn
  2. 2. Two or “Three” Subdivisions of the Nervous System Innervates skeletal muscle smooth muscle cardiac muscle secretory glands intestine controls intestinal motility secretion absorption Neurotransmitter ACh norepinephrine ACh neuropeptides norepinephrine ACh serotonin neuropeptides Receptors nicotinic muscle AChR adrenergic GPCRs muscarinic ACh GPCRs nicotinic neuronal AChR GPCRs ? Voluntary Autonomic Enteric
  3. 3. Principles of Neural Science , 3 rd Ed. Kandel et al., p. 762 Synaptic Connectivity – Voluntary vs Autonomic Nerves skeletal muscle somatic motor neuron dorsal ventral central nervous system central nervous system autonomic ganglion preganglionic fiber postganglionic fiber visceral effectors smooth muscle gland cells cardiac muscle Autonomic motor system Somatic motor system
  4. 4. Synaptic Transmission in Autonomic Ganglia Preganglionic neurons release acetylcholine http://www.pasteur.fr/recherche/banques/ LGIC/cys-loop.html Postganglionic Cell Receptors 1) Neuronal nicotinic acetylcholine receptors different pharmacology from muscle nAChR different subunit composition 2  : 3  cation-selective channel 2) Muscarinic (GPCR) receptors
  5. 5. Subdivisions of the Autonomic Nervous System Primary Neurotransmitter Sympathetic Parasympathetic
  6. 6. Cell body in spinal cord autonomic ganglion Focus on this synapse
  7. 7. Subdivisions of the Autonomic Nervous System Primary Neurotransmitter norepinephrine epinephrine (~20%) acetylcholine Receptors & Second Messenger Systems Adrenergic GPCRs  1 – IP 3 /DAG,  [Ca 2+ ] i  PKC  2 -  cAMP/PKA  1 -  cAMP/PKA  2 -  cAMP/PKA  3 -  cAMP/PKA Muscarinic GPCRs M 1 – IP 3 /DAG,  [Ca 2+ ] i  PKC M 2 –  cAMP/PKA,  PI(3)K M 3 –  cAMP/PKA, IP 3 /DAG,  [Ca 2+ ] i  PKC M 4 – M 5 – IP 3 /DAG,  [Ca 2+ ] i  PKC Adrenal Medulla (epi:norepi::80:20) Sympathetic Parasympathetic
  8. 8. Rockman et al., (2002) Nature 415:206-212 G-Protein Coupled Receptors
  9. 9. Principles of Neural Science , 3 rd Ed. Kandel et al., p. 768 Time Course of Post-Synaptic Potentials nicotinic AChR muscarinic GPCR peptidergic GPCR Fast EPSP Slow EPSP Peptidergic EPSP 20 msec 10 sec 1 min Nicotinic Muscarinic ACh Peptidergic
  10. 10. A Brief Digression on Parts of the Brain Berne and Levy, Physiology 3 rd Ed. p. 94-95 <ul><li>4 parts of the brain </li></ul><ul><li>Forebrain </li></ul><ul><li>Midbrain </li></ul><ul><li>Hindbrain </li></ul><ul><li>Spinal cord </li></ul>cervical thoracic lumbar sacral spinal cord
  11. 11. Berne and Levy, Physiology 3 rd Ed. p. 96 A Brief Digression on Parts of the Brain – Part 2
  12. 12. Principles of Neural Science , 3 rd Ed. Kandel et al., p. 763 Sympathetic Parasympathetic thoracic lumbar sacral brainstem cranial nerves
  13. 13. Principles of Neural Science , 3 rd Ed. Kandel et al., p. 772 Opposing Effects of Sympathetic and Parasympathetic Stimulation on Heart Rate
  14. 14. Goodman and Gilman’s The Pharmacological Basis of Therapeutics 9 th Ed. p. 110-111 Summary of Effector Organ Responses to Autonomic Stimulation Part I Be sure to memorize all entries in this table
  15. 15. Goodman and Gilman’s The Pharmacological Basis of Therapeutics 9 th Ed. p. 110-111 Summary of Effector Organ Responses to Autonomic Stimulation Part II This part of the table you do not need to memorize
  16. 16. Hemodynamics or Why Blood Flows and What Determines How Much Laminar vs Turbulent Flow Relation of Pressure, Flow and Resistance Determinants of Resistance Regulation of Blood Flow Role of Large Vessel Elasticity in Maintaining Continuous Flow Determinants of Blood Pressure Why do atherosclerotic blockages reduce blood flow? How does blood pressure change as it moves through a resistance vessel?
  17. 17. Laminar vs Turbulent Flow Berne and Levy, Physiology 3 rd Ed. p. 447
  18. 18. Difference Between Flow and Velocity Flow is a measure of volume per unit time Velocity is a measure of distance per second along the axis of movement radius (cm) 1 2 4 area (cm 2 ) (  r 2 ) 3.14 12.56 50.24 flow (cm 3 /sec) 100 100 100 fluid velocity (cm/sec) 32 8 2 100 ml/sec 100 ml/s Velocity = Flow /Cross sectional area Note: This assumes constant flow r = 1 r = 2 r = 4 velocity Flow
  19. 19. Relationship Between Velocity and Pressure Pressure is a form of potential energy. Differences in pressure are the driving force for fluid movement. Kinetic energy is proportional to (velocity) 2 If we ignore turbulence and friction, total energy (Potential + Kinetic) of the fluid is conserved and so as velocity increases, pressure decreases 100 ml/sec 100 ml/s ASSUMES CONSTANT FLOW velocity Flow Pressure P(r = 4) > P(r = 2) > P(r = 1) r = 1 r = 2 r = 4
  20. 20. Relationship Between Pressure , Flow and Resistance Similar to Ohm’s Law I = for electricity  V R or V = IR  P = Q R Change in Pressure = Flow x Resistance Flow = Change in Pressure Resistance Q =  P R
  21. 21. Resistance to Fluid Flow The preceding discussion ignored resistance to flow in order to focus on some basic concepts. Resistance is important in the Circulatory System. As fluid passes through a resistance pressure drops. A resistance dissipates energy, so as the fluid works its way through the resistance it must give up energy. It gives up potential energy in the form of a drop in pressure. P 1 > P 2 Pressure distance  P = QR Fluid flow resistance P 1 P 2
  22. 22. Origin of Resistance in Laminar Flow resistance arises due to 1) interactions between the moving fluid and the stationary tube wall 2) interactions between molecules in the fluid (viscosity) West, Physiological Basis of Medical Practice 11 rd Ed. p. 133
  23. 23. } r l length viscosity radius Q Determinants of Resistance in Laminar Flow – Poiseuille’s Law R = 8  l  r 4 <ul><li> = 3.14159 as always </li></ul><ul><li>l = tube length </li></ul><ul><li>= fluid viscosity </li></ul><ul><li>r = tube radius </li></ul>8  l  r 4 (  P) Q =  P R =
  24. 24. Some Implications of Poiseuille’s Law If  P is constant, flow is very sensitive to tube radius 8  l  r 4 (  P) = Q =  P R = 8  l  (  P) r 4 ( ) r (10 - r/10)*100 Q/X [1 - (Q/Q r=10 )]*100 10 0% 10,000 0% 9 10% 6,561 35% 5 50% 625 94% 1 90% 1 99.99% % decrease in flow % decrease in radius 8  l  (  P) X =
  25. 25. Path of Blood Flow in the Circulatory System Heart (left ventricle) aorta arteries arterioles capillaries venules veins vena cava Heart (right atrium)
  26. 26. West, Physiological Basis of Medical Practice 11 th Ed. p. 120 Blood Vessel Diameter and Blood Velocity
  27. 27. A Brief Digression on the Cardiac Pump Cycle Each pump cycle is subdivided into two times 1) Diastole – filling, no forward pumping (~2/3) 2) Systole – forward pumping (~1/3) Blood Pressure (mm Hg) = systolic / diastolic normal BP ??? 120/80 mmHg Hypertension > 140/90 mm Hg Berne and Levy, Physiology 3 rd Ed. p. 457 pressure (mm Hg) Arterial Blood Pressure
  28. 28. The heart is the pump that keeps the fluid circulating. The heart is a pulsatile, intermittent pump. During each pump cycle blood flows out of the heart for only 1/3 of the time. THE PROBLEM: To maintain continuous flow during diastole. Converting Intermittent Pumping to Continuous Flow THE SOLUTION: Large elastic arteries distend during systole to absorb ejected volume pulse relax during diastole maintaining arterial pressure and flow to the periphery volume ejected large elastic arteries distend aortic valve closes blood flows into periphery under pressure created by elastic recoil of arteries while the heart fills during diastole Berne and Levy, Physiology 3 rd Ed. p. 457
  29. 29. What Can the Body Regulate to Alter Blood Flow and Specific Tissue Perfusion?  P = Mean Arterial Pressure – Mean Venous Pressure  P, not subject to significant short term regulation R = Resistance 8,  , l,  are not subject to significant regulation by body r 4 can be regulated especially in arterioles, resistance vessels 8  l  r 4 (  P) Q =  P R = R = 8  l  r 4
  30. 30. Arterioles are Heavily Innervated Radius Controlled by Autonomic Nervous System and Local Factors In most arterial beds sympathetic stimulation > norepinephrine release > vasoconstriction of arterioles “ fight or flight” reflex Blood flow redirected from internal organs to large skeletal muscle groups. Vasoconstriction stimulation of  adrenergic receptors >  [Ca 2+ ] i in vascular smooth muscle cells In some arterial beds parasympathetic stimulation > acetylcholine release muscarinic receptors causes vasodilation of arterioles
  31. 31. Katzung, Basic and Clinical Pharmacology , 2001, p. 123  -Adrenergic Receptor Signal Transduction Pathways
  32. 32. West, Physiological Basis of Medical Practice 11 th Ed. p. 121 Autonomic Nervous System Regulates Distribution of Blood Volumes in Different Parts of the Vascular System
  33. 33. Vaso-Vagal Episodes – Neural Control Lying down > stand up quickly > briefly feel lightheaded Failure of the venoconstrictor system to respond in a timely fashion. To prevent blood pooling in large veins must constrict veins on standing or the rise in hydrostatic pressure will cause veno-dilation and thus blood pooling in the large veins of the legs and abdomen. This pooling reduces venous return to the heart. This in turn reduces forward cardiac output and reduces arterial blood pressure and perfusion of the brain. Thus, the feeling of lightheadedness.
  34. 34. Local Factors in the Control of Arteriolar Resistance endothelial derived relaxing factor (EDRF) – nitric oxide (NO) endothelin bradykinin angiotensin II vasopressin, ADH atrial naturetic peptide adenosine cGMP NO Ca ++ GTP GMP Intracellular Ca ++ Stores Ca ++ Ca ++ Arginine + Citrulline GTP NO PDE Membrane Bound Guanylate Cyclase Soluble Guanylate Cyclase C.M. Ion Channels cGMP-Dependent PK PDEase Activity NO Synthetase
  35. 35. hypoxia Other Local Factors in the Control of Arteriolar Resistance arteriolar vasodilation increased tissue perfusion
  36. 36. Determinants of Arterial Blood Pressure and Flow 1) Heart – Cardiac Output 2) Vascular Resistance 3) Vascular Volume (Capacitance) 4) Blood Volume
  37. 37. Factor #1: Heart – Cardiac Output Blood Pressure = (Blood Flow)*(Total Peripheral Resistance) BP = Q * TPR venous return and venous blood pressure (preload) duration of diastole (heart rate) ventricular wall relaxation during diastole arterial blood pressure (afterload) Determinants of Blood Flow (Cardiac Output) cardiac output = (heart rate) x ( stroke volume ) Determinants of Stroke Volume
  38. 38. West, Physiological Basis of Medical Practice 11 th Ed. p. 120 Arterial blood pressure – systole vs diastole Perfusion pressure largely determined by arterial blood pressure Major site of pressure drop is in arterioles Factor #2: Determinants of Vascular Resistance
  39. 39. Fractional Drop in Pressure Total Peripheral Resistance = R artery + R arteriole + R capillary + R venule + R vein  P = mean arterial pressure – mean venous pressure Drop in Pressure in the arterioles =  P*(R arterioles /TPR)
  40. 40. Factor #3: Vascular Volume - Capacitance CNS control arterial volume by regulating vessel diameter venous volume by regulating vessel diameter ratio of arterial to venous volume Examples vaso-vagal episodes shock – peripheral vasodilation drops pressure Factor #4: Determinants of Blood Volume Kidney Function in Lectures Coming on Wed. Nov. 3
  41. 43. <ul><li>The Contractile Event of Smooth Muscle </li></ul><ul><li>A scheme for smooth muscle contraction is shown on next slide. Contraction is initiated </li></ul><ul><li> by the increase of Ca 2+ in the myoplasm; this happens in the following ways: </li></ul><ul><li>Ca 2+ may enter from the extracellular fluid through channels in the plasmalemma. </li></ul><ul><li>These channels open, when the muscle is electrically stimulated depolarizing the </li></ul><ul><li>plasmalemma. </li></ul><ul><li>2. Due to agonist induced receptor activation, Ca 2+ may be released from the </li></ul><ul><ul><li>sarcoplasmic reticulum (SR). In this pathway, the activated receptor interacts with </li></ul></ul><ul><ul><li>a G-protein (G) which in turn activates phospholipase C (PLC). The activated PLC </li></ul></ul><ul><ul><li>hydrolyzes phosphatidyl inositol bisphosphate; one product of the hydrolysis is </li></ul></ul><ul><ul><li>inositol 1,4,5-trisphosphate (IP 3 ). IP 3 binds to its receptor on the surface of SR, </li></ul></ul><ul><ul><li>this opens Ca 2+ channels and Ca 2+ from SR is entering the myoplasm. </li></ul></ul><ul><li>3. Ca 2+ combines with calmodulin (CaM) and the Ca 2+ -CaM complex activates </li></ul><ul><li>myosin light chain kinase (MLCK), which in turn phosphorylates myosin LC. The </li></ul><ul><li>phosphorylated myosin filament combines with the actin filament and the </li></ul><ul><li>muscle contracts. </li></ul>http://www.uic.edu/classes/phyb/phyb516/smoothmuscleu3.htm#contractile http://www.uic.edu/classes/phyb/phyb516/ Mechanism of Smooth Muscle Contraction
  42. 44. Bárány, K. and Bárány, M. (1996). Myosin light chains. In Biochemistry of Smooth Muscle Contraction (M. Bárány , Ed.), pp. 21-35, Academic Press. CaM = Calmodulin MLCK = myosin light chain kinase IP 3 = inositol trisphosphate A Simplified View of Smooth Muscle Contraction SR actin myosin GPCR phospholipase C heterotrimeric G-protein myosin light chain
  43. 45. http://www.neuro.wustl.edu/neuromuscular/pathol/diagrams/smmusccont.htm Smooth Muscle Contraction: A More Complicated View

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